Cancer Flashcards

Question

What is a Lymphoma?

Answer 1

A malignant tumour of lymphocytes (usually) in lymph nodes --\> can normally be seen in the tissue

Answer 2

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

Answer 3

A Teratoma

Answer 4

1. In Males: almost always malignant 2. In Females: Most are benign

Answer 5

* 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,

Answer 6

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

Answer 7

The level of differentiation (high grade= low differentiation)

Answer 8

Stage of a tumor is how far the tumor has spread --\> TNM * Tumor * Node * Metastisis

Answer 9

1. High grade tumors tend to be high stage 2. BUT: stage is the most impoertant factor when it comes to prognosis!

Answer 10

* 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

Answer 11

* 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

Answer 12

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

Answer 13

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

Answer 14

* 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

Answer 15

Consists of two centrioles (barrels of nine triplet microtubules

Answer 16

* DNA replication * Replication of organelles (e.g. golgi, mitochondria, centromeres) * Increased protein synthesis

Answer 17

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

Answer 18

* condensation of DNA * centrosomes migrate to opposite sides in cell * spindels start to form

Answer 19

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)

Answer 20

* 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

Answer 21

* microtubule organizing center (MTOC) (also in interphase!!) * mitotic spindle

Answer 22

* Breakdown cohesin (protein that holds togehter sister chromatids) * Microtubules get shorter * Daughter chromosomes pulled toward opposite spindle poles

Answer 23

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

Answer 24

Chromosomes arrive at spindles Nuclear envelope resembels Assembly of contractile ring (for cytokinesis), made of actin and myosin

Answer 25

* CENP-E (signals when **not attached)** * BUB protein kinases (signals when **attached)** BUBs dissociate from kinetochore when chromosomes are properly attached to the spindle

Answer 26

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

Answer 27

* errors in DNA or centrosome replication * might lead to multipolar spindles * or in aberrant (irrtümliche) citokinesis

Answer 28

* 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.

Answer 29

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!!

Answer 30

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

Answer 31

They set of the signal cascade: * Response to extracellular factors * Signal amplification * Signal integration * Modulation by other pathways * Regulation of divergent responses

Answer 32

In present of a (dimeric) ligand--\> growth factors * Receptors form dimers * auto-crossphorylation causes activation of receptor * (phosphorylated AA in receptor)

Answer 33

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

Answer 34

Exchange of Hydroxy-group for a phosphate group (ATP dependant, katalysed by Kinase) Only 3 AA can be phosphorylated: * Serine * Threonine * Tyrosine

Answer 35

It causes receptor activation leading to * kinase cascade * binding of adaptor proteins

Answer 36

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

Answer 37

* Paired chromosomes separate to form two daughter chromosomes * Cohesin holds sister chromatids together * There is a anaphase A+ B

Answer 38

**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

Answer 39

Starts once MT are attached to Kinetochores * align at equator of spindles

Answer 40

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)

Answer 41

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

Answer 42

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

Answer 43

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

Answer 44

Epidermal growth factor (EGF) Platelet-derived growth factor (PDGF) --\> both bind to Receptor Protein Tyrosine Kinase (RPTK)

Answer 45

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**

Answer 46

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

Answer 47

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

Answer 48

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

Answer 49

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

Answer 50

Between Meta and Anaphase --\> Checks for Attachment of Telomeres

Answer 51

**Mitosis** because * Cells are more easily killed (irradiation, heat shock, chemicals) * DNA damage can not be repaired * Gene transcription silenced

Answer 52

initiation of translation and elongation increased; capacity is also increased

Answer 53

* 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

Answer 54

1. Surgery 2. Chemotherapy 3. Radiotherapy 4. Immunotherapy

Answer 55

* 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**

Answer 56

1. IV or PO administration 2. Non “targeted” – affects all rapidly dividing cells in the body --\> causes many of the side-effects

Answer 57

Neoajuvant

Answer 58

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

Answer 59

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

Answer 60

Alkylating agents

Answer 61

Pseudo-alkylating agents (add platinum group)

