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MHD - Exam 1 > MHD - Lecture 8 & 9 - Neoplasia II and III > Flashcards

MHD - Lecture 8 & 9 - Neoplasia II and III Flashcards

1
Q

Fundamental principles of cancer:

Cancer is a genetic disorder caused by ______

Most mutations ______or induced by environmental insults

Some mutations are _____in the germ line

Cancer arises from clonal expansion of a ______cell that has incurred damage

A
  1. DNA mutations
  2. spontaneous
  3. inherited
  4. single progenitor
    - (monoclonal)
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2
Q

A study is performed to analyze characteristics of malignant neoplasms in prostate bopsy specimens.
The biopsies were performed on patients who had palpable mass lesions on digital
rectal exam. Of the following microscopic findings,
which best indicates that the neoplasm is malignant?

Cellular pleomorphism
cellular atypia
invasion
increased nuclear to cytoplasmic ratio
necrosis
A

INVASION

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3
Q

A 33 year old woman had a nodule on the dome of uterus seen on ultrasound. siz years later ultrasound shows it is about twice the
size solid and circumscribed. which of the following neoplasms does she have?

adenocarcinoma
leiomyoma
adenocarcoma
metastases

A

Leiomyoma

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4
Q

What are the 4 target regulatory genes of cancer?

A
  1. Growth promoting proto-oncogenes
  2. Growth inhibiting tumor suppressor genes
  3. Genes that regulate apoptosis
  4. Genes involved in DNA repair
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5
Q

What do proto-oncogenes do? What are they?

What are oncogenes? What do they encode?

Do oncogenes require a dominant or recessive mutation to incur cellular transformation?

A

Drive cell growth
1. interaction between growth cytokines & ligands
cyclins and CDK are the workforces that allow things to progress through the cell cycle
2. Normal cellular genes whose products promote cell proliferation

3.ONCOGENES = mutant or over-expressed versions of normal proto-oncogenes

  1. Function autonomously
    Encode transcription factors, growth regulating proteins, cell survival proteins*
    Lost dependence on normal growth promoting signals
    Potent carcinogenic factors
  2. DOMINANT
    - only need 1 allele knocked out
    - heterogenous change
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6
Q

State the gene product and associated tumor for the following:

  1. ABL
  2. C-MYC
  3. ERB2
  4. RAS*
  5. L-Myc
  6. RET
  7. C-KIT
A
  1. ABL - tyrosine kinase - CML
  2. C-MYC - TF - Burkkit Lymphoma
  3. ERB2 - Tyrosine Kinase - Breast, ovarian, gastric carcinoma
  4. RAS* - GTPase - colon, pancreatic carcinoma
  5. L-Myc - TF - Lung cancer
  6. RET - tyr kinase - MEN
  7. C-KIT - Cytokine Receptor - GI stromal tumor
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7
Q

What is the most commonly mutated proto-oncogene in human tumors?

What is it bound in an inactive state? active?

Activation of this proto-oncogene forces what?

A
  1. RAS
  2. inactive = GDP
    active = GTP
    -Mutations interfere with GTP hydrolysis trapping RAS in its activate GTP bound form.
  3. Active RAS stimulates cell into contiously proliferating G1-S phase
    • ability to get turned OFF is gone
  • so constantly sending signals to cyclins & CDKs
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8
Q

What is the function of tumor suppressor genes?

For tumor suppressor genes, is this recessive or dominant?

A
  1. Normally prevent uncontrolled growth
    Mutation (or loss) leads to transformed cell
  2. RECESSIVE
    - both alleles must be damaged
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9
Q

What are the 4 most common tumor suppressors? (2 will be tested)

What is the associated tumor?
(ex: Li fraumeni syndrome, Retinoblastoma, osteosarcoma, breast, ovarian, both)

A
  1. Rb
    - blocks G1-S phase of cycle
    - Retinoblastoma
    - osteosarcoma
  2. p53
    - blocks G1-S phase cell cycle
    - LI FRAUMENI syndrome
  3. BRCA1
    - DNA repair protein
    - breast/ovarian cancer
  4. BRCA2
    - Dna repair protein
    - Breast cancer
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10
Q

What is the 1st tumor Suppressor discovered and is the basis of Knudson’s 2 Hit Hypothesis?

What are the symptoms of retinoblastoma? Median age of presentation?

Origin?

A

Rb!

  1. Intra-ocular neoplasms of children
    - present at age 2
    (poor vision, strabismus, whiteish hue to pupil)
  2. Neuronal Origin
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11
Q

Where does Retinoblastoma appear?

