Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

Year 2 MCD Cancer > Cancer > Flashcards

Cancer Flashcards

1
Q

What is a Metaplasia?

A

Reversible chane in a tissue where one type of adult cells is replaced with another adult cell type

  • usually epithelium
  • can be physiological, is normally functionla (e.g. reflux)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is Dysplasia?

A

an abnormal pattern of growth in which some of the cellular and architectural features of malignancy are present

•pre-invasive stage with intact basement membrane

–> no invasion meaning good chances if revmoved!

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is a Neoplasm?

A

An abnormal, autonomous proliferation of cells unresponsive to normal growth control mechanisms

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is a Tumor?

A

A neoplasm that forms a mass

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are the characteristical changes in dysplasia?

A
  • loss of architectural orientation
  • loss in uniformity of individual cells
  • nuclei: hyperchromatic, enlarged –> increased nucleus: cytoplasm ratio
  • mitotic figures: abundant, abnormal, in placeswhere not usually found
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What are the characteristics of a benign tumor?

A
  • Non-invasive
    • ​not into other tissues
    • no metastisis
  • usually well-differentiated –> characteristics of tissue of origin
  • encapsuled
  • slow growing
  • normal mitosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What are the cases in which a benign tumor can be fatal?

A
  1. When it sits at the wron spot
    1. brain, meningines, pituitary
  2. When it secretes something dangerous
    1. insulinoma
    2. pituitary adenoma
  3. gets infected
  4. bleeds or ruptures
  5. causes torsion of organs (e.g. ovaria cyst)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is a Metastisis?

A

•A metastasis is a discontinuous growing colony of tumour cells, at some distance from the primary cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What are the characteristics of a malignant

A
  1. invade surrounding tissues
  2. spread to distant sites
  3. no capsule
  4. well to poorly differentiated –> can’t see characteristics of tissue of origin
  5. rapidly growing
  6. abnormal mitoses
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

How would you call a benign epithelial tumor of surface epithelium (e.g. skin, bladder)

A

Papilloma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is a papilloma?

A

A benign tumor of surface epithelium (e.g. skin, bladder)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

How would you call a benign tumor of glandular epithelium?

A

Adenoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What is an adenoma?

A

A benign tumor of glandular epithelium

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What is a carcinoma?

A

•A malignant tumour derived from epithelium

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

How do you call a malignant tumour derived from epithelium?

A

Carcinoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Name some examples of different form of carcinomas

A
  1. squamous cell carcinoma
  2. adenocarcinoma,
  3. transitional cell carcinoma
  4. basal cell carcinoma

–> dependant on the tissue they derive from

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

How would you call a benign tumor of soft tissue?

A

E.g. lipoma, osteoma

–> ending oma, dependant on the tissue type

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What is an osteoma?

A

Benign tumor derived from bone

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

How would you call a malignant tumour derived from connective tissue (mesenchymal) cells?

A

Sarcoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What is a sarcoma?

A

a malignant tumour derived from connective tissue (mesenchymal) cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Name differnet types of maglignant soft tisseue tumors in

  • Fat
  • bone
  • cartilage
A
  1. Fat
    1. Liposarcoma
  2. Bone
    1. Osteosarcoma
  3. Cartilage
    1. Chondrosarcoma
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

How would you call malignant tumors of

  • striate muscle
  • smooth muscle
  • Nerve sheath•
A
  1. Muscle
    • striated = RhabdomyoSARCOMA,
    • smooth = LeiomyoSARCOMA
  2. Nerve sheath = Malignant Peripheral Nerve Sheath Tumour
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What is Leukemia?

A

A malignant tumor of bone marrow

(can usually be seen in blood cells )

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

How would you call a malignant tumor of bone marrow?

A

Leukaemia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

What is a Lymphoma?

A

A malignant tumour of lymphocytes (usually) in lymph nodes

–> can normally be seen in the tissue

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

How would you call a malignant tumour of lymphocytes (usually) in lymph nodes?

A

Lymphoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

What is a teratoma?

A

A tumor derived from germ cells –> Can differentiate into any adult cell type

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

How would you call a tumor of germ cells that can normally differentiate into any type of adult cell?

A

A Teratoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

Are teratomas usually benign or malignant?

A
  1. In Males: almost always malignant
  2. In Females: Most are benign
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

What is a HAMARTOMA?

A
  • localised overgrowth of cells and tissues native to the organ.
  • cells are mature but architecturally abnormal
    • –> When just looking at the cell, they look completely normal but are just organised in a different way
  • common in children, and should stop growing when they do,
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

How do you call localised overgrowth of cells and tissues native to the organ, just with abnormal architecture?

A

Hamartoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

What is a Anaplastic tumor?

A

When there is no differentiation seen and no origin cell type can be determined

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

What is the grade of a tumor?

A

The level of differentiation (high grade= low differentiation)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

What is the stage of a tumor?

Which Criteria are used to determine it?

A

Stage of a tumor is how far the tumor has spread

–> TNM

  • Tumor
  • Node
  • Metastisis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

Explain the relationship between grade and stage

A
  1. High grade tumors tend to be high stage
  2. BUT: stage is the most impoertant factor when it comes to prognosis!
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

List five morphological features that allow assessment of the differentiation of a tumor

A
  • loss of architectural orientation
  • loss in uniformity of individual cells
  • nuclei: hyperchromatic, enlarged
  • mitotic figures: abundant, abnormal, in places where not usually found
  • Evidence of normal function still present production of:

keratin,

mucin

bile

hormones

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

Which factors influence the speed of cell devision?

A
  • embryonic vs. adult cell
  • complexity of systems (e.g. rapid devision in yeast cells)
  • Necessitiy for renewal (intestinal epithelium vs. hepatocytes)
  • state of differentiation (e.g. neurons/cardiomyocytes that don’t replicate)
  • Tumor cells ?? –> different mechanisms
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

What happens when the appropriate regulation of cell devision goes wrong?

Which factors might lead to it?

A

Cancer might develop that

  • mutation in TSG/oncogenes (–> + aneupleudy)
  • chormosome instability (loss/gain of chromosome)
  • abnormal mitosis –> mistake in cell cylce regulatory proteins
  • Contact inhibition of growth –> cells don’t stop growing when they reach the edges of a space
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

What is the cell cycle?

A

Orderly sequence of events in which a cell duplicates its contents and divides in two

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

What are the different phases in the cell cycle of an eucariotic cell?

A
  • M Mitosis
  • Interphase
    • G0
      • cell cycle machinery dismantled –> cell fulfils normal function
    • G1
      • phase (Gap) - Decision point: are specific structures (e.g. centromeres) duplicated?
    • S
      • DNA dublication
    • G2
      • phase (Gap) - Decision point
      • check new DNA for mistakes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

Explain the structure of a centrosome

A

Consists of two centrioles (barrels of nine triplet microtubules

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
45
Q

What happens during the S-phase of the cell cycle?

A
  • DNA replication
  • Replication of organelles (e.g. golgi, mitochondria, centromeres)
  • Increased protein synthesis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
46
Q

Explain the life cycle and replication of the centrosomes

A

Split in G1 and are fully replicated at the end of S-phase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
47
Q

What happens during the prophase of mitosis?

A
  • condensation of DNA
  • centrosomes migrate to opposite sides in cell
  • spindels start to form
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
48
Q

Explain the formation of the mitotic spindles

A
  1. ASTERS form (radial micturtubule arrays) around each centromer –> Microtubule organisation centre)
  2. Tadial arrays meet
  3. Polar micrutubules form (= radial microtubules that meet in middle)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
49
Q

What happens during the early prometaphase in the cell cycle?

A
  • Chromosomes aligned at equator of the spindle

In the early:

  • break down of nuclear membrane
  • spindles are largely complete
  • attach of chromosomes to the spindles via kinetochores at the centromer region of chromosome
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
51
Q

What is the function of the centrosome?

A
  • microtubule organizing center (MTOC) (also in interphase!!)
  • mitotic spindle
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
52
Q

What happens during Anaphase A in mitosis?

A
  • Breakdown cohesin (protein that holds togehter sister chromatids)
  • Microtubules get shorter
    • Daughter chromosomes pulled toward opposite spindle poles
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
53
Q

What happens during Anaphase B?

A
  1. Daughter chromosomes migrate towards poles
  2. Spindle poles (centrosomes) migrate apart
    • so cytokinesis does not happen too close to chormosomes and they have enough space
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
54
Q

What happens during telophase of mitosis?

A

Chromosomes arrive at spindles

Nuclear envelope resembels

Assembly of contractile ring (for cytokinesis), made of actin and myosin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
56
Q

What are the different factors required in the Spindle Assembly checkpoint?

(aka Mitotic Checkpoint)

A
  • CENP-E (signals when not attached)
  • BUB protein kinases (signals when attached)

BUBs dissociate from kinetochore when chromosomes are properly attached to the spindle

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
57
Q

Explain the different things that can go wrong at the Spindle assembly checkpoint

A

Missatachmen of spindles to kinetochore might lead to aneupleudy

  • Meroteilic attachment (2 differnt spindels attach to the same chromatid)
  • one spindle attaches to both sister chromatids of one chromosomes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
58
Q

How might alterations in the cell cycle lead to aneupleudy?

A
  • errors in DNA or centrosome replication
  • might lead to multipolar spindles
  • or in aberrant (irrtümliche) citokinesis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
59
Q

Explaint the exploitation of chromosome-missegregation as an anti-cancer treatment

A
  • Inhibition of Checkpoint kinase (CHKE1 and CHKE2)
    • Normally : Serine threonine kinase activation holds cells in G2 phase until all is ready
      • inhibits attachment-error-correction mechanism ​
      • inhibition leads to untimely cell transition to mitosis –> not ready yet because there is still an error
  • Taxanes and vinca alkaloids
    • Alters microtubule dynamics
    • Produces unattached kinetochores
    • Causes long-term mitotic arrest.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
61
Q

What are the different check points in the cell that drive/ control cell proliferation?

How is that important in cancer?

A
  1. G1: Checkpoint in G1 (Growth Factor dependant)
    • initiate progession
  2. G2: Damage of DNA
  3. M: Sister chromatid alignment

All these checkpoints can be altered by tumors!!

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
62
Q

Explain the concept of De-regulation of cell cycle during tumorigenesis

A

Tumors can inhibit entering into G0 phase where the cell just does its nomal function and promote proliveration

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
64
Q

Summarise the intracellular signaling cascade that takes place during aktivation of cell proliveration by a growth factor

A

They set of the signal cascade:

  • Response to extracellular factors
  • Signal amplification
  • Signal integration
  • Modulation by other pathways
  • Regulation of divergent responses
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
66
Q

Explain the process of a growth factor binding to a growth factor receptor (RPTK)

A

In present of a (dimeric) ligand–> growth factors

  • Receptors form dimers
  • auto-crossphorylation causes activation of receptor
    • (phosphorylated AA in receptor)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
67
Q

What happens during the late prometaphase

A
  1. Microtubule from opposite pole is captured by sister kinetochore
  2. Chromosomes attached to each pole congress to the middle
  3. Chromosome slides rapidly towards center along microtubules
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
68
Q

Explain the process of phosphorylation

A

Exchange of Hydroxy-group for a phosphate group (ATP dependant, katalysed by Kinase)

Only 3 AA can be phosphorylated:

  • Serine
  • Threonine
  • Tyrosine
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
69
Q

What does the auto-phosphorylation in the tyrosine kinase domain of a growth factor receptor cause?

A

It causes receptor activation leading to

  • kinase cascade
  • binding of adaptor proteins
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
70
Q

Explain the protein kinase cascade

A

An activated kinase will often activate further kinases

  • will lead to signal amplification
  • and gives the opportunity for better regulation because
    • Phosphorylation in reversible (by a phosphatase) means that individual kinases can be inactivated
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
71
Q

What happes during the anaphase in mitosis?

A
  • Paired chromosomes separate to form two daughter chromosomes
  • Cohesin holds sister chromatids together
  • There is a anaphase A+ B
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
75
Q

What happens at the transition out of metaphase before Anaphase can start?

Explain its mechanism

A

Spindle Assembly checkpoint

  • are all chromosomes connected hthe kinetochore?
  • When kinetochores are connected they stop signaling
    • At the checkpoint it is waited, until there is no more signaling (i.e. all chormonsomes are connected) until Anaphase can start
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
76
Q

What happens during Metaphase of Mitosis?

A

Starts once MT are attached to Kinetochores

  • align at equator of spindles
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
77
Q

What is the difference in chromosome movement between Prometaphase and Metaphase?

A

In Prometaphase: try to bring a bit of order into the chromosomes + tries to get it at the right angle (picture)

In Metaphase: Alignment at eqator of spindle (begins once Microtubule are attached)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
80
Q

Explain the process of Cytokinesis

A

Actin myosin ring between two cells forms and contracts

  • new membrane is inserted
  • midbody remains (connection between the two daughter cells)
  • also midbody gets seperated
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
83
Q

What if something goes wrong during the cell cycle? e.g Cell is not big enough or DNA damage

A
  1. Cell cylce arrest at checkpoints (G1+ spindle checkpoint)
    1. can be temporarily and resolved e.g. with DNA repair
  2. Apoptosis
    1. if DNA damage to great, chromosomal abnormalities or toxic agents
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
86
Q

What are the physiological triggers that tell the cell to enter the cell cycle and devide?

A

Most cells in body are in G0 phase and fulfil their normal functions:

Exit from G0 highly regulated - requires growth factors and intracellular signalling cascades

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
88
Q

Name examples of two growth factors

Which receptor do they bind to?

A

Epidermal growth factor (EGF)

Platelet-derived growth factor (PDGF)

–> both bind to Receptor Protein Tyrosine Kinase (RPTK)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
90
Q

How can phosphorylation of an Amino-Acid lead to altered protein function?

A

The added phosphate group (negatively charged) can alter protein function by:

  1. causing a change in shape (conformation) leading to change in activity (+ve or –ve)
  2. creating a docking site for another protein
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
94
Q

What is An Amphiletic Microtubule attachment?

A

normal (centrosome-kinetochore1, centrosome-kinetochore2) pulled to 2 ends

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
95
Q

What is an Syntelic attachment of microtubule to the chromosome?

A

Same Centrosome

2 microtubules from 1 centrosome connect to both kinetochores, pulled to one end – one cell has duplication, other has one less chromosome

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
96
Q

What is Merotelic attachment of Mictotubule to the Chormosome?

A

Ripped

2 microtubules (each from different centrosome) connect to 1 kinetochore, ripped apart, both sister cells with one less chromosome

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
97
Q

What is a Monotelic attachment of Micturubule to Chromosome?

