neoplasia 2 2
Terms
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- neoplastic transformation
-
chemical carcinogens
radiant energy
oncogenic viruses and microbes - chemical carcinogenesis
- initiation, promotion, progression
- initiation
-
rapid, irreversible, memory
permanent damage to DNA of target - promoters
- can induce tumors in initiated cells, but are nontumorigenic by themselves. effect is reversible, does not affect DNA
- complete carcinogen
- chemicals that are both initiators and promoters
- incomplete carcinogen
- chemicals that are capable of initiation
- direct acting carcinogens
- do not require chemical transformation
- indirect acting or procarcinogen
- require metabolic conversion to the ultimate carcinogen
- what gene mutation is common in chemically induced tumors?
- Ras gene
- most widely used tumor promotor of carcinogenesis?
- TPA--activator of protein kinase C,which results in proliferation and modulates differentiation
-
alkylating agents
direct acting carcinogens - anti-cancer drugs
-
acylating agents
direct acting carcinogens - do not need metabolic conversion and are weak carcinogens; many are therapeutic agents, act by interacting with and damaging DNA
- procarcinogens
-
polycyclic and heterocyclic aromatic hydrocarbons
aromatic arimes, amides, and azo dyes
naturally occuring carcinogens - nitrosamines and amides
- formed in GI tract and implicated in gastric carcinoma, caused by conversion of bacteria of nitrates and nitrostable amines to nitrites
- asbestos
- lung cancer, mesotheliomas, GI cancers
- vinyl chloride
-
hemangiosarcoma of liver
plastic factory, then mass in liver; - chromium, nickel, and metals
- volatized and inhaled causes lung cancer
- saccharin
- cancer in rats
- hormones (estrogen)
- endometiral cancer in post menopausal women
- effects of UV light on cells
- inhibition of cell division, inactivation of enzymes, induction of mutation, cell death
- XP
- AR disorder with defect in the NER of DNA, photosensitivity, and 2000x increase risk of skin cancer
- xrays
- skin cancer
- miners of radioactive elements
- lung cancer x 10
- atom bomb
- leukemia, breast, thyroid, lung, colon
- therapeutic radiation
- carcinogenic. thyroid cancer in 9% of those exposed to head and neck radiation
- DNA oncogenic viruses
- HPV, EBV, HBV, KSHV
- HPV
-
70 subtypes; types 1,2,4 and 7 for benign squamous papillomas (warts); SCC of cervix and anogenital region--types 16 and 18; less frequently 31, 33.**
genital warts-- 6 and 11
E7 binds pRb; E6 binds p53. - EBV
- herbes; Burkitt's lymphoma; B cell lymphoma in immunocompromised; hodgkin lymphoma, nasopharyngeal carcinoma
- EBV induced Burkitt's
- infects nasopharynx epithelial cells and B lymphocytes via CD21 receptors; infxn of B cell is latent; actively dividing cells are at increased risk for mutation; t(8;14); 80% carry this translocation; 100% of nasopharyngeal carcinomas have EBV DNA
- HBV
- strong assoc with hepatocellular ca; endemic in far east and africa; HBV genome does not encode any oncoproteins and the pattern of integration is not constant; effect of HBV is indirect and multifactorial; liver injury and regenerative hyperplasia increase risk for genetic mutation
- HTLV-1
- assoc with T cell leukemia/lymphomas; endemic in japan and caribbean; sporadic in US; trophism for CD4+ T cells, which are target for neoplastic transformation; infected T cells transmitted by sex, blood products, and breast feeding. leukemia in 1% of infected; causes demyelinating neuro disorder
- helicobacter pylori
- causes gastric lymphomas (B cell)/MALTomas/marginal zone lymphomas more frequently than gastric carcinomas
- 3 factors determining growth of tumor
-
1. doubling time of tumor cells
2. fraction of tumor cells in replicative pool
3. rate at which the cells are shed or lost - GF
- proportion of cells in proliferative pool; in fast growing tumors, 20% or less; high cell turnover, increased production, and apoptosis; effect on susceptibility to chemo; also correlates with level of differentiation
- prognostic indicator correlating with malignancy?
- extent of angiogenesis; vessel density is prognostic indicator
- most important angiogenic factors?
-
VEGF and bFGF
elevated in serum and urine of many cancer patients
tumor cells may also produce anti-angiogenic factors like thrombospondin 1. - angiostatin, endostatin, and vasculostatin
- angiogenesis inhibitors derived by proteolytic cleavage of plasminogen, collagen, and transthyretin
- invasion of ECM
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detachment of tumor cells from each other
attachment to matrix components
degradation of ECM
migration of tumor cells - E cadherin
- transmembrane glycoprotein that is important adhesion molecule; linked by catenins, which lie under the plama membrane; downregulated in many tumors; fxn dependent on linkage to catenin. in some tumors, there is mutation in gene for catenin which reduces expression of Ecadheri
- attachment to ECM
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tumors with increased laminin receptors and integrins show increased ability to invade and metastasize
receptor mediated attachment to laminin and fibronectin - degradation of ECM
- serine, cysteine, and matrix metalloproteinases
- migration mediated by:
-
1. tumor cell-derived motility factor
2. cleavage products of matrix compounds (collagen and laminin) - tumor antigens
- TSA on tumor cells; TAA on tumor cells and some normal cells; TSA evoke cytotoxic T cell response; present within tumor cells on MHC I molecules