What is the characteristic histological finding?

A
  1. Optic nerve
  2. Rosette + lots of mitotic figures
    - little flowers
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12
Q

Rb controls the G1 to S transition of the cell cycle.

In its active form Rb is ______and binds to E2F transcription factor.

This interaction _____transcription of genes, like cyclin E (cyclins are proteins that regulate progression through the cell cycle), that are needed for DNA replication.

The cells are therefore arrested in _____

When is E2F released? .

RB mutation results in what?

Sporadic RB mutations are characterized by _____retinoblastomas.

Germline RB mutations are characterized by ______ retinoblastomas as well as primary bone malignancies called osteosarcomas.

A
  1. hypophosphorylated (unphosphorylated)
  2. prevents
  3. G1.
  4. E2F is released when RB is phosphorylated by the cyclinD/cyclin-dependent kinase 4 (CDK4) complex
  5. constitutively free E2F allowing progression through the cell cycle and uncontrolled cell growth.\
  6. unilateral
  7. bilateral= familial
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13
Q

What is the gaurdian of the genome and most commonly mutated gene in cancers?

What are the 3 results of this gene in the face of STRESS?

A

p53

  1. Activates temporary cell cycle arrest (quiescence)
  2. Induces permanent cell cycle arrest (senescence)
  3. Triggers programmed cell death (apoptosis)
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14
Q

If DNA damage is incurred, p53 is activated and binds to DNA –> what gene ultimately drives apoptosis?

What gene is a CDk inhibitor that after a signal by p53 can arrest the cell in G1?

A

BAX DRIVES APOPTOSIS

p21 (CDK inhibitor)

DNA damage: p53 not activated  no cell cycle arrest, no DNA repair, no senescence = MUTANT CELL

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15
Q

Li-Fraumeni syndrome:

Patients inherit one defective copy of _____in the germline

A
  1. p53
    - One additional “hit” —-

double hit = 25x greater risk of developing cancer by age 5
Sarcomas, breast cancer, leukemia, brain tumors, adrenal cortex carcinomas, multiple primary tumors

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16
Q

Apoptosis is mediated by _____which activate proteases which break down the cell cytoskeleton and endonucleases that break down DNA

These genes may be activated by what 2 pathways?

A
  1. caspases
    a) Intrinsic mitochondrial Pathway
    b) Extrinsic receptor ligand pathway
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17
Q

Of the following genes which are pro-apoptotic and which are ANTI apoptotic?

  1. Bcl-2,
  2. BCL- x
  3. BAX
  4. BAK
A
  1. Anti-apoptotic
    BCL-2, BCL-XL
  2. Pro-apoptotic
    BAX, BAK
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18
Q

Intrinsic mitochondrial pathway:

DNA damage leads to inactivation of _____ which normally stabilizes the mitochondrial membrane blocking release of cytochrome c.

Disruption of this gene allows what to leak out from inner mitochondria matrix into the cytoplasm?

What is then activated?

A

1, BCL2

  1. BLC2
  2. Cytochrome C
  3. Caspapses are activated –> initiate APOPTOSIS

**BCL2 is overexpressed in follicular lymphomas.

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19
Q

Extrinsic receptor ligand pathway:

FAS ligand binds to the ______ on the target cell, activating what? Responsible

A

FAS death receptor (CD95)

  1. caspases

**Responsible mechanism for elimination of self-reactive lymphocytes **

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20
Q

Which mechanism: Fas ligand or intrinsic mitochondrial pathway is responsible for elimination of self-reactive lymphocytes?

A

Extrinsic death receptor pathway (FAS)

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21
Q

What happens if BCl-2 is activated by a translocation? (will apoptosis be on or off?)

What disease is associated with a translocation of t14–>18 between heavy chain and the bcl gene? (heavy chain is 14)

A
  1. Perpetuation of “anti-apoptosis”
  2. turned off ability of
    cell to undergo apoptosis
  3. FOLLICULAR B CELL LYMPHOMA
    - b cells that would normally undergo apoptosis during somatic hypermutation in lymph node germinal center accumulate = lymphoma

(due to stabilization of mitochondrial membrane)

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22
Q

What is palbociclib?

A

Palbociclib  inhibitor inhibitor of CDK4

regulate proliferation of lumenal cells in breast

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23
Q

What is the function of BCl2?

What does it block?