A

•one microtubule attached to one kinetochore (no microtubule attached to other Kinetochore)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
98
Q

In which cell cycle phase does the Mitotic Checkpoint Happen?

A

Between Meta and Anaphase

–> Checks for Attachment of Telomeres

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
101
Q

What is the most vulnerable phase of the cell cycle?

Why?

A

Mitosis because

  • Cells are more easily killed (irradiation, heat shock, chemicals)
  • DNA damage can not be repaired
  • Gene transcription silenced
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
102
Q

What happens to protein synthesis in S-phase of the Cell cycle?

A

initiation of translation and elongation increased; capacity is also increased

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
104
Q

Which proteins stop processing in the cell cycle if damages/ errors are present at Checkpoints?

A
  • Checkpoint kinase (CHKE1 and CHKE2) – When kinase signals it holds the cell and stops transition into next phase
    • inhibition leads to untimely cell transition to mitosis
    • exploited by Vinca Alkaloids and Taxanes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
105
Q

What are the four main modalities for cancer treatment?

A
  1. Surgery
  2. Chemotherapy
  3. Radiotherapy
  4. Immunotherapy
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
106
Q

Which type of genetic mutations might cause cancer?

A
  • Chromosome translocation
  • Gene amplification (copy number variation)
  • Point mutations within promoter or enhancer regions of genes
  • Deletions or insertions
  • Epigenetic alterations to gene expression
    • Mutations Can be inherited
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
107
Q

What are the overall characteristics of systemically administerd chemotherapeutic agents?

A
  1. IV or PO administration
  2. Non “targeted” – affects all rapidly dividing cells in the body –> causes many of the side-effects
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
108
Q

How do you call a chemotherapeutic agent administerd post-surgery?

A

adjuvant

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
109
Q

How do you call a chemotherapeutic agent administered pre-operatively?

A

Neoajuvant

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
110
Q

What is the MOA of Akylating Agents?

A

Interfere with DNA synthesis

  • Add alkyl groups to guanine residues in DNA
    • Cross-link (intra, inter, DNA-protein) DNA strands and prevents DNA from uncoiling at replication
  • Trigger apoptosis (via checkpoint pathway)
  • Encourage miss-pairing - oncogenic
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
112
Q

What is the MOA of pseudo-alkylating agents?

A

Add platinum to guanine in DNA, otherwise causes the same effect as Alkylating agents

  • Cross-link (intra, inter, DNA-protein) DNA strands and prevents DNA from uncoiling at replication
  • Trigger apoptosis (via checkpoint pathway)
  • Encourage miss-pairing - oncogenic
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
113
Q

Which drug class do

Chlorambucil, cyclophosphamide, dacarbazine, temozolomide

belong to?

A

Alkylating agents

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
114
Q

Which drug class to

carboplatin, cisplatin, oxaliplatin

belong to?

A

Pseudo-alkylating agents (add platinum group)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
115
Q

What are the side-effect of alkylating and pseudoalkylating agents?

A
  • hair loss (not carboplatin),
  • nephrotoxicity,
  • neurotoxicity,
  • ototoxicity (platinums)
  • nausea, vomiting
  • diarrhoea
  • immunosuppression
  • tiredness
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
116
Q

Explain the MOA of Anti-metabolites

A

Interfere with DNA synthesis by

  • Masquerade as purine or pyrimidine residues leading to
    • inhibition of DNA synthesis,
    • DNA double strand breaks
    • apoptosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
117
Q

Which drug class do

methotrexate, 6-mercaptopurine, decarbazine and fludarabine, 5-fluorouracil, capecitabine, gemcitabine

belong to?

A

Anti-metabolites

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
118
Q

Explain the MOA of Anthracyclines

A
  • Inhibit transcription and replication by intercalating (i.e. inserting between) nucleotides within the DNA/RNA strand
    • thereby: inhibit Tropoisomerase II
  • Also block DNA repair - mutagenic
  • Create free oxygen radiacals that damage DNA and cell membrane

*

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
119
Q

What are the side-effects of anti-metabolites?

A
  • Hair loss (alopecia) – not 5FU or capecitabine
  • Bone marrow suppression causing anaemia, neutropenia and thrombocytopenia
  • Increased risk of neutropenic sepsis (and death) or bleeding
  • Nausea and vomiting
  • Mucositis and diarrhoea
  • Palmar-plantar erythrodysesthesia (PPE)
  • Fatigue
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
121
Q

Which drug class do

doxorubicin, epirubicin

belong to?

A

Anthracyclines

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
122
Q

What are the side effects of Anthracyclines?

A
  • Cardiac toxicity (arrythmias, heart failure) – probably due to damage induced by free radicals
  • Alopecia= spot hair loss
  • Neutropenia
  • Nausea and Vomiting
  • Fatigue
  • Skin changes
  • Red urine (doxorubicin “the red devil”)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
123
Q

Explain the MOA of Vinca Alkaloids and taxanes

A

Microtubule inhibiting drugs–> leading to mitotic arrest in mitosis by

  1. inhibiting assembly (vinca alkaloids)
  2. disassembly (taxanes) of mitotic microtubules
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
124
Q

Which drug type are the micrutubule targeting drugs?

A

Vinka alkaloids and taxanes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
125
Q

What are the side-effects of vinka alkaloids and taxanes?

A
  • Nerve damage: peripheral neuropathy, autonomic neuropathy
  • Hair loss
  • Nausea
  • Vomiting
  • Bone marrow suppression (neutropenia, anaemia etc)
  • Arthralgia (joint pain)
  • Allergy
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
126
Q

Explain the MOA o fTopoisomerase inhibitors

A

Topoisomerase is responsible for adding/removing supercoils during DNA replication + protect the free ends of DNA from aberrant( abweichenden, verwirrenden) recombination events

–> alter binding of the complex to DNA and allow permanent DNA breaks

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
127
Q

Which class of drug do

Topotecan, irinotecan, etoposide

belong to?

A

Topoisormerase inhibitors

Topotecan and irinotecan (topo I)

and etoposide (topoII)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
128
Q

What are the side effects of Topoisomerase inhibitors?

A
  • (irinotecan): Acute cholinergic type syndrome – diarrhoea, abdominal cramps and diaphoresis (sweating). Therefore given with atropine
  • Hair loss
  • Nausea, vomiting
  • Fatigue
  • Bone marrow suppression

•

•

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
129
Q

Through which mechanims might cancer cells develop resistance against the treatment?

A
  • Upregulation of DNA repair mechanisms and DNA damage is repaired
  • DNA adducts replaced by Base Excision repair (using PARP) –> specific repair mechanism
  • Drug effluxed from the cell by ATP-binding cassette (ABC) transporters
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
130
Q

What are the main characteristics of cancer cells?

(Hallmarks of cancer)

A
  1. Self –sufficient
  2. Insensitive to anti-growth signals
  3. Anti-apoptotic
  4. Pro-invasive and metastatic
  5. Pro-angiogenic
  6. Non-senescent
  7. Dysregulated metabolism
  8. Evades the immune system
  9. Unstable DNA
  10. Inflammation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
131
Q

Explain the role of receptor over-expression in cancer

A

Over-expression of some receptors (expecially growth factor receptors) can be seen in many cancers:

  • HER2 – amplified and over-expressed in 25% breast cancer
  • EGFR – over-expressed in breast and colorectal cancer
  • PDGFR- glioma (brain cancer)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
132
Q

Explain the relationship with overexpression of growth factor receptor ligands and cancer

A

Vascular Endothelial Growth Factor is overexpressed:

prostate cancer, kidney cancer, breast cancer

–> leading to increased Kinase cascade and signal amplification

–> angiogenisis in cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
133
Q

What is the MOA of a dual kinase inhibitor?

A

Inhibit 2 protein kinases to prevent cancer cells switching to other pathways (which needs another kinase)

But: are also more toxic

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
134
Q

Explain the role of Constitutive (ligand independent) receptor activation in cancer

A

EGFR (lung cancer) epidermal growth factor receptor

FGFR (head and neck cancers, myeloma)

Leading to. Kinase cascade and signal amplification

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
135
Q

What is the advantage of monoclonal cancers therapeutically?

A

A single “wire cutting”, inhibition of cellular pathway might be enough to kill the cell

But: only works for some cancers, other might regulate other pathways up

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
137
Q

What do normal cells require in order to grow and poliferate?

How is that different from cancer cells?

A

Normall cells need growth factors to proliferate

Cancer cells don’t need them/ develop strategies to get higher stimmulation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
138
Q

Explain the MOA of small molecule inhibitors

A

It is a type of targeted cancer treatment

  • bind to kinase domain of tyrosine kinase
  • can also bind to intracellular kinase pathways
  • block autophosphorilation and downstream regulation
  • e.g. Gleevac
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
139
Q

What is the general target of monochlonal antibodies in the treatment of cancer?

A

They are normally designed to target + inhibit growth factor receptors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
140
Q

Explain the MOA of the use of monochlonal antibodies in cancer treatment

A

They are designes to stop the

  • Groth Factor receptor system
    • neutralise the ligand
    • inhibit dimerisation
    • cause internilisation
  • might induce phagocytosis + cytolysis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
141
Q

What are the types of targeted cancer treatment?

A
  1. Monoclonal antibodies
  2. Small molecule inhibitors
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
143
Q

What is the overall principle of targeted cancer treatment?

A

Normally: targeted treatment acts on receptors and modulates cancer halmarks

  • VEGF alters blood flow to tumor
  • AKT inhibitors block reisistance to apoptosis

–> without toxicity of other treatments observed

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
144
Q

Explain the use of anti-sense oligonucleiotides in cancer treatment

A
  1. Single Stranded, DNA like molecole (17-22 nucleotides long)
  2. Binds to target mRNA hinders translation of proteins by break down of mRNA
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
145
Q

Explain the use of RNA interference in cancer treatment

A
  • SS complementary RNA
  • (lagging behind oligosense nucleotides)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
146
Q

What are the main disadvantages of targetet therapy of cancer?

A

Resistance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
147
Q

What are the main resistance mechanism in targeted cancer therapy?

A
  • Mutations in ATP-binding domain
  • Intrinsic resistance
    • Different gene mutations/ that might not make the targeted receptor/pathway responsible
  • Intragenic mutations
  • Upregulation of downstream or parallel pathways
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
148
Q

What are the endings used to classify different antibodies (e.g. used in anti-cancer treatment)

A
  • -momab (derived from mouse antibodies)
  • -ximab (chimeric) e.g cetuximab
  • -zumab (humanised) e.g. bevacizumab trastuzumab
  • -mumab (fully human) e.g. panitumumab
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
149
Q

Explain the MOA of glivec

In which type of disease is it used?

A

Glivec is a small molecule inhibitor and targets the ATP binding region within the kinase domain, inhibiting kinase activity of ABL1

–> Used in the treatment of specific form of CML

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
150
Q

Explain the use of anti-sense oligonucleiotides in cancer treatment

A
  1. Single Stranded, DNA like molecole (17-22 nucleotides long)
  2. Binds to target mRNA hinders translation of proteins by break down of mRNA
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
151
Q

Explain the use of RNA interference in cancer treatment

A
  • SS complementary RNA
  • (lagging behind oligosense nucleotides)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
152
Q

Briefly Summarise the overall events that happen from Growth factor bindin to receptor to change in gene expressions that trigger mitosis

A
  1. Mitogenic Growth Factor binds to Growth Factor receptor
  2. Dimerisation of Receptor causes activation of tyrosine kinase
  3. Tyrosine Kinase recruits receptor and adaptor proteins (e.g G-protein RAS)
  4. Adaptor Proteins set off Kinase cascase
  5. KInase cascade causes change in gene expression and activates mitotic proteins
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
153
Q

What is the result of phosphorylation of the intracellular tyrosine caused by dimerisation of the Growth factor receptor after Growth factor binding?

A

Phosphorylation of thyrosine caused by dimerisation of the growth factor receptor provides docking sites for adapter proteins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
155
Q

What are tha characteristics of adaptor proteins and what is their function?

A

They tend to facilitate binding between different proteins instead of having an enzymatic function itself (but can have enzymatic function) –> bring proteins together (protein-protein interactions)

Thereofre they are

  • modular –> many protein-binding molecules and domains (structural and functional units that can be seen in many other molecules)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
156
Q

What are adaptor proteins?

A

Proteins that bind to the phosphorylated Thyrosine Kinase in at the receptor membrane and assist in further signal transduction

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
158
Q

Explain the role of Grb2 in the activation of RAS

A

The exchange factor SOS binds to the SH3 domain of Grb2 and is activated by it

  • SOS exchanges GDP bound to RAS to GTP and thereby activates it
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
159
Q

How does RAS get activated and inactivated?

A

Activation

  • GDP is replaced by GTP (done by exchange factors e.g. SOS)

Inactivation

  • by GAP (GTPase activating protiens) that turn GTP to GDP again
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
160
Q

What kind of protein is Grb2?

What is its function?

A

Growth factor receptor-bound protein 2 is an adaptor protein

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
161
Q

Explain the structure and function of Gbr2

A

Is an adaptor protein–> brings proteins together

  • It has three domains
    • SH2 domain bindin to the phosphorylated tyrosine of GFR
    • 2 SH3 domains bindig to other molecules
      • proline-rich regions of other molecules
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
163
Q

What is the Name of the different tyrosine Kinases that are activated in the ERK cascade?

A
  1. Kinase
    • RAF
  2. Kinase
    1. MEK
  3. Kinase
    1. ERK
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
164
Q

Explain the involvement of the ERK cascade in the formation of cancer

A

B-Raf is an oncogene - mutationally activated in melanomas

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
165
Q

What does activation of the ERK cascase (or other kinase cascades) lead to?

A
  1. Change in protein activity
  2. Change in gene expression
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
166
Q

What are Cdks?

When are they present in the cell?

How are they regulated?

A

Cyclin-dependent kinases

  • always present in human cells but
  • only activated with cyclins and phosphorylation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
167
Q

What are cyclins?

When are they present in the cell?

How are they regulated?

A

Cyclins

  • only present at specific times in cell (often: mitosis)
  • regulated at the level of expression
    • synthesised and then quickly degraded
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
168
Q

What is the function of cyclins?

A

To bind to Cdks and activate them

  • quickly degraded so good as tightly control funciton in cell
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
169
Q

What is the gross function of activated Cdks?