Answer 62

* hair loss (not carboplatin), * nephrotoxicity, * neurotoxicity, * ototoxicity (platinums) * nausea, vomiting * diarrhoea * immunosuppression * tiredness

Answer 63

Interfere with DNA synthesis by * Masquerade as purine or pyrimidine residues leading to * inhibition of DNA synthesis, * DNA double strand breaks * apoptosis

Answer 64

Anti-metabolites

Answer 65

* 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 *

Answer 66

* 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

Answer 67

Anthracyclines

Answer 68

* 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”)

Answer 69

Microtubule inhibiting drugs--\> leading to mitotic arrest in mitosis by 1. inhibiting assembly (vinca alkaloids) 2. disassembly (taxanes) of mitotic microtubules

Answer 70

Vinka alkaloids and taxanes

Answer 71

* Nerve damage: peripheral neuropathy, autonomic neuropathy * Hair loss * Nausea * Vomiting * Bone marrow suppression (neutropenia, anaemia etc) * Arthralgia (joint pain) * Allergy

Answer 72

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

Answer 73

Topoisormerase inhibitors Topotecan and irinotecan (topo I) and etoposide (topoII)

Answer 74

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

Answer 75

* 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

Answer 76

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

Answer 77

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)

Answer 78

Vascular Endothelial Growth Factor is overexpressed: prostate cancer, kidney cancer, breast cancer --\> leading to increased Kinase cascade and signal amplification --\> angiogenisis in cancer

Answer 79

Inhibit 2 protein kinases to prevent cancer cells switching to other pathways (which needs another kinase) But: are also more toxic

Answer 80

EGFR (lung cancer) epidermal growth factor receptor FGFR (head and neck cancers, myeloma) Leading to. Kinase cascade and signal amplification

Answer 81

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

Answer 82

Normall cells need growth factors to proliferate Cancer cells don't need them/ develop strategies to get higher stimmulation

Answer 83

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

Answer 84

They are normally designed to target + inhibit growth factor receptors

Answer 85

They are designes to stop the * Groth Factor receptor system * neutralise the ligand * inhibit dimerisation * cause internilisation * might induce phagocytosis + cytolysis

Answer 86

1. Monoclonal antibodies 2. Small molecule inhibitors

Answer 87

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

Answer 88

1. Single Stranded, DNA like molecole (17-22 nucleotides long) 2. Binds to target mRNA hinders translation of proteins by break down of mRNA

Answer 89

* SS complementary RNA * (lagging behind oligosense nucleotides)

Answer 90

**Resistance**

Answer 91

* 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

Answer 92

* -momab (derived from mouse antibodies) * -ximab (chimeric) e.g cetuximab * -zumab (humanised) e.g. bevacizumab trastuzumab * -mumab (fully human) e.g. panitumumab

Answer 93

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

Answer 94

1. Single Stranded, DNA like molecole (17-22 nucleotides long) 2. Binds to target mRNA hinders translation of proteins by break down of mRNA

Answer 95

* SS complementary RNA * (lagging behind oligosense nucleotides)

Answer 96

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

Answer 97

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

Answer 98

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)

Answer 99

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

Answer 100

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

Answer 101

_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

Answer 102

Growth factor receptor-bound protein 2 is an **adaptor protein**

Answer 103

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

Answer 104

1. Kinase * **RAF** 2. Kinase 1. **MEK** 3. Kinase 1. **ERK**

Answer 105

B-Raf is an oncogene - mutationally activated in melanomas

Answer 106

1. Change in protein activity 2. Change in gene expression

Answer 107

Cyclin-dependent kinases * always present in human cells but * only activated with **cyclins** and **phosphorylation**

Answer 108

Cyclins * only present at specific times in cell (often: mitosis) * regulated at the level of expression * synthesised and then quickly degraded

Answer 109

To bind to Cdks and activate them * quickly degraded so good as tightly control funciton in cell

Answer 110

They phosphorylate proteins (on Serine or Threonine) to drive cell cycle progression 1. during mitosis 2. to initiate mitosis