A
  1. stabilizes the mitochondrial membrane

2. blocks release of cytochrome C

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24
Q

Neoplasms need what 3 things to occur in order for a malignant cancer to develop?

A
  1. Neoplasms Develop Limitless Replicative Potential
    - via telomerase*
  2. Neoplasms Develop Sustained Angiogenesis
    (VEGF, PDGF, Insulin like growth factor)
  3. Malignant neoplasms develop the ability to evade, invade, and metastasize
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25
Q

The following describes what:

  1. short repeat sequences of DNA
  2. w/ each somatic cell duplication they shorten
  3. DNA ends appear “broken”
  4. Cell cycle arrest
A

TELOMERES

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26
Q

What stabilizes telomere length? Cancers have more or less of this?

A

“Telomerase” – stabilizes telomere length

- Cancers often have upregulated telomerase which leads to cellular “immortality”.

27
Q

What growth factors are necessary for angiogenesis seen in neoplasms

A
  1. VEGF
    - Hypoxia inducible factor (HIF-1a) is a transcription factor which increases VGEF production.
  2. IGF - 1
  3. PDGF
  • produced by tumor cells
28
Q

What is Von Hippel Lindau (VHL)? What does it inhibit?

What happens when VHL is lost?

A

Von Hippel-Lindau (VHL) is a tumor suppressor gene which inhibits HIF-1a.

(Hypoxia inducible factor (HIF-1a) is a transcription factor which increases VGEF production.)

When VHL is lost it leads to the increased developed of VGEF.

29
Q

Which factor is an inducer of angiogenesis?

Which is an inhibitor

A

VEGF - inducer
- Hypoxia inducible factor (HIF-1a) transcription factor
Von Hippel-Lindau (VHL) suppressor (suppresed by VHL gene)

–> when VHL is lost = increased developed VEGF
= associated with renal cell carcinoma

INHIBITOR = Thrombospondin 1 (TSP-1)

30
Q

Malignant Neoplasms have the Capability to Metastasize:

  1. Epithelial tumor cells are normally attached to one another by cellular adhesion molecules such as ______.
  2. Downregulation of #1 leads to what?
  3. Cells attach to ______ and destroy/degrade the basement membrane (key component is collage type IV) via what?.
  4. Cells attach to _____in the extracellular matrix and spread locally.

RESULT?
.

A
  1. E-cadherin
  2. dissociation of attached cells
  3. laminin
    - collagenase
  4. fibronectin

Cells invade the vascular and/or lymphatic spaces which allows for metastatic spread

31
Q

What are the 3 MAIN steps in metastasis (general)

A
  1. Intravasate
    (break through BM, enter lumen, interact w/ lymphoid cells & evade check & balance)
  2. Homing
    - metastasize to certain cells
    (ex: prostate & bone)
  3. Extravasate
    - angiogenesis
    - new growth factors
32
Q

What mediates the adhesion of epithelial cells and is LOST in invasion by cancerous cells?

What is degraded next? By what?

What do these cells attach to?

What is the final step?

A

E-Cadherin

Basement membrane (Type4) by Collegenase

Attach to ECM proteins by fibronectin

MIGRATION of cells through degraded BM

33
Q

Tumors start out as monoclonal or polyclonal?

What do subclones arise from?

A
  1. Monoclonal
  2. Arise from descendants of the original transformed cell by multiple mutations

With progression, the tumor mass becomes enriched for variants that are more adept at evading host defenses and are likely to be more aggressive

34
Q

What are the 3 main carcinogenic agents?

A

Carcinogens are agents that inflict genetic damage – damage DNA

  1. Chemicals
  2. Radiant Energy
  3. Microbial Agents (viruses & bacteria
35
Q

What are direct acting Chemical carcinogens?
(example 1)
Indirect Chemical carcinogens? (example - 3)

A

Direct: Require no metabolic conversion
ie Cancer chemotherapeutics (alkylating agents)
- chemo kills bone marrow producing cells
- can develop new cancers unrelated to original cancer (leukemia/lymphoma)

2. Indirect Acting:
Require metabolic conversion to become ultimate carcinogens
- PCB (polycyclic hydrocarbons)
-animal fats
-Aromatic amines
-azo dyes
36
Q

Susceptibility to cancer after exposure to indirect carcinogen depends on what?

A

allelic form of enzyme inherited

37
Q

What is a chemical promoter?

How is uterine cancer related?