A

They phosphorylate proteins (on Serine or Threonine) to drive cell cycle progression

  1. during mitosis
  2. to initiate mitosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
170
Q

Explain the activation and regulation of Cdks activity

A

Regulated in 3 steps

  1. Cyclin binding
  2. Activating Phosphorylation by CAK (cdk activating kinase)
  3. Removal of inactivating phosphorylation by cdc25
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
171
Q

Explain how differnet cycline and Cdks are present in the cell cycle

A

At each step of the cell cycle different Cdks and cyclins are present and needed

  1. During Mitosis: M-Cdk (Cdk1+ Cyclin B)
  2. During G1: G1/S Cdk (Cdk2 + Cyclin E)
  3. During S: S-Cdk (Cdk2+Cyclin A)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
172
Q

How does Growh factor binding lead to the initiation of the cell cycle?

A
  1. Leading to set of of the ERK cascase
  2. Expression of c-Myc (transcriptionfactor)
  3. stimmulates transcription of other factors –> cyclin D –> Cdk 4/6 Complex initiates cell cycle
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
174
Q

How is the expression of cyclin/Cdk reguates?

A
  1. By transcriptionfactors, such as c-Myc
  2. Cdks also stimmulate synthesis of genes required for the next phase
    1. ​e.g. Cdk4/6+ Cyclin D stimmulate expression of Cyclin E
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
175
Q

Explain how Cdks can regulate gene expression

A

Example: inactivation of Rb protein by Cdk 4/6+ Cyclin D

  • Normally: Rb protein inhibits the transcription Factor E2F
  • Rb protein gets progressively inhibited by Cdk4/6+ Cyclin D
    • –> activation (disinhibition) of E2F
    • transcription of further molecules (e.g. cyclin E)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
176
Q

What is the Rb protein?

A

The Retinoblastom protein is a tumor supressor gene that normally inhibits E2F (transcription factor that drived cell cycle)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
177
Q

Explain the regulation of E2F and Rb protein throughout the cell cycle

A

E2F is more and more upregulated throughout the cell cycle due to progressive inhibition of Rb protein (via multiple phosphorylation)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
178
Q

What are possible oncogenic mutations in the RAS gene?

Why are they oncogenic?

A

Mutations can lead to permanent onswitch of RAS –> no inactivation possible

  • e.g. mutation prevents GAP binding –> no inactivation
  • e..g Mutation prevents GTP hydrolysis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
179
Q

How can Cdks be inactivated?

A
  1. Unbinding + degradatio of cyclins
  2. Cdk inhibitors (CKI)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
180
Q

What is the effects of an activated RAS protein?

A

it activates a protein kinase cascade

more specifically: Extracellular signal-regulated kinase (ERK) cascade

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
181
Q

What is the name of the intracellular kinase cascades that induce mitosis?

  1. Generally
  2. ACtivated by RAS
A
  1. Gneral Name= Mitogen-activated protein kinase (MAPK) cascades
  2. RAS activates (or extracellular binding) Extracellular signal-regulated kinase (ERK) cascade
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
182
Q

What can happen in mutations to CKIs?

A

May result in cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
193
Q

Which cdk/cyclin complex activates the transisiton from G0 to G1?

How is it activated?

A
  • Cdk 4/6 + cyclin D initiate transtion from G0 to 1

Activated via

  • cyclin D expression is regulated via c-Myc
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
198
Q

What are Genes regulated by the transcription factor EGF2?

A

Proto-oncogenes

  • c-Myc
  • N-Myc

Cell cycle genes

  • cyclins A+E
  • Cdk4, Cdk2
  • E2F genes
  • Rb protein

Many more+ DNA synthesis genes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
200
Q

What are the two families of CKIs?

A

CKI = Cdk imhibitors

  1. INK4 family
    1. in G1 phase
    2. inhibit CDK4/6 by displacing cyclin D
  2. CIP/KIP family (e.g. p27KIP1)
    1. S phase
    2. inhibit all Cdks
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
201
Q

What needs to happen to the CKIs to allow cell cycle regulation?

A

Must be degraded + gene supression to allow cell cyclie progression

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
203
Q

How do EGFR/HER2 lead to cancer?

A

They are often over-expressed in cancer and lead to increased cell proliferation by binding to Growth factor recetor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
204
Q

Why can DNA easily be damaged?

A

because the DNA bases are planar carbon rings –> easily chemically activated and then

  • be reactive, react with other molecules
  • are chemically similar –> can be transfered into one another
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
205
Q

What is Deamination in the process of modification of an AA?

What does it lead to?

A

The loss of one amine group of a DNA base (often converted to keto group)

  • can lead to mutation via conversion of
    • cytosin to uracil (essentially thymine)
    • adenine to hypoxanthine
    • guanine to xanthine
    • and 5-methyl cytosine to thymine.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
207
Q

What are “other chemical modificatios” of DNA?

What do they lead to?

A

Many reacgtions, often induced by free radicals or hyper-reactive oxygen molecules (byproducts of normal motabolism or can be produced by ionising radioation)

Leading to

  • formation of double-bonds
  • methylation, alkylation of DNA bases
  • adduct formation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
208
Q

What is photodamage?

How does it change the DNA?

A

intra-strandal change by UV light being absorbed by the DNA bases

  • UV light activates and causes
  • pyrimindien dimer (often thyamine dimers)
    • driver in skin cancer
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
209
Q

What are the different modifications/damages that can occur in DNA change?

A
  • Deamination
  • other chemical modification
    • methylation
    • alkylation
    • adduct formation
  • photodamage
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
210
Q

What is the consequence a Base-mismatch in the DNA?

A

There will be a bulge in DNA –> will be used to find the site of damage and repair of the DNA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
211
Q

How does Radiodamage modifies the DNA

A

It can sometimes break the phospho-diester bonds–> leading to gap in DNA

  • also used to find the site of damage and repair
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
212
Q

Overall spoken: What causes DNA damage?

A
  1. Carcinogens
  • dietary
  • lifestyle
  • environmental
  • occupational
  • medical
  • endogenous
  1. Radiation
  • ionizing
  • solar
  • cosmic
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
213
Q

Explain how polycyclic aromatic hydrocarbons might lead to DNA damage?

Where are they found?

A
  • Common environmental pollutants
  • Formed from combustion of fossil fuels
  • Formed from combustion of tobacco

E.g. Benzo(a) pyrene (B(a)P)

  • itself it nor carcinogenic but gets activated by metabolism (highly carciongenic)
  • Forms DNA adduct when activated
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
214
Q

Name an example of a food-born carcinogen and how it could cause cancer

A

Aflatoxin B1– >formed by fungi on grains and peanuts

  • metabolism converts it into carcinogen
  • activation–> highly reactive
  • adduct formation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
215
Q

Why is DNA damage problematic?

A

Damage can lead to mutation –> mutations can lead to cancer

  • damaging DNA is an important strategy in cancer therapy (might lead to apoptosis)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
218
Q

Why is DNA repair so important?

What are its physiological capacities?

A

There is a lot of DNA damage going on all the time needs to be repaired to not cause cancer

–> normally: cell has a lot higher capcity to repair than damage happens

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
219
Q

Explain adduct formation in DNA

A

Reactive proteins can bind to DNA (or DNA gets activated and forms Adduct itself) and alter its chemical structure by binding to it

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
220
Q

How does UV radioation cause cancer?

A

UV radiation might induce

  • Pyrimidine (thymine) dimers
  • mutation
  • melanoma
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
221
Q

Explain how ionizin radioation can cause DNA damage

A
  • Generates free radicals in cells
    • Includes oxygen free radicals
      • super oxide radical: O2•
      • hydroxyl radical: HO•
  • Possess unpaired electrons
    • electrophilic and therefore seek out electron-rich DNA
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
222
Q

Explain the effects of free radicals on the cell

A

They attack the DNA and cause:

  • Double and single strand breaks
  • Apurinic & apyrimidinic sites
  • Base modifications
    • ring-opened guanine & adenine
    • thymine & cytosine glycols
    • 8-hydroxyadenine & 8-hydroxyguanine (mutagenic)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
225
Q

When would Base-excision repair take place?

How does it waork?

A

BER repairs damages base with intace phosphate diester bonds

  1. DNA glycosylase removed wrong DNA
  2. AP endonuclease cuts phospho-diester bond
  3. Polymerase fills the gap with corect DNA
  4. Ligase binds the DNA pieces
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
226
Q

When is Nucleotide excision repair used?

Explain its principle

A

Used when there is damages Base with damages phosphate-diester bond (e..g in removal of large adducts)

  1. Xeroderma pigmentosum proteins (XP proteins) assemble at the damage
  2. Endonuclease cuts edges of diester bonds that need to be removed (?) –> larger area around damage
  3. Helicase cuts off large DNA piece
  4. DNA polymerase synthesises new DNA
  5. DNA ligase binds them
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
227
Q

When does DNA mismatch repair occur?

A

scrutinisation of DNA for apposed bases that do not paired properly

  • only during replication/ new synthesation of DNA
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
228
Q

How is DNA mismatch recognised?

A

By wrong Watson-crick base paring–> DNA forms bulges that can be recpgnised

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
229
Q

Which factors activate p53?

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
230
Q

What are the effects of p53 activation?

A

Upregulation of cellular pathways leading to

inhibits progression of cells with damaged DNA from S-phase, later produced CKI-21

  • In mild and moderate stress
    • antioxidant defence
    • DNA repair
    • growth arrest
    • senescense
  • In severe cellular stress
    • apoptosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
231
Q

What are the consequences carcinogen-DNA damge?

A
  1. Normal repair–> normal gene and function is restored
  2. Apoptosis –> damage too severe
  3. Incorrect repair+ altered primary structure
    1. Fixed mutations leading to
      1. Aberrant protiens (abweichend)
      2. If that is in TSG/oncogenes: carcinogenesis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
232
Q

How do you determine, wether a substance is a carcinogen or not?

A
  1. just looking at the chemical strucutre: is it likely to be a carcinogen?
  2. AMES test (in vitro) –> bacteria
  3. Chromosomal damge (in vitro), mammalian cells
  4. Micro-nuclei around DNA formed (in vitro), mammalian cells
  5. Murine Bone Marrow Micronucleus assay (in vivo)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
233
Q

Explain the AMES test in testing for Carcinogens

A
  1. A bacterium that cannot produce histidin is cultured in a histidine free environment
  2. Chemical to be tested + metabolite enzymes are added –> converstion to active metabolite?
  3. Given to bacteria –> see if they can cultivate
    1. If yes: mutation has occured and bacteria make histidin –> carciongenic
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
234
Q

Why do you look at micronuclei in mamalian cultivated cells when testing for a carcinogen?

A
  • Binucleate cells assessed for presence of micronuclei
  • Can stain the kinetochore proteins to determine if chemical treatment caused clastgenicity(chromosomal breakage) or aneuploidy (chromosomal loss)

–> It shows severe chormosomal damage

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
235
Q

Explain the Murine Bone Marrow Micronucleus Assay in testing for carciongens

A

Treat animals with chemical and examine bone marrow cells or peripheral blood erythrocytes for micronuclei

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
236
Q

What is an apurinic/ Apyrimidinic site?

A

It is a site in DNA that has no base (mosltly due to DNA damage)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
237
Q

Explain the process of DNA mismatch repair

A
  1. Recognition of the wrong base (using old base as a template)
  2. Cutting out the wrong DNA
    1. can be nucleotide-excision repair (NER) or base-excision repair (BER)
  3. Polymerase restores DNA and fills Base in

Can only occur during replication!

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
238
Q

Explain the process of direct DNA repair

A

Direct Repair involves the reversal or simple removal of the damage by the use of proteins which carry out specific enzymatic reactions

E.g.

  1. Photolyases repair thymine dimers.
  2. O6 methylguanine-DNA methyltransferase (MGMT) directly reverses some simple alkylation adducts.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
239
Q

What are the two different types of excision repair of DNA ?

A
  1. Base excision repair (BER)
  2. Nucleotide excision repair (NER)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
242
Q

When might a mutation in NER lead to cancer?

A

•Xeroderma Pigmentosum

  • •severe light sensitivity
  • •severe pigmentation irregularities
  • •early onset of skin cancer at high incidence
  • •elevated frequency of other forms of cancer
  • •frequent neurological defects

–> no repair made by NER possible

  • also other conditions that are often linked to cognitive impairment/neurological developmental issues
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
243
Q

What is the role of p53 to controll cellular repair pathways?

A

p53 is a TSG that is normallly supressed by MDM2

  • in cellular stress: p53 gets activated (trasncription factor) and acitvates DNA repair pathways
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
252
Q

Which kind of DNA damages are repaired by BER?

A
  • Oxidized bases: 8-oxoguanine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG, FapyA)
  • Alkylated bases: 3-methyladenine, 7-methylguanosine
  • Deaminated bases:
  • Uracil
  • single-strand breaks
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
253
Q

Which kind of DNA damages are repaired by NER?

A

Damages that are formed by UV light (dusruption of helical structure)

  • adducts (e.g. thymine dimers)
  • *
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
254
Q

What are the resons why apoptosis takes place?

A
  1. Harmful cells (e.g. cells with viral infection, DNA damage).
  2. Developmentally defective cells (e.g. B lymphocytes expressing antibodies against self antigens).
  3. Excess / unnecessary cells (embryonic development: brain to eliminate excess neurons; liver regeneration; sculpting of digits and organs).
  4. Obsolete cells (e.g. mammary epithelium at the end of lactation)

–> Can be Exploited therapeutically - Chemotherapeutic killing of cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
255
Q

What are the characteristics of necrosisi?

A
  • unregulated cell death
  • normally due to trauma
  • there is cellular disruption
  • associated with inflammation (due to release of intracellular contents)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
256
Q

What are the characteristics of apoptosis?

A
  • programmed, regulated cell death
  • controlled dissembly of contents without membrane disruption
  • no inflammation
  • ATP dependant
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
257
Q

How many different types of cell death are ther?

A

Many many types of cell death, ranging from Necrosis on the one end to Apoptosis on the other hand –> many are in the middle and have characteristics of both

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
258
Q

Explain the process of necrosis

A
  1. Plasma membrane becomes permeable
  2. Cell swelling and rupture of cellular membranes
  3. Release of proteases and intracellular contents leading to autodigestion and dissolution of the cell
  4. Localised inflammation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
260
Q

What are the two phases of Apoptosis?

What are theri characteristics?

A
  1. Latent phase
    • apoptosis pahtways activated but no morphological change in cell
  2. Execution phase
    • morphologican changes and destruction of cell
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
261
Q

Explain the processes that take place during the execution phase of apoptosis?

A

Example of epithelial cells

  • loss of microvilli and intracellular junctions
  • cell shrink
  • loss of plasma membrane assymetry (important in normal function, can be seen e.g. by phosphatidylserine lipid appearing on surface)
  • Chromatin and nuclear condensation
  • DNA fragmentation
  • Formation of memrane bleps
  • Fragmentation into membrane-enclosed bodies (get phagocytosed by macrophages etc)
    • no release of cell contents
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
262
Q

What happens in the latent phaese of apoptosis?

