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Pathology Block 1 > Block 1 Molecular Basis of Cancer > Flashcards

Block 1 Molecular Basis of Cancer Flashcards

1
Q

Causes of cancer

A

Chemical exposure, radiation, infection, inherited familial cancer syndromes

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2
Q

Direct vs. indirect-acting carcinogens

A

Direct: require no metabolic conversion, weaker, used as therapeutics
Indirect: require metabolic conversion, associated with polymorphisms in CYP-450; potency determined by inherent reactivity of electrophilic derivative, balance between metabolic activation & inactivation rxn

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3
Q

Carcinogens: initiators vs. promoters

A

I: cause DNA damage which must be heritable
P: do not cause mutation but stimulate division of mutated cells

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4
Q

Radiation carcinogenesis: severity, probability, latency period

A

Severity of induced cancer is independent of dose
Probability of cancer increases with dose with no threshold
Usually associated with a latency period

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5
Q

EBV-associated cancers

A

Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, 1’ CNS lymphoma (immunocompromised)

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6
Q

HBV, HCV-associated cancers

A

Hepatocellular carcinoma

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7
Q

HHV-8 and HPV-associated cancers

A

HHV-8: Kaposi sarcoma

HPV: cervical and penile/anal carcinoma (16, 18), head and neck cancer

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8
Q

H. pylori and HTLV-1-associated cancers

A

HP: gastric adenocarcinoma, MALT lymphoma

HTLV-1: adult T-cell leukemia/lymphoma

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9
Q

Liver fluke C. sinensis and S. hematobium-associated cancers

A

CS: cholangiocarcinoma
SH: bladder cancer (squamous cell)

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10
Q

Familial carcinogenesis features

A

Multiple cases in fam, AD transmission, early onset (earlier w/ generations), bilateral, synchronous (>2 at once), metachronous (more than 1 diagnosed at different times)

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11
Q

Steps in carcinogenesis

A

Initiation (irreversible mutation in regulation, heritable DNA alteration)
Promotion: selective growth & uncontrolled prolif in initiated cell & progeny
Progression: continuing evolution of unstable chromosomes -> further independence, invasiveness, metastasis, etc.

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12
Q

Classes of regulatory genes

A

Proto-oncogenes, tumor suppressor genes, apoptosis genes, DNA repair genes

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13
Q

Proto- and oncogenes

A

Proto: normal gene that if mutated = oncogene, contributes to cancer
Usually dominant mutations

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14
Q

Types of oncogenes

A

GFs, GF-Rs, protein kinases, cell cycle controllers, apoptosis proteins, TFs

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15
Q

Glioma & PDGF

A

Glioma: most common 1’ CNS tumor in adult
Overexp/hyperactive PDGF & receptor frequent -> auto/paracrine loops promoting cell survival, proliferation; also in pericytes of vasculature, fibro, myofibro have PDGF-R = tumorigenesis

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16
Q

Breast ca and HER2/Erb2

A

HER2/neu gene required no EGF signal -> hyperactive -> proliferation, survival; in 1/5 breast cancers (also in lung, ovary, salivary gland ca), more likely to spread, less likely to respond to treatment; treat with Ab Herceptin

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17
Q

RAS oncogene

A

Most commonly mutated in human tumors (30%); mutation prevents GTP hydrolysis = trapped in active form = continuous proliferation

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18
Q

Abl oncogene

A

ABL1 proto-oncogene codes for TK regulating cell diff, div, adh, stress response
C-abl (chr 9) + chr 22 = Philadelphia chr = bcr-abl, crosstalk with RAS signals
*Chronic myelogenous leukemia

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19
Q

Imatinib (Gleevac)

A

Blocks kinase activity bcr-abl = cell stops growing, may die by apoptosis

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20
Q

MYC nuclear protein

A

Activates txn growth-promoters like CDKs, inhibits CDKI txn; my (chr 8) + chr 14 = c-myc + Ig heavy chain constant region regulator -> overproduction normal myc
*Burkitt lymphoma

21
Q

Genomic amplification hallmarks

A 
Double minutes (dmin) - circular, extra-chromosomal amplifications of acentric DNA fragments [N-myc in neuroblastoma]
Homogeneously staining regions (hsr) [common in Her2/ErbB2]
22
Q

Warburg effect

A

Hypoxic tumors shift from ox phos -> aerobic glycolysis

*Mechanism of PET scan

23
Q

Tumor suppressors

A

Genes that encode proteins inhibiting proliferation; both copies must be faulty usually, if not = haploinsufficiency