Answer 111

Regulated in 3 steps 1. Cyclin binding 2. Activating Phosphorylation by CAK (cdk activating kinase) 3. Removal of inactivating phosphorylation by cdc25

Answer 112

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)

Answer 113

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**

Answer 114

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

Answer 115

Example: inactivation of Rb protein by Cdk 4/6+ Cyclin D * Normally: Rb protein inhibits the transcription Factor E2F * Rb protein gets *progressively i*nhibited by Cdk4/6+ Cyclin D * --\> activation (disinhibition) of E2F * transcription of further molecules (e.g. cyclin E)

Answer 116

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

Answer 117

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

Answer 118

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

Answer 119

1. Unbinding + degradatio of cyclins 2. Cdk inhibitors (CKI)

Answer 120

it activates a protein kinase cascade more specifically: **Extracellular signal-regulated kinase (ERK) cascade**

Answer 121

1. Gneral Name= Mitogen-activated protein kinase (MAPK) cascades 2. RAS activates (or extracellular binding) **Extracellular signal-regulated kinase (ERK) cascade**

Answer 122

May result in cancer

Answer 123

* Cdk 4/6 + cyclin D initiate transtion from G0 to 1 Activated via * cyclin D expression is regulated via **c-Myc**

Answer 124

Proto-oncogenes * c-Myc * N-Myc Cell cycle genes * cyclins A+E * Cdk4, Cdk2 * E2F genes * Rb protein Many more+ DNA synthesis genes

Answer 125

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

Answer 126

Must be degraded + gene supression to allow cell cyclie progression

Answer 127

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

Answer 128

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

Answer 129

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.

Answer 130

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

Answer 131

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

Answer 132

* Deamination * other chemical modification * methylation * alkylation * adduct formation * photodamage

Answer 133

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

Answer 134

It can sometimes break the phospho-diester bonds--\> leading to gap in DNA * also used to find the site of damage and repair

Answer 135

1. Carcinogens * dietary * lifestyle * environmental * occupational * medical * endogenous 1. Radiation * ionizing * solar * cosmic

Answer 136

* 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

Answer 137

Aflatoxin B1-- \>formed by fungi on grains and peanuts * metabolism converts it into carcinogen * activation--\> highly reactive * adduct formation

Answer 138

Damage can lead to mutation --\> mutations can lead to cancer * damaging DNA is an important strategy in cancer therapy (might lead to apoptosis)

Answer 139

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

Answer 140

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

Answer 141

UV radiation might induce * Pyrimidine (thymine) dimers * mutation * melanoma

Answer 142

* 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

Answer 143

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)

Answer 144

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

Answer 145

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

Answer 146

scrutinisation of DNA for apposed bases that do not paired properly * only during replication/ new synthesation of DNA

Answer 147

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

Answer 148

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

Answer 149

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

Answer 150

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)

Answer 151

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

Answer 152

* 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

Answer 153

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

Answer 154

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

Answer 155

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!

Answer 156

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.

Answer 157

1. Base excision repair (BER) 2. Nucleotide excision repair (NER)

Answer 158

•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

Answer 159

p53 is a TSG that is normallly supressed by MDM2 * in cellular stress: p53 gets activated (trasncription factor) and acitvates DNA repair pathways

Answer 160

* **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**

Answer 161

Damages that are formed by UV light (dusruption of helical structure) * adducts (e.g. thymine dimers) * *

Answer 162

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

Answer 163

* unregulated cell death * normally due to trauma * there is cellular disruption * associated with inflammation (due to release of intracellular contents)

Answer 164

* programmed, regulated cell death * controlled dissembly of contents without membrane disruption * no inflammation * ATP dependant

Answer 165

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

Answer 166

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

Answer 167

1. Latent phase * apoptosis pahtways activated but no morphological change in cell 2. Execution phase * morphologican changes and destruction of cell

Answer 168

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

Answer 169

death pathways are activated, but cells appear morphologically the same

Answer 170

•Chromatin and nuclear condensation ## Footnote **• DNA fragmentation**

Answer 171

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

Answer 172

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

Answer 173

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

Answer 174

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

Answer 175

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

Answer 176

Cysteine-dependent aspartate-directed proteases **(Caspases)**

Answer 177

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

Answer 178

Are the executers of apoptosis 1. Get activated by cleavage (proteolysis) by another protease 2. Set of a cascade of other activators