A

death pathways are activated, but cells appear morphologically the same

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
264
Q

What happens to the DNA during apoptosis?

A

•Chromatin and nuclear condensation

• DNA fragmentation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
265
Q

Explain the characteristics of Apoptosis-like PCD (programmed cell death)

A

some, but not all, features of apoptosis. E.g. Display of phagocytic recognition molecules before plasma membrane lysis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
266
Q

Explain the characteristics of Necrosis-like programmed cell death (PCD)

A

Variable features of apoptosis and necrosis before cell lysis present; “Aborted apoptosis”

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
267
Q

What two types of caspades are there?

What is their characteristic and function?

A

There are two types

  1. Initiator caspases
    • get activated directly by intrinsic/extrinsic pathways
  2. Effector caspases
    1. get activated by initiator caspases, set off futher routes
268
Q

What are the protien domains that all caspases have in common?

What are the additional domapins the different initiator capsades have?

What is their function?

A

All have in common: p20 and p10 domain

  • Caspase 9+2 also have a CARD domain (caspase recruitement domain –> will localise the caspases at specific sites in the cell)
  • Caspase 10+8 also have a DED domain (Ceath effector domain) –> binds to adaptor protein and involved in activation of the capsase
269
Q

What is meant by the term of caspase maturation?

Explain the process

A

It is the activation of a procaspase to the active form

  1. Pro-domain and SS domain of caspase are cleaved (proteolysis)
  2. Dimer formation of one Large (L) and one small(2 chain)
  3. 2 dimers come together to form the active heterotetramer, consisting of 2L2S
270
Q

Which proteins mainly execute Apoptosis?

A

Cysteine-dependent aspartate-directed proteases (Caspases)

271
Q

What are the different concepts by which the effector caspases can execute the apoptotic program?

(what do they do to proteins?)

A
  1. Inactivate by proteolysis (cleavage of proteins)
    • single proteins
    • protein complexes
  2. Activate enzymes by cleavage
    • direct activation
    • indirect by destruction of inhibitory molecules
272
Q

Summarise the role and activation of caspases (briefly!)

A

Are the executers of apoptosis

  1. Get activated by cleavage (proteolysis) by another protease
  2. Set of a cascade of other activators
276
Q

What are the main functions of activatio of the caspase cascade?

A
  • amplification of the apoptotic signal
  • divergent responses –> spread responses
  • regulation
278
Q

Name an example of how caspase induced inactivation of an enzyme/protein can lead to apoptosis

A

E.g. Inactivation of nuclear lamins leading to nuclear breakdown

279
Q

Explain the processe that happens after trimerisation of the death receptor at the example of FAS

A
  • adaptor Protein (FADD) will bind to FAS via the Death domain (they both have)
280
Q

What happens after FADD binds to FAS via the DD?

A

This will lead to an recruitement of caspase 8 that binds to FADD via the DED (both have it)

and will lead to oligomerisation that activated caspase

281
Q

Explain how oligomerisation of caspases lead to their activation

A
  1. Oligodimerisation leads to conformational change of proteins
  2. some caspases need transcleavage to be activated

Concept of Transcleavage:

  • FAS is a trimeric receptor
  • 3 FADD molecules with 3 DED bind to it
  • 1 caspase (8?) binds to each of them–> 3 caspases
  • Crosscleave each other leading to acitvation and
    • Release of activtive initiator caspase 8 (tetramer) –> at least 2 caspases required
282
Q

Explainn how FLIP inactivates the apoptotic pathway

A

It inhibits the activation of caspases competitevely

  • Binds to the DED ends of FADD
  • but has no proteolytic funtion–> no caspase tetramer formation
283
Q

Explain the caspase cascase (which caspase activated which

284
Q

Name an example of how caspase induced activation of an enzyme/protein can lead to apoptosis

A

incl. protein kinases; nucleases, e.g. Caspase-Activated DNAse, CAD

285
Q

Which proteins/facotrs are required in the formation of teh apoptosome?

A

Apaf-1 (Apoptotic activating factor-1),

Cytochrome c,

ATP,

procaspase 9

286
Q

Explain the formation and structure of the apoptosome

A
  1. Apaf-1 (Apoptotic activating factor-1) come together at the CARD domain and form a heptamer (7)
  2. Outside: there is the WD-40 domain that interactis with cytochrome c
  3. When cytochrome c bound–> caspase 9 (several, each Apaf-1 can bind one) bind to CARD of apoptosome and gets activated (oligomerisation and trans-cleavage)
  4. Caspase 3 recruitement
  5. Activation leading to caspase cascade acivation
287
Q

How are the intrinsic and extrinsic pathways of apoptosis initiation connected?

A
  1. When Extrinsic pathway is activated:
  2. Bid protein gets activated by caspase 8 and triggers mitochrondrial release of mitochrondrial proteins
  3. –> activation of intrinsic pathway
288
Q

What are the two pathways that can induce apoptosis?

How are they induced?

A
  1. Extrinsic pathways
    • by binding to extracellular receptors
  2. Intrinsic pathways
    • by mitochondria (cellular stress leading to the less ot mitochondrial membrane potential)
289
Q

What are proteins from the Bcl-2 family?

A

Proteins that are involved in regulation and modulation of apoptosis (can be pro-apoptotic and anti-apoptotic)

  • differnet groups/proteins with different domains but all: BH3 as dimerisation motif
290
Q

What are “death receptors”?

What is their stucture, and what do they all have in common?

A

Transmembrane receptors that all

  • form trimers when activated
  • have an intracellular DD (death domain)
291
Q

Explain the role of Phosphatidylinositol 3’-kinase (PI3’-K) in the cell survival

A

Phosphatidylinositol 3’-kinase (PI3’-K) is a lipid kinase that promotes cell survival

  • gets activated by Growth factor receptor
  • converts PIP2 into PIP3
  • PIP3 Activates protein kinase PKB/Akt which is anti-apoptotic
292
Q

Explain the structure of FADD

What is it and what is its function?

A

FADD= an adaptor protein binding to the death receptors

  • Has one DED(death effector domain) and one DD(death domain)
  • it activates the apoptotic programm
293
Q

Explain the relationship between the PKB/Akt pathway and the Bcl-2 proteins

A
  1. PKB/Akt are activated via the GF/PI3’-K pathway during growth factor binding
  2. they inactivate BAD
  3. which then means, that the heterodimers on the mitochondrium are inactive and and don’t cause activation of the intrinsic pathway
294
Q

Explain how the absence of GF might lead to apoptosis

A

If there is no GF –> no activation of PKB/Akt (PI3’-K, GF pathways)

  • no inhibition of Bad
  • displaces Bax/BAc from Bcl-2/-xL binding site (all bind together via BH3)
  • Bax/Bac are now released and form the Bax/Bac Pore -> Apoptosis via activation of the intrinsic pathway
295
Q

Explain the role of PTEN in the regulation of apoptosis

A

PTEN can induce apoptosis by inhibiting the phosphorylation of PIP2 into PIP3 (and thereby the pro survival(phosphoinositide 3 kinase (PI3K) ) signaling)

  • disinhibition of apoptosis
296
Q

Explain the structure of FLIP

What is it and what is its function?

A

FLIP is an adaptor protein that binds to the death receptors and inactivates the apoptotic programm

  • has only DED (Death effector domains)
297
Q

Explain the activation of the death receptor at the example of FAS

A

A ligand (e.g. FAS-L on lmyphocyte) will bind to FAS –> leads to receptor trimerisation

–> recruitement of adaptor protein

303
Q

Explain the intrinsic activation of apoptosis

A
  1. Cellular stress leads to
  2. loss of mitochondrial membrane potential
  3. Leading to release of cytochrome c and other factors
  4. Cause apoptosome formtation
307
Q

What are the two classes within the Bcl-2 protein family?

Where are they located?

A

There are

  1. Anti-apoptotic molecules in the mitochondrium
    • Bcl-2
    • Bcl-xL
  2. Pro-apoptotic molecules that travel between cytocsol and mitochondrium
    • Bid
    • Bad
    • Bax
    • Bak
309
Q

What are the anti-apoptotic proteins in the Bcl-2 protein family?

A

Bcl-2

Bcl-xL

311
Q

Explain the consequence of activation of protein kinase PKB/Akt

A

Its activation is anti-apoptotic because it

  • phosphorylates and inactivated bad
  • inactivation of caspase 9
  • inactivation of pro-apoptotic Transcriptionfactor FOXO
  • Indirect: Other, e.g. stimulates ribosome production and protein synthesis
315
Q

Explain the role of Inhibitor of Apoptosis Proteins (IAPs) in the regulation of apoptosis

How do they do it?

A

They inactivate apoptosis inthe extrinstic pathway by:

  • Bind to procaspases and prevent activation
  • •Bind to active caspases and inhibit their activity
316
Q

Which molecules regulate and increase cell survival in the intrinstic pathway?

A

Mainly the pro survival Bcl-2 family proteins

  • Bcl-2,
  • Bcl-xL
317
Q

Which molecules promote cell survival by inhibiting/modulating the apoptosis pathway?

A
  • FLIP (competitively inhibits the activation of caspases)
  • IAPs Inhibitor of Apoptosis Proteins (directly inhibits caspase activation and already activated caspases)
318
Q

How can apoptotical pathways be therapeutically useful?

A
  • Harmful (oncogenic) cells (e.g. cells with viral infection, DNA damage)
  • Chemotherapeutic killing of tumour cells, e.g. Dexamethasone stimulates DNA cleavage
319
Q

How do you call different forms of new vascular formation?

How do they differ?

A
  1. Vasculargenesis
    1. in emberyological development –> from bone marrow progenitor cells
  2. Ateriogenesis
    1. collateral growth
  3. Antiogenesis
    1. sprouting of blood vessels, important in adult life and tumor development
321
Q

Explain the role of Hypoxia in Angiogenesis

A

Hypoxia is a powerful stimulus that triggers antiogenesis

  • In presence of oxygen: HIF release is inhibited by pVHL: Von Hippel–Lindau tumor
  • Hypoxia causes release of HIF (hypoxia-inducible transcription factor)
  • –> HIF triggers VEGF release and other Growth factors
322
Q

Explain the release of VEGF?

A

Often released due to Hypoxia:

In presence of oxygen: HIF release is inhibited by pVHL: Von Hippel–Lindau tumor

Hypoxia causes release of HIF (hypoxia-inducible transcription factor)

–> HIF triggers VEGF release and other Growth factors

323
Q

Explain the overall concept of regulation of angiogenesis

A

Regulated by many proteins:

  • Some molecules are essential (i.e. VEGF), other are required for modulation (i.e. VWF)
  • Many are best known for other functions (i.e. TNF-a, VWF)
  • Factors can have both: pro and anti-angiogenic effects
326
Q

How many forms of VEGF are there?

To which receptors do they bind?

A

There a 5 different VEGF (Vascular Endothelial Growth Factor)

  • VEGF A-D
    • PIGF (Placental Growth Factor)
  • Bind to thyrosine kinase receptors: VEGF receptors 1-3
327
Q

Which receptor and signaling molecule is mainly incvolvedn in angiogenesis?

A

•VEGFR-2 is the major mediator of VEGF-dependent angiogenesis, activating signalling pathways that regulate endothelial cell migration, survival, proliferation.

328
Q

What are the stalk cells?

How do they get activated?

A

Stalk cells are the cells next to the endothelia tip cells

  • get activated via the Notch system
  • Notch ligand on tip cell activates the Notch receptor on stalk cell
  • this sets of the production of notch intracellular domain (NICD)
  • NICD is brought to nucleus where it activates transcription factors RBP-J
329
Q

Explain the cellular process of the tip cell selection

A
  1. In stable blood vessels, Dll4 and Notch signalling maintain quiescence
  2. VEGF increases expression of Dll4 (Tip Cell)
  3. –> Dll4 drives Notch signalling, which inhibits expression of VEGFR2 in the adjacent cell
  4. Tip-cell phenotype by Dll4-expressing tip cells acquire a motile, invasive and sprouting phenotype
  5. Adjacent cells forms Stalk cells
330
Q

How does VGEF activate angiogenesis?

A

Binds to receptor on one cell that becomes the tip cell

  • also gives direction of antiogenesis: vessesl sprout towards the VEGF gradient
331
Q

How do tip cells move and lead the path to angiogenesis?

A

They navigate in response to guidance signals

Adhere to Extracellular Matrix to migrate

Stalk cells behind the tip cell proliferate, elongate and form a lumen, and sprouts of tip cells fuse to establish a perfused neovessel.

332
Q

What is the tip cell in angiogenesis?

A

Tip cell is the top cell that gives direction for cell growth –>signals to surrounding cells, thex become the stalk cells

333
Q

Explain the role of platelets in angiogenesis

A

They are both: pro-angiogenic and anti-angiogenic and involved in physiolgical and pathological angiogenesis

334
Q

What happens during stabelisation and quiescence of newly formed vessels?

A
  1. Lumen formation allows perfusion of neovessels (possible after fusion of neighboring branches)
  2. Stabelisation of new vessel via
    • re-establishing junctions
    • deposition of basement membrane
    • maturation of pericytes
    • production of vascular maintenance signals
335
Q

Explain the role and regulation of tight junctions and adherence junctions in endothelial cells in angiogenesis

A

Very important to restore connections and Barrier formations during stabelisation of neovessel:

Mainly regulated via VE-cadherin

  • Constitutively expressed at junctions
  • mediates adhesion between endothelial cells and intracellular signalling
  • Controls contact inhibition of cell growth
  • Promotes survival of EC
336
Q

Which signals activate the tip cell?

What happens upon activation?

A

DLL4 and JAGGED

Processes that enable cell migration take place:

  • degradation of the basement membrane
  • loss of connections to adjacent endothelial cells (junctions and perycyte detachents)
  • matrix remodeling and
  • increased permeability
338
Q

Explain the role of Ang-1 in angiogenesis

How is it released?

A

Ang-1 is an agonist of the Tie 2 receptor, importnat in stabelising of neovessels

  • when bindin to it
    • promotes vessel stability
    • reduces inflammatory gene expression

Released by the pericytes

339
Q

Explain the role and release of Ang-2 in angiogenesis

A

It is released upon inflammatory stimmuli and antagonises the Tie2 receptor

  • blocks the effects of Ang-1:
    • increases vascular instability
    • promotes VEGF dependant angiogenesis
340
Q

Summarise the process of angiogenesis

342
Q

What is the function of the stalk cell?

A

form the base of the emerging sprout, proliferate to support sprout elongation.

343
Q

What is meant by the term the angeiogenic switch?

What happes there?

