Block 1 Molecular Basis of Cancer

Question 1

Causes of cancer

Answer 1

Chemical exposure, radiation, infection, inherited familial cancer syndromes

Question 2

Direct vs. indirect-acting carcinogens

Answer 2

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

Question 3

Carcinogens: initiators vs. promoters

Answer 3

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

Question 4

Radiation carcinogenesis: severity, probability, latency period

Answer 4

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

Question 5

EBV-associated cancers

Answer 5

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

Question 6

HBV, HCV-associated cancers

Answer 6

Hepatocellular carcinoma

Question 7

HHV-8 and HPV-associated cancers

Answer 7

HHV-8: Kaposi sarcoma

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

Question 8

H. pylori and HTLV-1-associated cancers

Answer 8

HP: gastric adenocarcinoma, MALT lymphoma

HTLV-1: adult T-cell leukemia/lymphoma

Question 9

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

Answer 9

CS: cholangiocarcinoma
SH: bladder cancer (squamous cell)

Question 10

Familial carcinogenesis features

Answer 10

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

Question 11

Steps in carcinogenesis

Answer 11

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.

Question 12

Classes of regulatory genes

Answer 12

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

Question 13

Proto- and oncogenes

Answer 13

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

Question 14

Types of oncogenes

Answer 14

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

Question 15

Glioma & PDGF

Answer 15

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

Question 16

Breast ca and HER2/Erb2

Answer 16

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

Question 17

RAS oncogene

Answer 17

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

Question 18

Abl oncogene

Answer 18

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

Question 19

Imatinib (Gleevac)

Answer 19

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

Question 20

MYC nuclear protein

Answer 20

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

Question 21

Genomic amplification hallmarks

Answer 21

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

Question 22

Warburg effect

Answer 22

Hypoxic tumors shift from ox phos -> aerobic glycolysis

*Mechanism of PET scan

Question 23

Tumor suppressors

Answer 23

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

Question 24

Sporadic vs. familial carcinogenesis

Answer 24

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

Question 25

Rb gene

Answer 25

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

Question 26

E7 protein

Answer 26

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

Question 27

p53

Answer 27

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

Question 28

Viruses that target p53 for degradation

Answer 28

HPV (E6), HBV, EBV

Question 29

Li-Fraumeni syndrome

Answer 29

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

Question 30

Other mechanisms of inhibiting p53

Answer 30

Oncogenic activation Myc or Ras can inhibit p53

Question 31

APC

Answer 31

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

Question 32

B-catenin

Answer 32

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

Question 33

Familial adenomatous polyposis (FAP)

Answer 33

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

Question 34

Bcl2 and Bax

Answer 34

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

Question 35

BRCA-1,2

Answer 35

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

Question 36

Steps of metastasis

Answer 36

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

Question 37

Hematogenous vs. lymphatic metastasis

Answer 37

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

Question 38

Cadherins & metastasis

Answer 38

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

Question 39

Metastasis & basement membrane

Answer 39

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

Question 40

Integrins & metastasis

Answer 40

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

Question 41

Locomotion & metastasis

Answer 41

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

Question 42

Epithelial-mesenchymal transition

Answer 42

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

Question 43

TGF-b

Answer 43

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

Question 44

Intravasation

Answer 44

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

Question 45

Metastasis survival in circulation

Answer 45

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

Question 46

Anoikis

Answer 46

Apoptosis due to loss of adhesion

Question 47

Extravasation

Answer 47

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

Question 48

Stages of new growth and survival of metastases

Answer 48

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