A

Compounds, themselves nontumorigenic, which facilitate the induction of cell proliferation (clonal proliferation)

“initiation- promotion” sequence

Some chemical carcinogens may act in concert with viruses or radiation to induce neoplasias

ex: uterine cancer: obese women with increased circulating estrogens, women taking exogenous estrogens
ESTROGENS THEMSELVES NOT CANCEROGENIC = promoter

endometrial cancer have key gene mutated, and if exposed to estrogen will develop cancer (proliferation of endometrium by estrogen)

38
Q

What cancer do the following toxins cause?

  1. Vinyl chloride
  2. Nitrosamine (smoked meats)
  3. Asbestos
  4. Arsenic
  5. Naphthalene Dyes
  6. Aflatoxin B
A
  1. Vinyl chloride - Angiosarcoma
  2. Nitrosamine - Gastric cancer(smoked meats)
  3. Asbestos - MESOTHELIOMA, BRONCHOGENIC CARCINOMA
  4. Arsenic - Squamous Cell Carcinoma (makes skin white)
  5. Naphthalene Dyes - Urothelial Carcinoma
  6. Aflatoxin B - Heptaocellular carcinoma
39
Q 
The following are examples of what?
Sunlight - ultraviolet radiation
X-rays			
Nuclear fusion/ Ionizing Radiation
Fission by-products 	
Radionucleotides
A

Radiation Carcinogenesis

40
Q

What are the mechanisms of action for the following radiation carcinogenesis?

  1. Ionizing radiation
  2. UV light
A
  1. Ionizing radiation
    - chromosome breakage, translocations, point mutations
  2. UV light
    - damages DNA by forming pyrimidine dimers
    - normally repaired by NER

cancers: skin squamous cell, basal cell, melanoma
2. UV light

41
Q

The following describes what type of carcinogenesis:

  1. long latent period
  2. initiation is IRREVERSIBLE
  3. Continued exposure is additive
A

RADIATION

ex: Early radiologists - (skin cancer, leukemia)
Fair skinned people/sun rays - (skin cancer)
Miners of uranium - (lung cancer)
Atomic bomb survivors - (leukemia)
Therapeutic irradiation - (thyroid cancer)
Patients getting multiple diagnostic radiologic scans

42
Q

What is an autosomal recessibe syndrome of defective DNA repair?

  • defect is in NER (nucleotide excision repair)
  • Due to pyrimidine dimers
A

XERODERMA PIGMENTOSUM

43
Q

What are some examples of Microbial oncogenesis in the following:

  1. RNA
  2. DNA
  3. Bacteria
A
  1. RNA =
    HTLV - 1 (human T cell lymphotropic virus)
  2. DNA:
    a) HPV –> causative of cervical cancer
    b) Epstein Barr Virus (EBV) = Burkitt lymphoma, nasopharyngeal carcinoma

c) Hepatitis B & C virus
- hepatocellular carcinoma

  1. BACTERIA:
    H. Pylori
    - Gastric adenocarcinoma, MALT lymphoma
44
Q 
HTLV-1 infects many T cells and 
initially causes \_\_\_\_\_
proliferation by autocrine and 
paracrine pathways triggered by 
the TAX gene.

What is the function of TAX?

What is the result of one proliferating T cell suffering additional mutations?

A

polyclonal

  1. TAX neutralizes growth inhibitory signals by affecting TP53 and CDKN2A/p16 genes
    - ultimately a monoclonal T cell leukemia/ltymphoma results when one proliferating T cell suffers additional mutations
45
Q

HPV affects the activity of what tumor suppressor gene?

A

p53

46
Q

How does our immune system recognize tumor antigens?

What are the 3 anti - tumor mechanisms?

A

T cells!

  1. Cytotoxic T lymphocytes = primary ANTI - TUMOR cell
  2. NK cells
  3. Macrophages
    -check to proliferation of cancer OR
    secrete growth stimulator to propagate cancer
47
Q

What patients are at an increased risk of cancer development?

A

Immunosuppressed

  • congenital immune deficiencies
  • transplant recipients
  • AIDs
48
Q

What are 4 ways cancers can evade the Immune system?

A
  1. Eliminate strongly immunogenic subclones
  2. Fail to express HLA class I, escape CTL attack
  3. Tumors can Suppress host immune response
    a) Secrete TGF-b
    b) Express FasL  extrinsic apoptosis
    c) Activate regulatory T cells
  4. Produce thicker coat of glycocalyx molecules blocking access to immune cells
49
Q

What is the function of Ipilimab?