A

It is the initiation of angiogenesis in a tumor cell

  • mostly a hypoxia induced release of angiogenic factors leading to
  • angiogenesis ( perivascular detachment and vessel dilation (b), followed by angiogenic sprouting (c), new vessel formation and maturation, and the recruitment of perivascular cells (d))
345
Q

Explain the role of macrophages in angiogenesis

A

Important in angiogenesis (physiologically and pathologically)

  • •Macrophages carve out tunnels in the extra cellular matrix (ECM), providing avenues for capillary infiltration

•Tissue-resident macrophages can be associated with angiogenic tip cells during anastomosis

347
Q

What is the role of Cance-associated Fibroblasts in angiogenesis of cancer cells?

A

secrete extracellular matrix; pro-angiogenic growth factors,

350
Q

Explain the role of pericyte maturation in senscence of neovessels in angiogenesis

A

Mural cells (pericytes) help to stabilise the neovessels by modulation of the:

via the Angiopoietin/Tie-2 system

351
Q

What is the Angiopoietin-Tie2 ligand-receptor system?

What is its role?

A

Pathway that is invoved in an intracellular siganling pathway that controls stability of neovessels in angiogenesis

352
Q

What are the potential mechanisms of resistance of tumor cells agaisnt anti-VEGF therapy?

A
  • Other hypoxia induced growth factors might be produced by tumor
  • Tumours vessels maybe less sensitive to VEGF inhibition due to vessel lining by tumour cells or endothelial cells derived from tumours
  • Tumour cells that recruit pericytes maybe less responsive to VEGF therapy
353
Q

What is the aim for anti-angiogenic therapies in cancer treatment?

Why?

A

If there is too much anti- angiogenesis

  1. formation of resistance
  2. damage of healthy vasculature
  3. no adequate delivery of chemotherapy/drugs to cancer cells

So aim for: anti-angiogenic therapy that normalises vasculature

  1. reduces hypoxia
  2. Increase efficacy of conventional therapies
354
Q

What is vascular mimicry?

A

It is the ability of a cancer to form vessesl-like channels in cancer cells (not via signaling of body cells)

–> agressive and poor prognosis!

358
Q

When does a tumor needs vessels?

A

Needs vessels when it becomes larger than 1mm3

359
Q

How do tumors induce angiogenesis?

A

Tumor secretes angiogenic that stimmulate angiogenesis to tumor of adjacent vessels:

–> dependant on the hosts vasculature

361
Q

What are the characteristics of tumor blood vessels?

A

Tumour blood vessels

  • irregularly shaped, dilated, tortuous
  • not organized into definitive venules, arterioles and capillaries
  • leaky and haemorrhagic, partly due to the overproduction of VEGF
  • perivascular cells often become loosely associated

–> not like a normal vessel!

362
Q

Why do tumor vesseld differ from normal vessels?

A

Because they don’t have all the Factors involved in angiogenesis available

–> might only have a few so e.g. can’t stabelise as well or have overexpresseion of other factors (e..g VEGF)

363
Q

Which other cells (other than the actual cancer cells) are involved in tumor angiogenesis?

A
  1. Cancer-associated fibroblasts
  2. Pericytes
  3. Platelets
365
Q

Explain the role of pericytes in tumor angiogenesis

A

Pericytes are loosely associated with with tumour-associated blood vessels (TABVs), and this favours chronic leakage in tumours. This is enhanced by angiopoietin 2 (ANGPT2)

366
Q

Explain the role of platelets in tumor angiogenesis

A

Overall: pro-angiogenic

Tumors cause platelet activation leading to

  • release of pro-angiogenic factors (VEGFA, platelet-derived growth factors (PDGFs), FGF2)
  • some antiostatic molecules, but tend to play a minro roll
367
Q

How can the VEGF pathway be therapeutically be exploited in cancer treatment?

A

It is often highly expressed in Cancer:

  • might be inhibited to inhibits tumor angiogenesis –> Avastin (Bevacizumab)
368
Q

What are the limitations and side-effects in the use of Avastin (Bevacizumab)

A

Side effects:

GI perforation, Hypertension, Proteinuria, Venous thrombosis, Haemorrage, Wound healing complications –> because it is needed in Endothelial survival

But also just has limited effects on survival rate and quality of life

369
Q

What are the potential mechanisms of resistance of tumor cells agaisnt anti-VEGF therapy?

A
  • Other hypoxia induced growth factors might be produced by tumor
  • Tumours vessels maybe less sensitive to VEGF inhibition due to vessel lining by tumour cells or endothelial cells derived from tumours
  • Tumour cells that recruit pericytes maybe less responsive to VEGF therapy
370
Q

What is the aim for anti-angiogenic therapies in cancer treatment?

Why?

A

If there is too much anti- angiogenesis

  1. formation of resistance
  2. damage of healthy vasculature
  3. no adequate delivery of chemotherapy/drugs to cancer cells

So aim for: anti-angiogenic therapy that normalises vasculature

  1. reduces hypoxia
  2. Increase efficacy of conventional therapies
371
Q

What is vascular mimicry?

A

It is the ability of a cancer to form vessesl-like channels in cancer cells (not via signaling of body cells)

–> agressive and poor prognosis!

372
Q

Explain the different steps in tumor Progession

When do benign Tumors turn to malignant tumors?

A
  1. Homeostasis (normal cells)
  2. Genetic alteration
  3. Hyper-proliferation

–> Benign

  1. De-differentiation
  • dissasembly of cell-cell contacts
  • loss of polarity
  1. Invasion
  • increase motility
  • cleavage of ECM proteins and basemsent membranes –> Metastisis
373
Q

What are the two main types of tumor cell migration?

How do they differ?

A
  1. Individual cell migration
    1. Ameoboid cells
    2. Mesenchymal (single) cells
    3. Mesenchymal(chain) cells
  2. Collective cell migration
    1. Cluster cohorts
    2. Multicellular strands/sheaths
375
Q

What factors are needed in Cluser/multicellular cell migration of tumors?

A
  1. Integrins and proteases to cleave basement membrane
  2. Gap junctions and cadherins for coordination of movements
376
Q

What are the characteristics of tumor cell metastisis?

A

They mimic normal morpholigical movements

  • as seen in angiogenesis
  • branching morphogenseis like in mamillary gland
  • etc.
378
Q

Which factors are needed in individual cell migration?

A

Individual cell migration requires

  • integrins and proteases for Basememnt membrane cleavage
380
Q

What are focal adhesions?

A

They are connections between the cell and the extracellular matrix through integrins

  • Extracellularly: integrins bind to extracellular ligands
  • Intracellularly: multiproteins assemble (Plaque) and are connected to the actin cytoskeleton
381
Q

What is the role of focal adhesions?

A

Important in signaling of movement

  1. anchor the cell
  2. Signaling: inform the cell about the composition of the ECM –> influence behaviour of cell
382
Q

What are filopodia?

A

Finger like projections of cell membrane made of actin filaments, involved in cell motility

383
Q

Explain the structure of Fillopodia

A

They are organised in

  • straight, crosslinked actin filaments
  • fomed by
    • Polerymerisation
    • Bundling of actin filaments
    • Crosslinking of the filaments
384
Q

What are Lamellipodia?

A

Shee-like pertrusions of cell membrane, rich in actin filaments needed for cell motility

*

385
Q

What are the four steps that repetitively happen in cell movement?

A
  1. Extention
    • Lamellipodia and Fillopodia grow into direction of movement
  2. Adhesion
    1. New adhesions (focal adhesions) with ECM+ Basement membrane found
  3. Translocation
    • Cell body is moves in the direction of the movement, via contraction of actin filaments on the side opposite of movement
  4. De-adhesion of old adhesion
386
Q

How does the overall cell shape change in a migrating cell compated to a normal cell?

A

It will become a polerised (in shape) cell

388
Q

How does migration of a tumor differ from normal cell migration?

A

Often they try to mimic morphological cell movement but are different in

  • deattaches from another (no cell-cell junctions and signaling)
  • grow randomly + unorgansied
  • fast growth
389
Q

How does the Gen profile of migrating tumor cells differn from those that don’t migrate?

A

Often:

  • upregulation in cytoskeleton regulation
  • and machinery

–> Normally they don’t have more oncogenic mutations but are just more mobile (EGF mouse experiment)

390
Q

What is the first and rate limiting step in actin assembly?

What happens durin this step

A

Nucleation

  • Attachment of actin to the inner cell membrane
  • Arp proteins form a complex and bind actin monomers to create a nucleated actin filament
    • Actin monomers bind to Arp-complex
391
Q

Which proteins are important in the nucleation of actin filaments (other than G actin itself?)

A

Arp complexes

392
Q

After initial formation of a actin trimer, what is the next step in actin filament formation?

Which protein is neede for it?

A

Elongation

  • Controlled by
    • +: profilin
    • inhibited by thymosin
393
Q

When does a cell move?

A

Normally due to external stimuli like

  • organogenesis and morphogenesis
  • wounding
  • growth factors/chemoattractants

But can also happen in oncogenesis

  • dedifferentiation (tumor formation)
394
Q

What happens after the Elongation of actin monomers to form an actin filament?

A

Capping

  • further elongation inhibited
  • done by proteins like: (also Arp protein involved)
395
Q

After capping of Actin filaments, what is the next step?

Why is it importantn?

A

Severing

  • enables quicker break down and reassembly of actin filaments (because chunks of actin are available, not jut monomeres)
397
Q

What ar the possible fates of single severed actin filaments?

A
  1. De-polymerisation and monomer recylcling
  2. Annealing to other parts
  3. Elongation (at (+)Barbed-end with profilin actin filaments)
398
Q

What is the next step after formation of a fully functional indivudual actin filament?

A

Cross-linking and bundling of strands

  • functional dependant, many proteins can cross link e.g.
    • Bundling
    • Buckling if needed for contraction
399
Q

Explain the role and the protein involved in actin branching

A

Branching forms a stable network of actin filaments

–> needed in formation for Lemelipodia

  • 70° angle used

Mediated by the Arp complex

400
Q

What happens during the Gel-Sol transition of actin filaments?

Why does it happen?

A

A process of severing

  • a few actin filaments are cleaved to allow movement (sol-phase) from steady gel phase
401
Q

Which cytoskeletal changes occur during Extention of the cell during movement?

A

Cell polymerisation is needed and all processes happen to deassambly/re-assembly actin filaments(e..g for lamellae protrusion)

  • Disassembly
  • Nucleation
  • Branching
  • Severing
  • Capping
  • Bundling
402
Q

Which cytoskeletal changes occur durin lamellae portrusion?

A

Polymerization, disassembly, branching, capping

403
Q

Which cytoskeletal processes occur during Filopodia bulding?

A
  1. Polimerization
  2. Bundling
  3. Crosslinkin
406
Q

Which proteins regulate the cytoskeleton?

Name indivudual ones that controll

A

Overall: Rho proteins

  • Folopodia: Cdc42
  • Lamellipodia: Rac
  • Stress fibres: Rho
407
Q

How do Rho proteins get activated?

A

activated by

  • receptor tyrosine kinase
  • adhesion receptors
  • signal transduction pathways.

–> Cause GTP binding and therefore acivation (quick indactivation via phosphorylation)

409
Q

How do Rho proteins controll the cytoskeleton?

A
  • They set of a set of intracellular messenger systems and activate actin bindin proteins
  • Lead to actin polerization/organisation
    • Arp2/3 in nucleation
    • Cofilin, Profilin
    • etc.
411
Q

Explain the role of Rac in cell migration and movement

A

Needed in the

  1. Adhesion
  2. and Extention phase of cell migration
  • controlles lamellipodia and therefore needed for
    • focal adhesion assembly
    • actin polimerizsation and branching
412
Q

Explain the role of Rho (specific protein, not family) in cell migration and movement

A

Controlls stress fibres therefore needed in

  1. Adhesion
  2. Translocation
  3. De-adhstion of cell

Via

  • tension and contraction of filamnents
415
Q

What are stress fibres?

What is their role in cell migration?

A

Antiparralel strucztures actin filaments needed in cell migration

–> contraction of the cell

416
Q

What are the different forms /organisations of actin (tip: differ in number)

A
  1. G Actin
    • monomers, get assemblied to
  2. F Actin
    • polymers, assembly to different structures
417
Q

When is the assembly and disassembly of G and F actin important in cell migration?

A

It is important to disassembyl the F actin to G proteins to make them available

  • The G need to be converted to F to form new structures for migration (e.g. Filopodia, Laemlipodia)
421
Q

What are the different steps in formation of an actin filaments for cell movement?

A
  1. Nucleation
  2. Elongation
  3. Capping
  4. Severing
  5. Cross linking and bundle formation
  6. Branching
  7. Gel-sol transition by actin filament severing
424
Q

What is the role of Arp in the formation and disassembly of actin filaments?

A

It is involved in

  • nucleation
  • Capping
  • Branching of the filaments

The same protein has different functions and do many things, dependant on their current regulation

432
Q

Which signals regulate the actin cytoskeleton?

A
  1. ion flux changes (i.e. intracellular calcium)
  2. Phosphoinositide signalling (phospholipid binding)
  3. Kinases/phosphatases (phosphorylation cytoskeletal proteins)
  4. Signalling cascades via small GTPases
433
Q

What kind of proteins are Rho proteins?

Which protein class do they belong to?

What is their function?

A

Rho proteins are a subfamily of small GTPases, belonging to the RAS superfamily

They are needed in regulation of the cytoskeleton

436
Q

What is the role of Rho protiens in cancer?

A

They might be upregulated in differenet kind of cancers

–> more cytoskeletal activity

438
Q

What is the role of Cdc42 in cell migration?

A

They are involved in the regulation of the Fillopodia and therefore needed for

  • regulation of the polerized motility
  • regulation of actin polymerization
441
Q

What is the role of the actin polarity?

A

Have a + and - end

  • different proteins can bind to the different ends
  • depending on the bound protein, fibres can have different functions
442
Q

What kind of external influences can the cell detect?

A
  1. Chemical
    • hormones, Growth factors, ions, nutrinents, dissolved gases etc.
  2. Physical
    • mechanical, temperature, stretch,
443
Q

What are the main external influcences to the cell are often important in cancerous cell behaviour?

A
  • •Growth factors
  • •Cell-cell adhesion
  • Cell-ECM adhesion
444
Q

Next to Growth factors, what is the other importnat part needed for cell proliferation?

A

Binding to the extracellular matrix

  • Achorage dependance!
445
Q

Explain the concept of Anchorage dependance

A

Cells need bindin to ECM (+ a degree of spreading of cells) for

  • survival
  • Protein synthesis and DNA replication
  • proliferation
446
Q

Explain the role of ECM in cell phenotype

A

The composition of the ECM has a crucial role in determenin the cells organisation and phenotype

447
Q

How do cells “sense” the composition of the ECM?