Answer 179

* amplification of the apoptotic signal * divergent responses --\> spread responses * regulation

Answer 180

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

Answer 181

* adaptor Protein (FADD) will bind to FAS via the Death domain (they both have)

Answer 182

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

Answer 183

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**

Answer 184

It inhibits the activation of caspases competitevely * Binds to the DED ends of FADD * but has no proteolytic funtion--\> no caspase tetramer formation

Answer 185

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

Answer 186

Apaf-1 (Apoptotic activating factor-1), Cytochrome c, ATP, procaspase 9

Answer 187

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

Answer 188

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

Answer 189

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

Answer 190

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

Answer 191

Transmembrane receptors that all * form trimers when activated * have an intracellular DD (death domain)

Answer 192

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

Answer 193

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

Answer 194

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

Answer 195

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

Answer 196

PTEN can induce apoptosis by inhibiting the phosphorylation of PIP₂into PIP₃ (and thereby the pro survival(phosphoinositide 3 kinase (PI3K) ) signaling) * disinhibition of apoptosis

Answer 197

FLIP is an adaptor protein that binds to the death receptors and i**nactivates the apoptotic programm** * has only DED (Death effector domains)

Answer 198

A ligand (e.g. FAS-L on lmyphocyte) will bind to FAS --\> leads to receptor trimerisation --\> recruitement of adaptor protein

Answer 199

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

Answer 200

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

Answer 201

Bcl-2 Bcl-xL

Answer 202

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

Answer 203

They inactivate apoptosis inthe extrinstic pathway by: * Bind to procaspases and prevent activation * •Bind to active caspases and inhibit their activity

Answer 204

Mainly the pro survival Bcl-2 family proteins * Bcl-2, * Bcl-xL

Answer 205

* FLIP (competitively inhibits the activation of caspases) * IAPs Inhibitor of Apoptosis Proteins (directly inhibits caspase activation and already activated caspases)

Answer 206

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

Answer 207

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

Answer 208

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

Answer 209

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

Answer 210

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

Answer 211

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

Answer 212

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

Answer 213

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**

Answer 214

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

Answer 215

Binds to receptor on one cell that becomes the **tip cell** * **also gives direction of antiogenesis:** vessesl sprout towards the VEGF gradient

Answer 216

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.

Answer 217

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

Answer 218

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

Answer 219

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

Answer 220

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

Answer 221

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

Answer 222

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

Answer 223

It is released upon inflammatory stimmuli and antagonises the Tie2 receptor * blocks the effects of Ang-1: * increases vascular instability * promotes VEGF dependant angiogenesis

Answer 224

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

Answer 225

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))

Answer 226

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

Answer 227

secrete extracellular matrix; pro-angiogenic growth factors,

Answer 228

Mural cells (pericytes) help to stabilise the neovessels by modulation of the: via the **Angiopoietin/Tie-2 system**

Answer 229

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

Answer 230

* 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

Answer 231

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

Answer 232

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!

Answer 233

Needs vessels when it becomes larger than 1mm³

Answer 234

Tumor secretes angiogenic that stimmulate angiogenesis to tumor of adjacent vessels: --\> dependant on the hosts vasculature

Answer 235

Tumour blood vessels * **irregularl**y 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!

Answer 236

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)

Answer 237

1. Cancer-associated fibroblasts 2. Pericytes 3. Platelets

Answer 238

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)**

Answer 239

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

Answer 240

It is often highly expressed in Cancer: * might be inhibited to inhibits tumor angiogenesis --**\> Avastin** (Bevacizumab)

Answer 241

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

Answer 242

* 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

Answer 243

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

Answer 244

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!