24
Q

Sporadic vs. familial carcinogenesis

A

Sp: both copies of TS genes lost through somatic mutations
Fa: affected people inherit a defective copy, and lose second through somatic mutation
*Knudson’s two-hit hypothesis

25
Q

Rb gene

A

Active: hypo-P binds E2F TF, preventing genes like cyclin E = cells arrest in G1; inactivated by P by cyclin-D/CDK-4/6 complex -> mitosis

26
Q

E7 protein

A

Encoded for by oncogenic DNA virus like HPV, binds Rb and renders nonfunctional

27
Q

p53

A

TS gene, determines response of cell to DNA damage and hypoxia; promotes cell cycle arrest through CDK1 & apoptosis through Bax
*Mutations in >70% cancers

28
Q

Viruses that target p53 for degradation

A

HPV (E6), HBV, EBV

29
Q

Li-Fraumeni syndrome

A

Inherited one defective copy p53; high occurrence of breast ca, brain tumor, acute leukemia, sarcomas, adrenal cortical carcinoma

30
Q

Other mechanisms of inhibiting p53

A

Oncogenic activation Myc or Ras can inhibit p53

31
Q

APC

A

Tumor suppressor; anti-prolif by regulating destruction of B-catenin, inhibited by wnt; mutation = continuous cell cycle; in FAP and 70-80% sporadic colon cancers

32
Q

B-catenin

A

Destroyed by APC normally, with wnt signaling -> nucleus to activate TCF -> cell cycle continues

33
Q

Familial adenomatous polyposis (FAP)

A

1% colorectal cancers; 100-1000s polyps initially benign but will become cancerous if untreated

34
Q

Bcl2 and Bax

A

Bcl2 = anti-apoptotic; on chr 18 + chr 14 Ig heavy chain enhancer locus = B-cell lymphoma
Bax = pro-apoptotic
Also implicated in melanoma

35
Q

BRCA-1,2

A

BRCA-1 in complex repairing dsDNA breaks; mutation = impaired DNA repair
*Breast and ovarian cancers

36
Q

Steps of metastasis

A 
Invade through basement membrane
Intravasate into vasc/lymph channels
Survive/arrest while circulating
Exit circulation to new tissue
Survive & grow
37
Q

Hematogenous vs. lymphatic metastasis

A

Hem: dissemination through capillaries, venules
Lym: through lymphatic channels

38
Q

Cadherins & metastasis

A

Cadherins: cell-cell adhesion molecules, down-reg (b-catenin) to allow malignant cells to leave tumor

39
Q

Metastasis & basement membrane

A

Tumor cells secrete or induce stroma to secrete proteases (MMPs, cathepsin D, urokinase plasminogen activator [u-PA]) to degrade basement membrane

40
Q

Integrins & metastasis

A

Integrins: cell-cell and cell-ECM interactions to promote cell div, migration, survival
Altered to attach to “sticky ends” of degraded matrix to promote survival

41
Q

Locomotion & metastasis

A

Cleavage products of matrix components (collagen, laminin, some GF like IGF-1,2) have chemotactic activity

42
Q

Epithelial-mesenchymal transition

A

Epithelial cells lose polarity and cell-cell adhesion, gaining migratory and invasive properties = mesenchymal cells
Dec E-cadherin, inc vimentin, N-cadherin, a-SMA

43
Q

TGF-b

A

Enforces homeostasis, suppresses tumor progression by cytostasis/apoptosis or by suppressing inflammation, stroma-derived mitogens
CA cells lose response to it, can use it to initiate immune evasion, GF production, differentiation into invasive phenotype, metastatic dissemination/expansion

44
Q

Intravasation

A

Paracellular: through endothelial junction, disrupts cell-cell contact
Transcellular: through endothelial cells in smaller vessels assisted by endothelial contraction (myosin contraction, localized increase MLCK)

45
Q

Metastasis survival in circulation

A

Platelet shield: ca cells bind coagulation factors on platelets, forming embolus protecting them from immune-mediated lysis, decreases shear stress = enhanced survival

46
Q

Anoikis

A

Apoptosis due to loss of adhesion

47
Q

Extravasation

A

Microthrombus increases pressure, tumor pushes out of capillary, interacts with BM, then begins proliferating and can break through BM to invade surrounding tissue

48
Q

Stages of new growth and survival of metastases

A

Homing: mechanical trapping, site-specific adhesion/ chemoattraction, pre-metastatic niche
Colonization: quiescence, micrometastasis, macrometastasis

Pathology Block 1 (12 decks)

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