A

Via binding of integrins

  • Special ECM receptors that can bind to many different ECM molecules
  • Link to cytoplasm
    • Contunitnity between cytoplasm and external environment
448
Q

Explain the structure of Integrins

A

Are compsed of

  • alpha and ß subunit
  • have a head binding to ECM molecules
  • and a tail/Leg which has the membrane and cytoplasmic domains
449
Q

How do integrins sense different ECM compositions?

A

There are different combiations of the alpha and beta subunits

  • Each recognises different short AA sequences of ECM molecules
  • They can be specific to one ECM molecule or are found in more than one molecule
451
Q

Explain the structure of focal adhesions

A

Integrins cluster togetheer to then form focal adhesions (sometimes can also form hemidesmosomes)

  • involved in signal transduction
    *
453
Q

Explain ther role of Intrgrins during “outide in” -signal regulation

A

Integrins can undergo confirmational change and therefore change ability to

  1. bind ligands
  2. change the signaling pathway
454
Q

How can integrins sense the mechanical properties of the surrounding?

A

Via the amoun of force that is generated at a focal adhesion depends on

  • both the force generated by the cytoskeleton (F cell)
  • and stiffness of the ECM
455
Q

What is “inside-out” integrin signalling?

A

An intracellular signal (e.g. as response to a homone binding etc.) can

  • change the integrin affinity for the ECM
    • used e.g. in inflammation, blood clotting
456
Q

Explain the mechanism of anchorage dependance

A
  1. growth factor receptors and integrin signalling complexes can each activate identical signalling pathways (e.g. MAPK)
  2. Alone: this activation is weak and/or transient
    1. •Both needed for strong proliferative signal!
459
Q

Explain the intracelluar organisation of integrins

A

Bind to Actin (exeptino in epithelial cells–> can also bind to intermediate filaments) Intracellularly via actin binding proteins

  • induce signal transduction intracellularly
460
Q

Explain the concept of Contact-induced spreading of epithelial cells

A

When epitelial cells meet:

  • form stable junctions/cell-cell adhesions
  • leading to cell spreading to form stable mono-layers
461
Q

Explain the intracellular mechanism how cell-cell adhesions influence proliferation

A

Cell-cell junctions are calcium dependant: low Ca2+= low juncitons= high proliferation

  • Without cell-cell junction
    • high MAPK activity
    • low p27KIP1 (CKI)
    • promote proliferation
  • With cell junctions
    • MAPK inhibited
    • inhibit proliferation
462
Q

What is the mediator molecule that might be responeible for the link of cell-cell adhesions and proliferation

A

Thought to be mediated by ß-cadenin (link between calcium dependant junction and further intracellular signaling)

463
Q

Explaint the role and regulation of ß-catenin in cell proliferation

A

ß-catenin is bound to cell-cell junction molecules

  • When there is no junction–> ß-catenenin is free in cytoplasms
    1. Binds to LEF-1 and promotes gene transcription and cell proliferation
    2. Gets inactivated by APC complex
464
Q

Explain the formation and Mechanism of Adenomatous polyposis coli (APC)

A

It is a form of inhierited disease forming uncontrolled colorectal polyps

  • Due to a disfunciton of the APC gene that cannot degrade ß-catenin
  • No degradation of ß-catenin –> uncontrolled proliferation
466
Q

What is “outiside-in” signaling?

A
  • ECM receptors (e.g. integrins) can act to transduce signals
  • e.g. ECM binding to an integrin complex can stimulate the complex to produce a signal inside the cell,
  • This changes the cells phenotype
467
Q

What are the different steps in metastisis formation?

A
  1. Cells must break away from the primary tumour
  2. travel to a blood or lymph vessel
  3. enter the vessel
  4. lodge at a distant site
  5. leave the vessel,ultimately
  6. establish a secondary tumour
468
Q

What do primary carcinomal cells alter/have to metastisise?

A
  1. Reduction of cell-cell adhesions (e.g. cadherin levels reduced)
  2. Primary cells must be motile
  3. degradation of ECM must take place; matrix metaloproteinase (MMP) levels increased in order to migrate through basal lamina and interstitial ECM
    1. the degree of carcinoma cell-cell adhesion is an indicator of how differentiated the primary tumour is, and indicates its invasiveness and the prognosis
469
Q

What is Blebbing?

A

Happens when Cells are detached from ECM

  • membrane swells into several spherical bubbels

Can end

  • apoptotic
  • Non-apoptotic = cell locomotion, cell division and stresses
474
Q

Explain the concept of density dependance of cell devision

A

In cell monolayers–> cells compete for GF and therefore proliferate less (not just inhibted by contact inhibition)

475
Q

Explain the two different types of cell-cell contacts that can occur

A
  1. Short term
    • normally non-epithelial cells
    • transient intercations, don’t form stable junctions
  2. Long term
    • normally epitheilial cells
    • stable cell-cell junctions
476
Q

Explain the concept of contact inhibition of locomotion

A

Mostly

  • collision of non-epithelial cells repells the cells
    • paralisation of motiliy at contact side
    • promoting formation of otile front at other side and moving to opposide direction
482
Q

Other than ß-catenin mediatied, how can cell-cell jucntions als alter cell proliferation?

A
  1. Cadherin clusterin after cell-cell junciton can activate small GTPases (e.g. Rac activation, Rho inhibitiob)–> proliferation
  2. GF receptors involved in Cell-Cell junctions reduced their ability to respond to extracellular stimmuli
483
Q

What happens to contact inhibtion in tumor cells?

What does that lead to?

A

Tumor cell often loose contact-inhibition leading to

  1. Uncontrolled proliferation
  2. Multilayering
  3. Epithelial break down of cell-cell contacts

–> Solid tumor formation and invasion of tissues

484
Q

What are the different steps in metastisis formation?

A
  1. Cells must break away from the primary tumour
  2. travel to a blood or lymph vessel
  3. enter the vessel
  4. lodge at a distant site
  5. leave the vessel,ultimately
  6. establish a secondary tumour
485
Q

What do primary carcinomal cells alter/have to metastisise?

A
  1. Reduction of cell-cell adhesions (e.g. cadherin levels reduced)
  2. Primary cells must be motile
  3. degradation of ECM must take place; matrix metaloproteinase (MMP) levels increased in order to migrate through basal lamina and interstitial ECM
    1. the degree of carcinoma cell-cell adhesion is an indicator of how differentiated the primary tumour is, and indicates its invasiveness and the prognosis
486
Q

What is Blebbing?

A

Happens when Cells are detached from ECM

  • membrane swells into several spherical bubbels

Can end

  • apoptotic
  • Non-apoptotic = cell locomotion, cell division and stresses
487
Q

What are the 6 original hallmarks of cancer?

A

SARCOMA
S – Self-sufficiency of growth signaling
A – Apoptosis evasion
R – Resistance to anti-growth factor signaling
CO – Continuous replication (Immortality)
M – Metastasis
A – Angiogenesis

488
Q

What are the 4 additional Hallmarks of cancer?

489
Q

What are proto-oncogenes?

A

Genes that code for essential proteins involved in maintenance of cell growth, division and differentiation

491
Q

What kind of mutations normally occur in proto-oncognes that convert them into oncogenes?

A

A single mutation can be enough:

  • point mutation
  • deletion
  • Gene-amplification
  • Chromosomal translocations / Insertional mutagenes
    • E.g. Philadelphia chromosome – > hyperactiveness of transcribed gene
    • E.g. Burkitts lymphoma –> stonger enhancer in front of gene increase normal protein levels
492
Q

What kind of mutation is the phildelphia chromosome?

How does it lead to the formation of cancer?

A

It is a chromosomal translocation resulting in

  • via the BCR-ABL gene fusion product
  • BCL causes permanent activation of the ABL-gene product
  • ABL is important in proliferation
495
Q

explain how tumour suppressor genes have been discovered through heritable malignancies

A

Via the Retinoblastoma gene, development of the 2 hip hypothesis

  1. Each cell has 2 copies of a TSG
  2. Need loss of both copies for Cancer
  3. If one is already damaged –> can be inherited and only one hit is required to develop malignangy, leading to
  • Family history of related cancers.
  • Unusually early age of onset.
  • Bilateral tumours in paired organs.
  • Synchronous or successive tumours.
  • Tumours in different organ systems in same individual.
  • Mutation inherited through the germline.
496
Q

What happens when a proto-oncogene mutates?

A

It can convert into an oncogene

  • no longer responds to control influences
  • can be aberrantly expressed, over-expressed or aberrantly active
497
Q

At the example of colorectal cancer, explain how gene mutations can lead to cancer

498
Q

When does p53 get activated?

A

It gets activated at cellular damage

  • cellular stress
    • hypoxia
    • nitric oxide
    • oxidative stress
  • Damage
    • oncogene activation
    • Double strand breaks
    • Telomere erosion
499
Q

How does p53 get activated?

A

Via inhibiton of MDM2

  • Normally: MDM2 inhibits p53 activtiy
  • When activated: sets off repair mechanisms
500
Q

Explain the function of PTEN and its role in carciogenesis

A

It is a Tumor supressor gene

  • PTEN can induce apoptosis by inhibiting the phosphorylation of PIP2 into PIP3 (and thereby the pro survival signaling)
503
Q

Name some commonly mutated oncogenes and their location/MOA

A
  1. Transcription factors
    • c-Myc
    • JUN
  2. RAS, raf –> activation of kinase cascade
  3. Tyrosin kinases
    • SRC

–> Leading to permanent activation of proliferation!

504
Q

What are the characteristics of tumor-supressor genes?

A
  1. Normally proteins that regulate (supress) cell proliferation and function
  2. Each cell: 2 copies of each TSG
    1. normally loss of both copies required to induce malignancy
506
Q

Explain the role of APC in Familial adenomatous polyposis coli

A

APC is a tumor supressor gene, regulating the break down of ß-catnin

  • Damage on APC can be inherited leading to
  • formation of multiple benign adenomatous polyps of the colon.
  • There is a 90% risk of developing colorectal carcinoma.
511
Q

Explain the role of BRCA in carciogenesis

A

BRCA is a tumor supressor gene normally

  • repairing DNA damage
  • often mutated in Breast cancer
512
Q

Name 4 Tumor supressor genes

A
  1. PTEN
  2. p53
  3. BRCA
  4. APC
513
Q

Explain the trend of cancer incidence rates in western countries

A

Overall: it used to increase, now further followed by a plateau of cases in many countries (might even decrease in some wetern countries)!

515
Q

What are the reasons for the change in incidence of cancer in western countries?

A

The change (increase/plateau, might even decrease) is predominantly due to

  • increased sensitivity of diagnostic test–> more and earlier diagnosis
  • increased access to healthcare
  • ageing
  • achnge of risk factor exposure (e..g now: decrease in smoking)
516
Q

What is the trend of cancer incidences in developing/threshold contries?

A

It increases

  • due to more access to healthcare (+ more testing)
  • ageing
  • not diing from other causes
517
Q

What is the trend in cancer mortality in western countries?

Why?

A

It overall decreases due to

  • earlier diagnosis
  • better therapies
518
Q

What is the trend of cancer mortality in developing /non-western countries?

A

It increases

519
Q

How many percent of cancers are hereditary?

What is meant by that word?

A

Only 5-10% are hereditary

  • people e.g. inhierit a defect TSG and only need one more hit to develop cancer
520
Q

What are the main environmental risk factors for cancer?

A
  1. Smoking
  2. Diet
    1. red meat consumption, processed meat and salt
    2. fibre
  3. Alcohol
  4. Obesity
    1. chronic inflammatory diseae
  5. Occupation
  6. Reproductive hormone
521
Q

What is the role of infections in cancer?

A

16% cases of cancer likely caused by infectious agents worldwide

  • 25% in Africa
  • <10% in Europe (1 in 33 in UK)
522
Q

What are the consequences of a western lifestyle in regards to cancer

A
  • Causes
    • Energy dense diet, rich in
        • fat,
        • refined carbohydrates
        • animal protein
    • Low physical activity
    • Smoking and drinking
  • Consequences:
    • Greater adult body height
    • Early menarche
    • Obesity
    • Diabetes
    • Cardiovascular disease
    • Hypertension
523
Q

What are the 5 cancers with the highes incidence in women worldwide?

A
  1. Breast cancer
  2. Colorectal cancer
  3. Lung
  4. Cervix Uteri
  5. Thyroid
524
Q

What are the cancers with the highes mortality in women worldwide?

A
  1. Breast
  2. Lung
  3. Colorectal
  4. Cervical
  5. Stomach
525
Q

What are the 5 cancers with the highest incidence among men worlwide?

A
  1. Lung
  2. Prostate
  3. Colorectal
  4. Stomach
  5. Liver
526
Q

What are the 5 cancers most men die from worldwide?

A
  1. Lung
  2. Liver
  3. Prostate
  4. Colorectal
  5. Stomach
527
Q

What are the 5 leading cancers in countries with high HDI? (incidence)?

A
  1. Breast
  2. Colorectal
  3. Lung
  4. Prostate
  5. Bladder
528
Q

What are the 5 leading cancers in countries with high HDI? (mortality)

A
  1. Lung
  2. Colorectal
  3. Pancreas
  4. Breast
  5. Stomach
530
Q

Explain the methods of how epidemiological studies establish cancer causation

A

A lot is done via Migrant studies

  • People migrating from a low/high risk are to the opposite area
  • If there is a mainly genetic risk: risk for individual would not change
  • If they are environemtal risks: risk adapts the one in new country
531
Q

Summarise the epidemiology of breast cancer

A

Mainly: post-menopausal women

  • 1/5 of all female cancer deaths
  • 1/9 of women will get breast cancer
  • increasing incidence but decreasing mortality
532
Q

What is the trend of the incidence in breast cancer in the UK?

A

The incidence is increasing

533
Q

What is the trend of the mortality rates in breast cancer?

Why?

A

The mortality is decreasing due to

  • Early Diagnosis
  • Better therapies
    • Chemo/Radiotherapies
    • Hormonal Therapies
534
Q

What kind of tumors are most breast cancers?

A

Normally Carcinomas! (epithelial tissues of ducts)

but might be:

  • e.g. Sarcoma of fatty tissue (rare but agressive)
535
Q

Explain the strucutre of the ductural epithelium in the mamillary gland

A

The ductural epithelium surrounds the ducts consisting of 2 layers

  1. Luminal epithelium (inner layer)
  2. Outer Myopithelial cells
    1. contract during milk ejection
536
Q

Which cells are the main site of development of a Mamma Ca?