Answer 245

1. Homeostasis (normal cells) 2. Genetic alteration 3. Hyper-proliferation --\> Benign 4. De-differentiation * dissasembly of cell-cell contacts * loss of polarity 5. Invasion * increase motility * cleavage of ECM proteins and basemsent membranes --\> Metastisis

Answer 246

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

Answer 247

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

Answer 248

They mimic normal morpholigical movements * as seen in angiogenesis * branching morphogenseis like in mamillary gland * etc.

Answer 249

Individual cell migration requires * integrins and proteases for Basememnt membrane cleavage

Answer 250

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

Answer 251

Important in signaling of movement 1. anchor the cell 2. Signaling: inform the cell about the composition of the ECM --\> influence behaviour of cell

Answer 252

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

Answer 253

They are organised in * straight, crosslinked actin filaments * fomed by * Polerymerisation * Bundling of actin filaments * Crosslinking of the filaments

Answer 254

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

Answer 255

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

Answer 256

It will become a polerised (in shape) cell

Answer 257

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

Answer 258

Often: * upregulation in cytoskeleton regulation * and machinery --\> Normally they don't have more oncogenic mutations but are just more mobile (EGF mouse experiment)

Answer 259

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

Answer 260

Arp complexes

Answer 261

Elongation * Controlled by * +: **profilin** * inhibited by thymosin

Answer 262

Normally due to external stimuli like * organogenesis and morphogenesis * wounding * growth factors/chemoattractants But can also happen in oncogenesis * dedifferentiation (tumor formation)

Answer 263

Capping * further elongation inhibited * done by proteins like: (also Arp protein involved)

Answer 264

Severing * enables quicker break down and reassembly of actin filaments (because chunks of actin are available, not jut monomeres)

Answer 265

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

Answer 266

Cross-linking and bundling of strands * functional dependant, many proteins can cross link e.g. * Bundling * Buckling if needed for contraction

Answer 267

Branching forms a stable network of actin filaments --\> needed in formation for Lemelipodia * 70° angle used Mediated by the **Arp complex**

Answer 268

A process of severing * a few actin filaments are cleaved to allow **movement** (sol-phase) from steady gel phase

Answer 269

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

Answer 270

Polymerization, disassembly, branching, capping

Answer 271

1. Polimerization 2. Bundling 3. Crosslinkin

Answer 272

Overall: Rho proteins * Folopodia: Cdc42 * Lamellipodia: Rac * Stress fibres: Rho

Answer 273

activated by * receptor tyrosine kinase * adhesion receptors * signal transduction pathways. --\> Cause GTP binding and therefore acivation (quick indactivation via phosphorylation)

Answer 274

* 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.

Answer 275

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

Answer 276

Controlls **stress fibres** therefore needed in 1. Adhesion 2. Translocation 3. De-adhstion of cell Via * tension and contraction of filamnents

Answer 277

Antiparralel strucztures actin filaments needed in cell migration --\> contraction of the cell

Answer 278

1. G Actin * monomers, get assemblied to 2. F Actin * polymers, assembly to different structures

Answer 279

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)

Answer 280

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

Answer 281

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

Answer 282

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

Answer 283

Rho proteins are a subfamily of small GTPases, belonging to the RAS superfamily They are needed in regulation of the cytoskeleton

Answer 284

They might be upregulated in differenet kind of cancers ## Footnote --\> more cytoskeletal activity

Answer 285

They are involved in the regulation of the Fillopodia and therefore needed for * regulation of the **polerized motility** * regulation of **actin polymerization**

Answer 286

Have a + and - end * different proteins can bind to the different ends * depending on the bound protein, fibres can have different functions

Answer 287

1. Chemical * hormones, Growth factors, ions, nutrinents, dissolved gases etc. 2. Physical * mechanical, temperature, stretch,

Answer 288

* •Growth factors * •Cell-cell adhesion * Cell-ECM adhesion

Answer 289

Binding to the extracellular matrix * Achorage dependance!

Answer 290

Cells need bindin to ECM (+ a degree of spreading of cells) for * **survival** * Protein synthesis and DNA replication * proliferation

Answer 291

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

Answer 292

Via binding of integrins * Special ECM receptors that can bind to many different ECM molecules * Link to cytoplasm * Contunitnity between cytoplasm and external environment

Answer 293

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

Answer 294

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

Answer 295

Integrins cluster togetheer to then form focal adhesions (sometimes can also form hemidesmosomes) * involved in signal transduction *

Answer 296

Integrins can undergo confirmational change and therefore change ability to 1. bind ligands 2. change the signaling pathway

Answer 297

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

Answer 298

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

Answer 299

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!

Answer 300

Bind to Actin (exeptino in epithelial cells--\> can also bind to intermediate filaments) Intracellularly via **actin binding proteins** * induce signal transduction intracellularly

Answer 301

When epitelial cells meet: * form stable junctions/cell-cell adhesions * leading to cell spreading to form stable mono-layers

Answer 302

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

Answer 303

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

Answer 304

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 an**d promotes gene transcription and cell proliferation 2. **Gets inactivated by APC complex**

Answer 305

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

Answer 306

* 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**

Answer 307

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

Answer 308

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

Answer 309

Happens when Cells are detached from ECM * membrane swells into several spherical bubbels Can end * apoptotic * Non-apoptotic = cell locomotion, cell division and stresses

Answer 310

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

Answer 311

1. Short term * normally non-epithelial cells * transient intercations, don't form stable junctions 2. Long term * normally epitheilial cells * stable cell-cell junctions

Answer 312

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

Answer 313

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

Answer 314

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**

Answer 315

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

Answer 316

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

Answer 317

Happens when Cells are detached from ECM * membrane swells into several spherical bubbels Can end * apoptotic * Non-apoptotic = cell locomotion, cell division and stresses

Answer 318

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

Answer 319

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

Answer 320

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

Answer 321

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

Answer 322

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.

Answer 323

It can convert into an oncogene * no longer responds to control influences * can be aberrantly expressed, over-expressed or aberrantly active

Answer 324

It gets activated at cellular damage * cellular stress * hypoxia * nitric oxide * oxidative stress * Damage * oncogene activation * Double strand breaks * Telomere erosion

Answer 325

Via inhibiton of MDM2 * Normally: MDM2 inhibits p53 activtiy * When activated: sets off repair mechanisms

Answer 326

It is a Tumor supressor gene * PTEN can induce apoptosis by inhibiting the phosphorylation of PIP2 into PIP3 (and thereby the pro survival signaling)

Answer 327

1. Transcription factors * c-Myc * JUN 2. RAS, raf --\> activation of kinase cascade 3. Tyrosin kinases * SRC --\> Leading to permanent activation of proliferation!

Answer 328

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

Answer 329

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.

Answer 330

BRCA is a tumor supressor gene normally * repairing DNA damage * often mutated in Breast cancer

Answer 331

1. PTEN 2. p53 3. BRCA 4. APC

Answer 332

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

Answer 333

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)

Answer 334

It increases * due to more access to healthcare (+ more testing) * ageing * not diing from other causes

Answer 335

It overall decreases due to * earlier diagnosis * better therapies

Answer 336

It increases

Answer 337

Only 5-10% are hereditary * people e.g. inhierit a defect TSG and only need one more hit to develop cancer

Answer 338

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

Answer 339

16% cases of cancer likely caused by infectious agents worldwide * 25% in Africa * \<10% in Europe (1 in 33 in UK)

Answer 340

* 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

Answer 341

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

Answer 342

1. Breast 2. Lung 3. Colorectal 4. Cervical 5. Stomach

Answer 343

1. Lung 2. Prostate 3. Colorectal 4. Stomach 5. Liver

Answer 344

1. Lung 2. Liver 3. Prostate 4. Colorectal 5. Stomach

Answer 345

1. Breast 2. Colorectal 3. Lung 4. Prostate 5. Bladder

Answer 346

1. Lung 2. Colorectal 3. Pancreas 4. Breast 5. Stomach

Answer 347

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

Answer 348

Mainly: post-menopausal women * 1/5 of all female cancer deaths * 1/9 of women will get breast cancer * increasing incidence but decreasing mortality

Answer 349

The incidence is increasing

Answer 350

The mortality is decreasing due to * Early Diagnosis * Better therapies * Chemo/Radiotherapies * Hormonal Therapies

Answer 351

Normally Carcinomas! (epithelial tissues of ducts) but might be: * e.g. Sarcoma of fatty tissue (rare but agressive)

Answer 352

The ductural epithelium surrounds the ducts consisting of 2 layers 1. Luminal epithelium (inner layer) 2. Outer Myopithelial cells 1. contract during milk ejection

Answer 353

The luminla (inner layer) epithelial cells

Answer 354

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

Answer 355

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

Answer 356

It is done by histological staining with antibodies against human Estrogen Receptor (ER) * 80% of IDCs (infiltrating ductal carcinomas) are ER positive!

Answer 357

It is an steroid (intracellular) receptor * Estrogen binds to it and releases hsp90 * Causing dimerisation of ER * Travel into cell and alter DNA transcription

Answer 358

Normally upregulates pro- proliferative and anti-apoptotic factors * upregulation of Progesterone Receptor (PR) * Cyclin D1 * c-myc * TGF-a

Answer 359

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

Answer 360

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

Answer 361

Normally 1. Surgery * remove the tumor 2. Adjuvant therapy --\> kill everything that is left behind) * radiotherapy * chemotherapy * endocrine therapy

Answer 362

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

Answer 363

* It increases the riks of thrombosis/embolisms * It stimmulates growh of the endometrium --\> endrometrial cancer * increased frequency of cataracts

Answer 364

Aim: to reduce Estrogen production in pre-menopausal women 1. Ovarin ablation * surgical oophorectomy * Ovarian Irradiation 2. Supress production of LH/FSH

Answer 365

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

Answer 366

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

Answer 367

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.

Answer 368

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

Answer 369

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

Answer 370

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

Answer 371

Mainly in fatty tissue --\> breast is a fatty tissue But also in * liver * muscle

Answer 372

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

Answer 373

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)

Answer 374

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)

Answer 375

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

Answer 376

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

Answer 377

An adenoma is a benign neoplasm of the mucosal epithelial cells

Answer 378

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

Answer 379

* 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

Answer 380

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

Answer 381

* **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

Answer 382

* 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

Answer 383

**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*

Answer 384

Because it is the gene that turns off ongoing proliferation in the crypts --\> in colon proliferation is needed all the time!

Answer 385

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

Answer 386

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

Answer 387

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

Answer 388

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

Answer 389

Autosomal recessive condition that leads to imparied mitssmatch repair and therefore to increased microsattelite instability --\> Inherited high risk of cancer

Answer 390

It has a hugh influence. Increased risk if * western diet (high temperature red meat) * high fat * low fibre * refined carbohydrates * Dietarey deficiencies

Answer 391

Red flags: * **Change in bowel habit** * **Bleeding PR** * **Unexplained Iron deficiency anaemia** + * Mucus PR * Bloating * Cramps (‘colic’) * Constitutional (weight loss, fatigue)

Answer 392

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

Answer 393

FOB/FIT kit * detects blood in stool

Answer 394

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**

Answer 395

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**

Answer 396

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**

Answer 397

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

Answer 398

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

Answer 399

–Acute lympho**blastic** leukaemia (ALL) –Chronic lympho**cytic** leukaemia (CLL)

Answer 400

Acute/Chronic myeloid leukaemias

Answer 401

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

Answer 402

Some inherited mutations e.g. in * down syndrome * defects in DNA repair etc. Or exposure to * Irradiation * Anti-cancer drugs * Cigarette smoking * Chemicals—benzene

Answer 403

, 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**

Answer 404

* 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

Answer 405

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

Answer 406

* cell kinetics and funcitons are not as seriously affected as in AML * BUT: reduced apoptosis and increase proliferation --\> slow progression of leukaemic clones ## Footnote **Increased production of end cells**

Answer 407

* •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

Answer 408

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

Answer 409

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) * **A**naemia casuing Fatigue, lethargy, pallor, breathlessness * **N**eutropenia: Fever and other features of infection * **T**hrombocytopenia: Bruising, petechiae, bleeding

Answer 410

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

Answer 411

•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 *

Answer 412

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)

Answer 413

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

Answer 414

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

Answer 415

* 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)

Answer 416

Analysisng individual patient to **determine prognosis** * E.g. •Hyperdiploidy—good prognosis * •t(4;11) translocation—poor prognosis

Answer 417

* 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

Answer 418

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)

Answer 419

1. Epidermis 2. Dermis 1. separated by BM 3. Hypodermis

Answer 420

Overall called: Non-melanoma skin cancer 1. Squamous Cell Carcinoma (SCC) 2. Basal Cell Carcinoma (BCC)

Answer 421

Malignant Melanoma

Answer 422

Mycosis fungoides cutaneous T-cell lymphoma

Answer 423

Overall: rare * Kaposi’s sarcoma, associated with HIV and HHV8 * angiosarcoma

Answer 424

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**

Answer 425

It is increasing in the past years * expecially in white people (small change in other ethnicities)

Answer 426

Also increasing incidence

Answer 427

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

Answer 428

* Radiation directly causes mutations * causes formation of base dimers (thymine or cytosine dimers) * Normally repaired by nucleotide excision repair

Answer 429

Also promotes skin cancer by * formation of pyrimidine dimers (but less potentn than UVB) * formation of free radicals

Answer 430

1. Apoptosis (e.g. in sunburn) 2. DNA repair 3. **Carcinogenesis**

Answer 431

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

Answer 432

Depeinging on different genetic influences, expecially skin phototype

Answer 433

They ususally sit at the basement membrane in the epidermis * produce melanin as reaction to UV light exposure

Answer 434

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

Answer 435

Sunburn causes **Keratinocyte apoptosis** --\> release of inflammatory mediators --\> inflammation of the dermis

Answer 436

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

Answer 437

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

Answer 438

* 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

Answer 439

•Vertical proliferation of malignant melanocytes (no previous horizontal growth) **Risk of metastasis --\> worst prognosis and most agressive form of melanoma**

Answer 440

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

Answer 441

* Eumelanin – brown or black * Phaeomelanin – yellowish or reddish brown Dependant on present polymorphism on **MCR1 gene**

Answer 442

* 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

Answer 443

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

Answer 444

Lentigo Maligna Melanoma

Answer 445

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

Answer 446

* UV exposure * **HPV** * Immunosuppression * May occur in scars or scarring processes

Answer 447

Malignant tumors of Keratinocytes They might metastisis but lower risk than in melanomas

Answer 448

They commonly occur on * generally sun-exposed skin * lips (worsening with smoking) * ears (expecially in men) * and legs of women

Answer 449

It is a cutaneous T-cell lymphoma * chronic disease, slow progression

Answer 450

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

Answer 451

Rare autosomal recessive condition predisposition to HPV induced warts and SCCs

Answer 452

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)**

Answer 453

* In the UK: highest incidence in cancer * 2nd commonest cause of cancer death (after lung)

Answer 454

Not known yet but often * PTEN defect (TSG) * also something known in BRCA2 (TSG--\> involved in DA repair)

Answer 455

Prostatic hyperplasia * polyuira * problems with urination * RArer * lower back pain * blood in urine * in metastisis: bone pain

Answer 456

Can metastasis or directly spread to * bladder * seminal vesicles * metastisis: lymph and bone

Answer 457

Polypeptide, which is part of the seminal fluid (not found in blood)

Answer 458

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

Answer 459

* Digital rectal exam * MRI scan * Biopsy + Grading (Gleason scoring) --\> often not accurate

Answer 460

* 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)

Answer 461

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

Answer 462

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

Answer 463

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 2. + Anti-androgen (for adrenal testosterone)

Answer 464

* osteoporosis * loss of libido * anaemia * muscle atrophy * memory loss * gynaecomastia

Answer 465

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)

Answer 466

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

Answer 467

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.

Answer 468

* inactivates FOXO (pro-apoptotic) * AKT phoyphorylates BAD * inhibits caspase 9 * Overall: anti-apoptotic!

Answer 469

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