Block 1 Molecular Basis of Cancer Flashcards
Causes of cancer
Chemical exposure, radiation, infection, inherited familial cancer syndromes
Direct vs. indirect-acting carcinogens
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
Carcinogens: initiators vs. promoters
I: cause DNA damage which must be heritable
P: do not cause mutation but stimulate division of mutated cells
Radiation carcinogenesis: severity, probability, latency period
Severity of induced cancer is independent of dose
Probability of cancer increases with dose with no threshold
Usually associated with a latency period
EBV-associated cancers
Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, 1’ CNS lymphoma (immunocompromised)
HBV, HCV-associated cancers
Hepatocellular carcinoma
HHV-8 and HPV-associated cancers
HHV-8: Kaposi sarcoma
HPV: cervical and penile/anal carcinoma (16, 18), head and neck cancer
H. pylori and HTLV-1-associated cancers
HP: gastric adenocarcinoma, MALT lymphoma
HTLV-1: adult T-cell leukemia/lymphoma
Liver fluke C. sinensis and S. hematobium-associated cancers
CS: cholangiocarcinoma
SH: bladder cancer (squamous cell)
Familial carcinogenesis features
Multiple cases in fam, AD transmission, early onset (earlier w/ generations), bilateral, synchronous (>2 at once), metachronous (more than 1 diagnosed at different times)
Steps in carcinogenesis
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.
Classes of regulatory genes
Proto-oncogenes, tumor suppressor genes, apoptosis genes, DNA repair genes
Proto- and oncogenes
Proto: normal gene that if mutated = oncogene, contributes to cancer
Usually dominant mutations
Types of oncogenes
GFs, GF-Rs, protein kinases, cell cycle controllers, apoptosis proteins, TFs
Glioma & PDGF
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
Breast ca and HER2/Erb2
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
RAS oncogene
Most commonly mutated in human tumors (30%); mutation prevents GTP hydrolysis = trapped in active form = continuous proliferation
Abl oncogene
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
Imatinib (Gleevac)
Blocks kinase activity bcr-abl = cell stops growing, may die by apoptosis
MYC nuclear protein
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
Genomic amplification hallmarks
Double minutes (dmin) - circular, extra-chromosomal amplifications of acentric DNA fragments [N-myc in neuroblastoma] Homogeneously staining regions (hsr) [common in Her2/ErbB2]
Warburg effect
Hypoxic tumors shift from ox phos -> aerobic glycolysis
*Mechanism of PET scan
Tumor suppressors
Genes that encode proteins inhibiting proliferation; both copies must be faulty usually, if not = haploinsufficiency
Sporadic vs. familial carcinogenesis
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
Rb gene
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
E7 protein
Encoded for by oncogenic DNA virus like HPV, binds Rb and renders nonfunctional
p53
TS gene, determines response of cell to DNA damage and hypoxia; promotes cell cycle arrest through CDK1 & apoptosis through Bax
*Mutations in >70% cancers
Viruses that target p53 for degradation
HPV (E6), HBV, EBV
Li-Fraumeni syndrome
Inherited one defective copy p53; high occurrence of breast ca, brain tumor, acute leukemia, sarcomas, adrenal cortical carcinoma
Other mechanisms of inhibiting p53
Oncogenic activation Myc or Ras can inhibit p53
APC
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
B-catenin
Destroyed by APC normally, with wnt signaling -> nucleus to activate TCF -> cell cycle continues
Familial adenomatous polyposis (FAP)
1% colorectal cancers; 100-1000s polyps initially benign but will become cancerous if untreated
Bcl2 and Bax
Bcl2 = anti-apoptotic; on chr 18 + chr 14 Ig heavy chain enhancer locus = B-cell lymphoma
Bax = pro-apoptotic
Also implicated in melanoma
BRCA-1,2
BRCA-1 in complex repairing dsDNA breaks; mutation = impaired DNA repair
*Breast and ovarian cancers
Steps of metastasis
Invade through basement membrane Intravasate into vasc/lymph channels Survive/arrest while circulating Exit circulation to new tissue Survive & grow
Hematogenous vs. lymphatic metastasis
Hem: dissemination through capillaries, venules
Lym: through lymphatic channels
Cadherins & metastasis
Cadherins: cell-cell adhesion molecules, down-reg (b-catenin) to allow malignant cells to leave tumor
Metastasis & basement membrane
Tumor cells secrete or induce stroma to secrete proteases (MMPs, cathepsin D, urokinase plasminogen activator [u-PA]) to degrade basement membrane
Integrins & metastasis
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
Locomotion & metastasis
Cleavage products of matrix components (collagen, laminin, some GF like IGF-1,2) have chemotactic activity
Epithelial-mesenchymal transition
Epithelial cells lose polarity and cell-cell adhesion, gaining migratory and invasive properties = mesenchymal cells
Dec E-cadherin, inc vimentin, N-cadherin, a-SMA
TGF-b
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
Intravasation
Paracellular: through endothelial junction, disrupts cell-cell contact
Transcellular: through endothelial cells in smaller vessels assisted by endothelial contraction (myosin contraction, localized increase MLCK)
Metastasis survival in circulation
Platelet shield: ca cells bind coagulation factors on platelets, forming embolus protecting them from immune-mediated lysis, decreases shear stress = enhanced survival
Anoikis
Apoptosis due to loss of adhesion
Extravasation
Microthrombus increases pressure, tumor pushes out of capillary, interacts with BM, then begins proliferating and can break through BM to invade surrounding tissue
Stages of new growth and survival of metastases
Homing: mechanical trapping, site-specific adhesion/ chemoattraction, pre-metastatic niche
Colonization: quiescence, micrometastasis, macrometastasis