A

The luminla (inner layer) epithelial cells

537
Q

How do you call the pre-cancerous state in “breast cancer”?

What are its characteristics?

A

It is called “carcinoma in situ”

  • pre-invasive
  • often: the characterisitcs of individual cells are normal but they have an abnormal growth pattern

Picture: carcinomal im situ of luminal epitheilal cells

538
Q

What are the differnet forms of cancer that can develop from a mamillary carcinoma in situ?

What is the most common one?

A

Carcinoma in situ can go on and develop differnt types of cancer– >originate in terminal duct lobular unit

  • Lubular carcinoma (10-15%)
  • Infiltrating Ductal Carcinoma, not otherwise specified​
    • 80%!
  • Medullary carcinoma, rare, agressive
539
Q

How do you asses if a Mamma Ca is oestrogen positive or negative?

How many carcinomas show each characteristic?

A

It is done by histological staining with antibodies against human Estrogen Receptor (ER)

  • 80% of IDCs (infiltrating ductal carcinomas) are ER positive!
540
Q

Explain the location, activation and effect of the Estrogen Receptor and ER activation

A

It is an steroid (intracellular) receptor

  • Estrogen binds to it and releases hsp90
  • Causing dimerisation of ER
  • Travel into cell and alter DNA transcription
541
Q

Which molecules get expressed via the activation of an Estrogen Receptor?

A

Normally upregulates pro- proliferative and anti-apoptotic factors

  • upregulation of Progesterone Receptor (PR)
  • Cyclin D1
  • c-myc
  • TGF-a
544
Q

What is the main rationale behind endocrine therapy in breast cancer?

What are the different approaches used?

A

RAtionale: To reduce Estrogen and therefore growth and proliferation of the tumor

  1. In pre-menopausal women: ovarian supression
  2. Blocking estrogen production by enzymatic inhibition
  3. Inhibiting estrogen responses
547
Q

Explain the process of hormonal supression in the treatment of breast cancer

A

LHRH Agonist used to supress the production of LH/FSH

  • overstimmulation of LHRH-receptor leads to its downregulation –> less/no response to LHRH
  • reduced Estrogen production
549
Q

Explain the usuall treatment approach for Breast Cancer

A

Normally

  1. Surgery
    • remove the tumor
  2. Adjuvant therapy –> kill everything that is left behind)
    • radiotherapy
    • chemotherapy
    • endocrine therapy
550
Q

What is the normal response to Estrogen stimmulation in normal breast cells and in cancerous cells

A

Though activation of ER leads to increased expression of pro-proliferative and anti-apoptotic signals,

  • Normal cells: don’t proliferate/grow themselves but signal adjacent cells to grow (e.g. via TGF)
  • In tumor cells: drives tumor growth
551
Q

What are the main side-effects of the use of Tamoxifen?

A
  • It increases the riks of thrombosis/embolisms
  • It stimmulates growh of the endometrium –> endrometrial cancer
  • increased frequency of cataracts
553
Q

When would you chosse to treat breast cancer via ovarian supression?

Which strategies do you have?

A

Aim: to reduce Estrogen production in pre-menopausal women

  1. Ovarin ablation
    • surgical oophorectomy
    • Ovarian Irradiation
  2. Supress production of LH/FSH
554
Q

Explain the process of ovarian ablation in the treatment of breast cancer

What are the disadvantages

A

Reduce estrogen production in pre-menopausal women

  1. Surgical removal
  2. ovarina irradiation (destruction via radiation)

–> Steps are irreversible and lead to infertility, increased morbidity due to risk of procedures

556
Q

What is the main issue with endocrine treatments in breast cancer?

A

Resistance

  • expecially in metastatic disease, all patients become resistant
  • But still express ER and are driven by estrogen –> switch from tamoxifen to aromatase inhibitors

–> Use endocrine treatments as long as possible but after that: additional treatment required

557
Q

Explain the MOA of antiestrogens in breast cancer

A

ER antagonists

  • negate the stimulatory effects of estrogen by blocking the ER, causing the cell to be held at the G1 phase of the cell cycle.
558
Q

Name an example of an anti-estrogenic drug and its clinical use

A

e.g. Tamoxifen

  • used as adjuvant therapy in Breast cancer
  • metastatic disease in postmenopausal patients –> effective and few side effects

Also use as HRT in poastmenopause

559
Q

Explain the effects of Tamoxifan and its use

A

It is a Selective-Estrogen Receptor Modulator (SERM)

  • anti-estrogenic in breast tissue –> blocks growth of cancer cells
  • pro-estrogenic in bone + CVS
    • prevents osteoporosis + enhances estrogenic CVS protection
561
Q

What are the effects of tamoxifen in contalateral breast cancer/ prevention

A

Reduces the incidence of contralateral breast cancer of 30% –> might be considered as preventative treatement for high risk patients

562
Q

Where does the peripheral enzymatic conversion of androgens to estrogens mainly occur?

A

Mainly in fatty tissue –> breast is a fatty tissue

But also in

  • liver
  • muscle
563
Q

Explain the role of the Progesterone receptor in cancer treatement

A

In advanced cases

  • Progesterone Receptor positive diseases were a lot more likely to respond to treatment
  • Can be used as a target in Breast cancer treatment
564
Q

Which other receptor/Hormone could you use to treat breast cancer?

A

Progesterone Receptors

  • use progestin in breast cancer –> high dose to cause downregulation of receptors and therefore low responses to treatment
  • used in uterine and breast cancer
  • for breast cancer: 2nd/ 3rd line therapy in metastatic disease
  • (megestrol acetate)
566
Q

What are risk factors for developing breast cancer?

A

Mainly: Exposuter to estrogen

  • early onset of menstruation, late menopause
  • age at first full-term pregnancy
  • Forms of contraceptive pill
  • HRT
  • obesity (aromatase in fatty tissue)
  • lDiet, physical activity, height, medication (Aspirin)
567
Q

Explain the epidemiology of colorectal cancer

A
  1. 4th most common type of cancer
  2. 2nd leading cause of cancer death
  3. age: mainly 50-70/80
  4. diet + genetic risk factors
568
Q

What is a polyp?

A

any projection from a mucosal surface into a hollow viscus, and can have many causes (e.g. m

569
Q

What is an adenoma?

A

An adenoma is a benign neoplasm of the mucosal epithelial cells

570
Q

What are the characteristics of hyperplastic polyps in the colon?

A
  • Very common
  • <0.5 cm
  • 90% of all LI polyps
  • Often multiple
  • Most: No malignant potential
  • 15% have k-ras mutation
571
Q

What are the different types of adenomas that can occur in the colon?

What are their differences?

A
  • Tubular (>75% tubular)
    • Normally Pedunculated –> harder to invade into submucosa and mucosa
  • Tubulovillous (25- 50% villous)
    • mixed type)
  • Villous ( > 50% villous)
    • normally sessile –> easier to invade into submucosa and mucularis
572
Q

Explain the microscopic structures of tubular adenomas

A
  • Columnar cells with nuclear enlargement, elongation, multilayering and loss of polarity
  • Increased proliferative activity
  • Reduced differentiation
  • Complexity/disorganisation of architecture
573
Q

What are the microscopic changes and characteristics of villous adenomas?

A
  • Mucinous cells with nuclear enlargement, elongation, multilayering and loss of polarity
  • Exophytic, frond-like extensions –> finger like
  • Rarely may have hypersecretory function and result in excess mucus discharge and hypokalemia
577
Q

Explain the epidemiology of colonic adenomas and their potential to turn carcinomas

A
  • 25% of adults have adenomas at age 50
    • 5% of these become cancers if left
  • Large polyps have higher risk than small ones (so 5% > 1 cm 50-60, 15% at 75)
  • Likely to turn to carcinomas in 10years-15 years
  • Cancers stay at a curable stage c. 2 years
578
Q

Explain the adenoma-carcinoma sequence in the formation of Colorectal cancer

A

AK 53: 1: APC, 2nd K-ras, 3rd. P53

  1. First hit of TSG (can be inherited or or aquired)
    • E.g. APC, MSH2 (missmatch repair)
    • nothing happens
  2. 2nd hit of TSG
    • APC, MSH2, ß-catenin
    • nothing happens
  3. Protooncogene mutation
    • e.g. K-Ras
    • adenoma formation
  4. Homozygous loss of additional cancer supressor
    • P53, LOH
    • Carcinoma
  5. Irregulated control and loss of many genes
579
Q

Why is APC Especially Important in Colon Cancer?

A

Because it is the gene that turns off ongoing proliferation in the crypts

–> in colon proliferation is needed all the time!

580
Q

What are the main genes involved in the adenoma carcinoma sequence of Colorectal cancer?

A
  1. APC,
  2. K ras,
  3. Smads (signal transducers of TGF-ß)
  4. p53,
  5. telomerase activation
581
Q

What are microsattelites?

What is their role in the formation fo colorectal cancer?

A

Areas of repeated DNA sequences, more prone to mutation than other areas

  • Encode form many proteins, e.g. of some TSG
    • inhibit Growth and apoptosis
    • mismatch gene repair
    • –> Need 2 hits
582
Q

What are the macroscopic features of Colorectal Cancer?

A

Small carcinomas may be present within larger polypoid adenomas, pedunculated or sessile

583
Q

What is the distribution of colorectal carcinomals in the gut

584
Q

What is the Dukes Classification?

A

A way of staging Colorectal carcinomas

A-C with increasing severity

  • Dukes A - growth limited to mucosa/submucosa
  • nodes negative

Dukes B - growth into or beyond muscpropria

  • nodes negative

Dukes C1 - nodes positive

  • apical LN negative

Dukes C2 - apical LN positive

585
Q

What is HNPCC ?

A

Autosomal recessive condition that leads to imparied mitssmatch repair and therefore to increased microsattelite instability

–> Inherited high risk of cancer

588
Q

Explain the role of diet in the formation of colorectal cancer

A

It has a hugh influence. Increased risk if

  • western diet (high temperature red meat)
  • high fat
  • low fibre
  • refined carbohydrates
  • Dietarey deficiencies
589
Q

What is the clinical presentation of colorectal cancer?

A

Red flags:

  • Change in bowel habit
  • Bleeding PR
  • Unexplained Iron deficiency anaemia

+

  • Mucus PR
  • Bloating
  • Cramps (‘colic’)
  • Constitutional (weight loss, fatigue)
593
Q

Who is being screened in the screening for colorectal cancer?

What is done when the test result is positive?

A
  1. High risk patients (family history, previous adenoma, evidence of familiar cancer trait)
  2. Patients Aged 55-75, Positives referred for:
  • 60-75 years
    • colonoscopy
  • 55-60 years
    • sigmoidoscopy
594
Q

How is the screening test fo colorectal cancer performed?

A

FOB/FIT kit

  • detects blood in stool
595
Q

What is the site disease in Leukaemia?

A

Leukaemia is “cancer of the blood”, more specifically

  • bone marrow disease (not all patients have abnormal cells in the blood)
  • it is cancer in lymphoid/myeloid stem cells
596
Q

What are the different types of cells that can be affected in leukaemia?

A
  1. Pluripotent haematopoietic Stem Cell
    • would lead to mixed phenotype leukaemia
    1. Myeloid Stem Cell
      1. Myeloid leukaemia
    2. Lymphoid Stem Cell
      1. Lmphatic leukaemias
      2. Pre B Lymphocyte
      3. Pro T Lymphocyte
597
Q

Explain and summarise the development of leukaemias

A

Leukaemias need

  • multiple mutations in a single myelod/lympoid stem cell
    • leading to a potency of cell for increased proliferation, differentiation, or cell survival
  • Leading to expansion of the leukaemic clone
601
Q

Why can’t the concepts of invasion and metastisis not be applied to leukaemias?

A

Because blood cells (also haematopoietic stem cells) are physiologically found in the body and infiltrate tissues

602
Q

How are “benign” and “malignant” forms of leukaemia determined and named?

A

The words chronic and acute are used

  1. Chronic
    • behave in a “benign” manner, the disease goes on for a long time
  2. Acute
    • behaves “malignant”, untreated the disease is agressive and the patient dies rapidly
603
Q

How are the chronic and acute forms of leukaemias derived from lymphoid precursor cells called?

A

–Acute lymphoblastic leukaemia (ALL)

–Chronic lymphocytic leukaemia (CLL)

604
Q

How are leukaemias derived from Myeloid cells called?

A

Acute/Chronic myeloid leukaemias

605
Q

What are the important factors in the development of leukaemia?

A

Requires a series of mutations (basically just like any other cancer)

Importnatn identified mutations include

  • in proto-oncogenes
  • creatin of a novel gene (chiameric/fusion gene)
  • mutation in promoter/enhancer of a structurally normal gene
  • loss of TSG
606
Q

What are certain risk factors to the development of leukaemias?

A

Some inherited mutations e.g. in

  • down syndrome
  • defects in DNA repair etc.

Or exposure to

  • Irradiation
  • Anti-cancer drugs
  • Cigarette smoking
  • Chemicals—benzene
607
Q

What happens during AML?

A

, cells continue to proliferate but they no longer mature so there is

  • Built up of immautre (myeloblast) cells in the BM and spread into the blood
  • Together with a Failure to produce normal cells e.g. neutrophils, monocytes, erythrocytes, platelets

Failure of production of End Cells

608
Q

What are the genetic causes for the production of AML?

A
  • Often Transcription factors involved
    • Transcripition of multiple genes affected
  • Normal function of proteins are not possible (because they are supressed by an oncogene product)

–> Cell behaviour is profoundly disturbed

609
Q

What are the genetic causes for developement of CML?

A

mutations usually affect a gene encoding a protein in the signalling pathway between a cell surface receptor and the nucleus

610
Q

What happes during CML?

A
  • cell kinetics and funcitons are not as seriously affected as in AML
  • BUT: reduced apoptosis and increase proliferation –> slow progression of leukaemic clones

Increased production of end cells

611
Q

What is the Differnce between acute and chronic LL?

A
  • •Acute lymphoblastic leukaemia (ALL)
    • increase in immature cells (lymphoblasts)
    • no maturation into B and T cells
  • Chronic lymphoid leukaemias (CML)
    • , the leukaemic cells are mature,
    • although abnormal, T cells or B cells
612
Q

What are the general symptoms of leukaemia?

What is the underlying cause?

A

Normally caused by an accumulation of cells or infiltration of tissues

  • bone pain (if acute)
    • high metabolic rate and high proliferation
  • hepatomegaly and splenomegaly
    • extramedullary blood formation (due to no more formation in BM) and increased infiltration of tissues by cells
  • lymphadenopathy (if lymphoid),
  • thymic enlargement (if T lymphoid),
  • skin infiltration
  • overall: increased metabolic rate
    • weight loss sweating, low grade fever
613
Q

What are symptoms of ALL?