A

Blocks CTLA - 4 to promote anti-tumor immunity

50
Q

What are the effects of tumor (neoplasia) on the host?

A
  1. Location
    Compress adjacent structures (both benign & mailgnant  ex: the brain)

b) Ulcerate through surfaces

  1. Hormone production
    Endocrine glands  tumors can produce hormones & develop increased amounts of hormones
    ex: insulinoma = tumor of pancreas
51
Q

What is cancer cachexia?

What mediates this?

A

Clinical aspect of neoplasia

Loss of body fat, lean body mass
Weakness, anorexia, anemia

  • Cytokine mediated**
  • TNF
  • Proteolysis inducing factor

*No satisfactory treatment if neoplasm cannot be removed

52
Q

What are paraneoplastic syndromes?

Example?

A

Symptom complexes that cannot be readily explained by local or distant spread
 not producing anything inherent to parent tissue
Hormone elaboration not indigenous to tumor parenchyma

  • Cushing Syndrome
    from small cell carcinoma of lung
  • Hypercalcemia from PTHrP from squamous cell of lung
  • Myasthenia Gravis associated with thymomas
53
Q

The following parameters are used to assess what?

a) . Degree of cellular differentiation
b) . Degree of cellular pleomorphism
c) . Degree of loss of normal architecture
d) . Mitotic index

A

GRADING

-Based on cytologic differentiation of the tumor cells, an attempt is made to estimate the aggressiveness of the tumor.

54
Q

What is anaplasia?

A

Based on cytologic differentiation of the tumor cells, an attempt is made to estimate the aggressiveness of the tumor.

55
Q

Sarcoma is a malignant ____ cell

A

Mesenchymal cell

56
Q

What is used more often, staging or grading?

What is staging based on? (3)

A

STAGING
-Few cancers where grading has shown particular relevance
Prostate Cancer
Chondrosarcoma (cartilage)

T - size of tumor (T4>T1)
N - lymph node spread (N0 = none, N3= distant)
M - metastasis present or absent (M0 or M1)

57
Q

What contributes significantly to diagnosis of cancer?

A

C1. linical data invaluable for optimal pathologic diagnosis
HPI, social hx, family hx, ROS, PE

2.Radiologic studies contribute significantly (endoscopic)

  1. Tissue Sampling:
    Should be adequate and representative of lesion
    Excision, biopsy, fine-needle aspiration, cytology smears
58
Q

The following are what:

  1. Histologic studies
  2. IHC
  3. Biochemistry studies
  4. Ultrastructural studies
  5. Molecular Biology studies
A

methods aiding diagnosis

59
Q

Examples:

  1. epithelial neoplasms stain positive for ___;
  2. mesenchyme stains positive for ____
  3. prostatic epithelium stains positive for ___
  4. melanoma stains positive for ____
A
  1. keratin
  2. vimentin
  3. PSA
  4. S-100
60
Q

Cancer arising from EPITHELIUM, can use IHC and an antibody for what?

A

Anti - Cytokeratin stain

61
Q

In biochemical studies, markers are generally more valuable for detecting ___ of disease rather than primary diagnosis.

The following can be detected with what:

  1. Liver carcinomas
  2. Tumor of yolk sac remnants
  3. Gonadal tumors

What about:
Colon, Pancreas, Lung, Stomach, Breast

A

RECURRENCE

  1. Alpha -fetoprotein (AFP)
  2. Carcinoembryonic antigen (CEA)
62
Q

What are the 8 steps of carcinoma formation

A

If we have a tumor w. normal epithelium
hyperproliferative  why? lost cellular growth checkpoints
develop adenoma (hyperplastic epithelium)
becomes dysplastic due to DNA hits
mutation of RAS gene
more dysplastic adenoma
more oncogene/tumor suppressor hits = LATE ADENOMA
FINAL HIT = LOSS OF P53  loss of check & balance
ADENOMA BECOMES CARCINOMA

63
Q

What is the most important point about cancers made in lecture?

A

MULTI STEP PROCESS

  1. telomerase
  2. angiogenesis involved
  3. mutation of tumor suppressor or protooncogene
64
Q

In an experiment it is observed that chronic increased exposure to ionizing radiation results in damage

to cellular dna . As a consequence a protein is now absent that would arrest in the G1 phase of the cell cycle. Subsequent to this, the cell is transformed to acquire the property of unregulated
cell growth. The absent protein is most likely the product of which of the following genes?

ras
p53
myc

A

p53

MHD - Exam 1 (13 decks)

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