A

Resulting from accumulation of abnormal cells (+inflitration of tissues) leading to:

  • Bone pain
  • Hepatomegaly
  • Splenomegaly
  • Lymphadenopathy
  • Thymic enlargement
  • Testicular enlargement

And Resulting from crowding out of normal cells (ANT symptoms)

  • Anaemia casuing Fatigue, lethargy, pallor, breathlessness
  • Neutropenia: Fever and other features of infection
  • Thrombocytopenia: Bruising, petechiae, bleeding
614
Q

What are haematological findings in ALL?

A
  • Leucocytosis with lymphoblasts in the blood
  • Anaemia (normocytic, normochromic)
  • Neutropenia
  • Thrombocytopenia
  • Replacement of normal bone marrow cells by lymphoblasts
615
Q

What are general haematological findings that cause symptoms in Leukaemia?

A

•Crowding out of normal cells leading to

  • anaemia,
  • neutropenia,
  • thrombocytopenia

–> + associated symptoms

In CLL

  • loss of function of T+B-lymphocytes: loss or normal immune function
    *
616
Q

Explain the importance of immunophenotyping in ALL

A

It is important to determine the cause of the Leukaemia

  • B cell? T cell?
  • Done by flourescent analysis of cells (binding to CD factors of cells)
617
Q

When does Acute lymphblastic leukaemia usually occur?

What might protect you from developing ALL?

A

Main incidence in children

  • Protective: early exposure to common antigens
    • relates to family size, new towns, socio-economic class, early social interactions, variations between countries
618
Q

What might be causes of ALL in children?

A

Some (limited) evidence for:

  • Irradiation in utero
  • In utero exposure to certain chemicals ? Baygon, ? Dipyrone
  • ? Epstein–Barr virus infection

•Rarely any ALL results from exposure to a mutagenic drug

621
Q

Which investigations would you perform in someone you suspect having an ALL?

A
  • Blood count and film
  • Check of liver and renal function and uric acid (because of high DNA turnover)
  • Bone marrow aspirate
  • Cytogenetic/molecular analysis –> which type of ALL?
  • Chest X-ray (thymoid swelling)
623
Q

Explain the use of cytogenetic and molecular genetic analysis in ALL

A

Analysisng individual patient to determine prognosis

  • E.g. •Hyperdiploidy—good prognosis
  • •t(4;11) translocation—poor prognosis
624
Q

Which genetic factors often lead to the development of ALL?

A
  • Formation of a fusion gene (translocation) (9,22 Philadelphia and 12+21) –> production of abnormal intracellular proteins
    • can be detected via FISH analysis
  • Dysregulation of a proto-oncogene by juxtaposition of it to the promoter of another gene, e.g. a T-cell receptor gene (tranlocations)
  • Point mutation in a proto-oncogene
625
Q

Summarise the treatment in ALL

A
  1. Supportive treatment
    1. blood/platelet transplants if needed
    2. antibiotics in signs of infection
  2. Systemic chemotherapy
  3. Intrathecal chemotherapy –> otherwise poorer prognosis+ higher chance of return of disease (often vie LP)
626
Q

Recall the gross anatomy of the skin

A
  1. Epidermis
  2. Dermis
    1. separated by BM
  3. Hypodermis
628
Q

What are the differnet skin cancers that are derived from keratinoytes?

A

Overall called: Non-melanoma skin cancer

  1. Squamous Cell Carcinoma (SCC)
  2. Basal Cell Carcinoma (BCC)
629
Q

What kind of cancer is Melanocyte derived?

A

Malignant Melanoma

630
Q

Name a skin cancer that is lymphocyte derived

A

Mycosis fungoides

cutaneous T-cell lymphoma

631
Q

Which types of skin cancers are vasculature derived?

A

Overall: rare

  • Kaposi’s sarcoma, associated with HIV and HHV8
  • angiosarcoma
633
Q

Name different causes for skin cancer

A
  1. Genetic mutations
    1. Gorlin’s syndrome
      1. increases the risk of basal cell carcinoma
    2. xeroderma pigmentosum
      1. mutation in DNA mismatch repair
  2. Viral infections
    1. HHV8 in Kaposi’s syndrome
    2. HPV in SCC
  3. UV light
  4. Immunosupression
634
Q

What is the trend of the incidence of Malignantn melanoma?

A

It is increasing in the past years

  • expecially in white people (small change in other ethnicities)
635
Q

Explain the trend of the incidence of Basal cell carcinoma

A

Also increasing incidence

636
Q

Differentiate between the different types of UV light

A
  1. UVA
    • 100x higher exposure than UVB
    • contributes to skin ageing
    • might contribute to carcinogenesis
    • but also exploited therapeutically because of immunosupressant effects
  2. UVB
    • causes Cancer (most important in carcinogenesis)
  3. UVC
    1. absorbed in athmosphere
637
Q

Explain how UVB radiation causes cancer

A
  • Radiation directly causes mutations
    • causes formation of base dimers (thymine or cytosine dimers)
  • Normally repaired by nucleotide excision repair
638
Q

Explain how UVA radiation might cause cancer

A

Also promotes skin cancer by

  • formation of pyrimidine dimers (but less potentn than UVB)
  • formation of free radicals
639
Q

What are the possible outcomes to photodamaged cells?

A
  1. Apoptosis (e.g. in sunburn)
  2. DNA repair
  3. Carcinogenesis
640
Q

Explain the effect of UV light on the immune system

A

Influence immunity (UV ligh supresses immmune system)

  • Via:Change of immunoregulatory genes in epidermis
    • Depleting Langerhans cells in the epidermis
  • reduce immunocompetence and surveilance
    • used therapeutically e.g. in psoriasis (schuppenflechte)

–> Further increase in cancer risk

641
Q

What does the host response to UV light depend on?

A

Depeinging on different genetic influences, expecially skin phototype

642
Q

Where do melanocytes sit?

What do they do?

A

They ususally sit at the basement membrane in the epidermis

  • produce melanin as reaction to UV light exposure
643
Q

What kind of mutatins can cause skin cancer?

A
  1. Mutations that stimmulate uncontrolled proliferation
    • P53 mutation leading to abolished control of normal cell cycle
  2. Mutations that alter responses to growth factors/stimmulation
  3. Mutation interferin with apoptosis
644
Q

Explain the effect of sunburn on the skin

A

Sunburn causes Keratinocyte apoptosis –> release of inflammatory mediators

–> inflammation of the dermis

646
Q

What is the prognosis of someone with malignant melanoma?

A

Depending on the stage of the disease and spreading

  • measurement of granular layer to bottom of layer
    • <1mm: thin
    • 1-4 intermediate
    • >4mm thick

but overall:

possibility of metastasis

647
Q

What is a Lentigo maligna?

How would it usually look like?

A

A melanoma in situ

  • proliferation of melanocytes within the epidermis
  • non-invasive –> no risk of metastisis

Presentation

  • Irregular shape
  • Light & dark brown colours
  • Size usually >2.0 cm
649
Q

What are the characteristics of superficial spreading malignant melanoma?

A
  • Lateral proliferation of malignant melanocytes
  • Invade basement membrane
  • Risk of metastasis

Can be diagnosed via ABCD(E)

  1. Asymmetry
  2. Border irregular
  3. Colour variation (dark, brown)
  4. Diameter >0.7mm and increasing
  5. Erythema
650
Q

What are the characteristics of a nodular malignant melanoma?

A

•Vertical proliferation of malignant melanocytes

(no previous horizontal growth)

Risk of metastasis –> worst prognosis and most agressive form of melanoma

653
Q

Explain the production of Melanin

A

UV light exposure causes paracrine signaling from keratinocytes to melanocytes:

  • They produce Melainin
    • From tyrosine via a series of enzymes
  • Accumulates intracellularly in the Keratinocytes to protect the nucleus
654
Q

What are the different types of Melanin?

What determines which type you produce?

A
  • Eumelanin – brown or black
  • Phaeomelanin – yellowish or reddish brown

Dependant on present polymorphism on MCR1 gene

655
Q

What is a basal cell carcinoma?

What are its chracteristics, causes and usuall sites of occurence?

A
  • Malignant tumour arising from basal layer of epidermis
    • Caused
      • sun exposure
      • Genetics
  • Characteristics
    • Slow growing
    • Invades tissue, but does not metastasise
  • Common on face
  • offen appear “parly”: greyish, red colour with shiny and dialated capillary vessels on top
656
Q

What are the ususal causes and risk factors of malignant melanomas?

A

Causes:

  • UV exposure
  • Genetic factors

Risk factors:

  • family history
  • personal history
  • light skin type
  • UV radiation
  • sunburn durign childhood (burning is more critical than increased exposure to sun
659
Q

How do you call an invasive form of a Lentigo Maligna?

A

Lentigo Maligna Melanoma

662
Q

Name different types of malignant melanomas

A
  1. Lentigo Maligna (Melanoma
  2. Superficial spreading
  3. Nodular Melanoma
  4. Acral lentiginous
    1. slow horizontal growth
    2. often below feet
  5. Amelanotic
    1. no pigmentatin
663
Q

What are different causes of Squamous cell carcinoma?

A
  • UV exposure
  • HPV
  • Immunosuppression
  • May occur in scars or scarring processes
664
Q

What are squamous cell carcinomas?

What is its prognosis?

A

Malignant tumors of Keratinocytes

They might metastisis but lower risk than in melanomas

665
Q

What are common sites for Squamous cell carcinomas to occur?

A

They commonly occur on

  • generally sun-exposed skin
    • lips (worsening with smoking)
    • ears (expecially in men)
    • and legs of women
667
Q

What is mycosis fungoidis?

A

It is a cutaneous T-cell lymphoma

  • chronic disease, slow progression
668
Q

What is a Kaposi’s sarcoma?

A

Cancer of the endothelial cells of lymphatics

Associated with infections of HIV (AIDS) and HHV8 (Human Herpes Virus 8)

  • Form: nodules, plaques and flat lesions
669
Q

What is Epidermodysplasia veruciformis?

A

Rare autosomal recessive condition predisposition to HPV induced warts and SCCs

670
Q

What is the role of HPV in the development of SCC?

A

HPV infection is associated with increase in

  • cervical cancers
  • and caners in the head and neck region
    • In squamous cell carcinomas (e.g. oral scc)
671
Q

Summarize the epidemiology of prostate cancer

A
  • In the UK: highest incidence in cancer
  • 2nd commonest cause of cancer death (after lung)
672
Q

Which genetical components might be important in prostate cancer?

A

Not known yet but often

  • PTEN defect (TSG)
  • also something known in BRCA2 (TSG–> involved in DA repair)
673
Q

What are the symptoms of prostate cancer?

A

Prostatic hyperplasia

  • polyuira
  • problems with urination
  • RArer
    • lower back pain
    • blood in urine
    • in metastisis: bone pain
674
Q

Which organs does prostate cancer spread to?

A

Can metastasis or directly spread to

  • bladder
  • seminal vesicles
  • metastisis: lymph and bone
675
Q

What is PSA physiologically?

A

Polypeptide, which is part of the seminal fluid

(not found in blood)

676
Q

What does an increase in PSA show?

A

PSA: should only be found in seminal fluid

  • shows defect in basement membrane in the prostate but only shows some sort of prostate irritation. It could be
    • inflammation
    • rigous cycling
    • benign hyperplasia
    • prostate cancer
677
Q

What are further diagnostic test after someone presenting with a raised PSA and symptoms of prostate cancer?

A
  • Digital rectal exam
  • MRI scan
  • Biopsy + Grading (Gleason scoring) –> often not accurate
678
Q

What are the liminations of the GLeason scoring in prostate cancer?

A
  • often under or overestimates the cancer
  • not accurate, might miss things
  • Even if grading is correct:
    • no way of predicting weather is is slow growing (most men) or fast growing + metastatic (rarer)
679
Q

Whay is PSA testing not used as a screening test for prostate cancer?

A

Because its sensitivity + spcificity is too low and would be

  1. too expensive
  2. make little /no difference
  3. too many unnecessary tests and anxiety
680
Q

Which general treatment options for the treatment of prostate cancer are avialable

A
  1. “Active observation”, expecially in older patients with low grade
  2. Surgery (depending on age) + cancer only in prostate
    • side effects of incontinence and impotence
  3. Radiotherapy ( if tumor is only in prostate)
  4. Hormone Therapy
681
Q

Summarise the rationale behind Hormone Therapy in Prostate cancer

A

Normally: Prostatic growht is promoted by the pituitary

  1. GnRH analogue: overstimmlation of pituitary leading to desensitiation of pituitary LHRH receptors –> don’t respond to it anymore –> No LH+ FSH secretion –> no testicular androgens
    • Anti-androgen (for adrenal testosterone)
682
Q

What are the side effects of hormone therapy in prostate cancer?

A
  • osteoporosis
  • loss of libido
  • anaemia
  • muscle atrophy
  • memory loss
  • gynaecomastia
683
Q

Why can prostate cancers still grow despite haveing no ciruculating andrognes?

A
  1. Often: become “androgen independence”
    • become very sensitive to androgen, possible via
      • co-activation (overexpression of proteins that are required for androgen receptor signaling)
      • overexpression of androgen receptor
      • amplification of low levels of androgens
      • decrease of co-repressors
      • mutation of androgen receptor becoming sensitive to other steroids (e.g. oestrogen, anti-andrognes)
    • ligant-indipendant activvation of androgen receptor
    • bypass of androgen receptor pathway (PTEN loss)
684
Q

What are the drug names for the drugs used in prostate cancer treatment?

A
  1. LHRH analogut: Leuprorelin
  2. flutamide= anti-androgen
685
Q

What is the Role of PI3 Kinase and FOXO?

A

PI-3’-kinase phosphorylates PIP2 to PIP3 thus activating PDK1 and Akt/PKB

Akt phosphorylates FOXO transcription factors and inactivates it by moving the transcription factors to the cytoplasm –> no expression of negative cell cycle regulators p27Kip and apoptotic protein Fas ligand. FOXO is apoptotic and anti-proliferative, so the PI3-kinase cascade increases proliferation and reduces apoptosis.

686
Q

What are the effects of AKT (activated by PI3’-Kinase)

A
  • inactivates FOXO (pro-apoptotic)
  • AKT phoyphorylates BAD
  • inhibits caspase 9
    • Overall: anti-apoptotic!
687
Q

How does PI3’K promotes cell cycle progression?

A
  • it inacitvates GSK3b
    • normal function is to inactivate cyclins/CDK complexes leading to cell cylcle arrest

Year 2 MCD Cancer (17 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions