neoplasm 5 Flashcards
define Gene APC
- function = prevents nuclear transcription
- associated with familial polyposis coli (adenocarcinoma of colon)
define genes BRCA-1 and BRCA-2
- function = regulates DNA repair
- associated with breast and ovarian cancer
define RB gene
- function = inhbits G1 to S phase
- associated with retinoblastoma and osteogenic sarcoma
define WNT signaling pathway
- controls cell fate, adhesion and cell polarity during embryonic development
- self-renewal of hematopoeitic stem cells
- APC gene/B-catenin pathway is apart of WNT signaling pathway
why is APC gene/B-catenin pathway important?
- APC protein down regulates B-catenin that prevents it accumulation
- inactivation of APC results in increase levels of B-catenin which results in B-catenin being translocated to the nucleus
- continuous WNT signaling causes FAP, non-familial colorectal CA and sporadic adenomas
what are the cancers associated with Rb gene mutations
- retinoblastoma
- osteosarcoma
- soft tissue sarcoma
describe Knudson’s two-hit hypothesis about retinoblastoma
- both allelles of Rb locus must be inactivated
- 1st hit in all somatic cells of the body (inherited from affected parent, other copy is normal)
- 2nd hit in retinal cells results in somatic mutation –> loss of normal RB gene –> causes retinoblastoma
describe sporadic cases of retinoblastoma
- both normal Rb alleles are lost by somatic mutation in one of the retinoblasts
- cells homozygous for mutant tumor suppressor genes develop cancer
- recessive cancer genes = heterozygous cells are normal
define p53 gene
- function:
- -> cell-cycle arrest at G1/S = acts via p21 (cyclin/CDK4 inhibition)
- -> apoptosis - induces pro-apoptotic genes (BAX)
- associated with lung, colon, breast Carcinoma
- associated with Li-Fraumeni syndrome
describe HPV and p53
- HPV E6 inhibits p53 causing lack of apoptosis and excessive growth
- HPV E7 inhibits p53, p21 and RB-E2F causing lack of apoptosis and excessive growth
describe VHL gene
- tumor suppressor gene located on chromosome 3p
- part of ubiquitin ligase complex
- -> regulates nuclear transcription via HIF-1a
- Associated with hereditary renal cell carcinomas (RCC), hemangioblastomas of CNS, retinal angiomas, renal cysts
describe the warburg effect
- in the presence of ample O2, cancer cells demonstrate a distinct form of metabolism characterized by high levels of glucose uptake and increased conversion of glucose to lactose via the glycolytic pathway
- detected by PET (positron emission tomography) scan
- -> most tumors are PET positive
- -> rapidly growing ones are markedly PET positive
describe the steps in carcinogenesis
- accumulation of successive mutations
1) normal epithelium loses APC
2) hyperproliferative epithelium loses DNA methylation
3) early adenoma has Ras mutation
4) intermediate adenoma loses DCC
5) Late adenoma loses p53
6) adenocarcinoma
describe epigenetic changes
- epigenetics refers to reversible, heritable changes in gene expression that occur without mutation
- it involves post-translational modifications of histones and DNA methylation, both of which affect gene expression
- -> DNA methylation reduces expression and hisstone modifications lead to compaction of DNA into heterochromatin
define carcinogenic agents
- agents that cause genetic damage and induce neoplastic change
- -> chemical carcinogens, radiation, oncogenic viruses/other microbes
how do chemical carcinogens act?
- chemical carcinogens are highly reactive electrophiles that remove electrons from DNA, RNS or proteins –> cause cell damage
- Direct acting = act without modification
- Indirectly acting (pro-carcinogens) = require metabolic activation
describe the initiation step in chemical carcinogenesis
- chemicals that initiate carcinogenesis produces cell alteration
- alone- not sufficient for tumor formation
- permanent DNA damage
- rapid, irreversible
describe the promotion step in chemical carcinogenesis
- induces tumors in initiated cells
- non-tumorigenic by themselves
- -> do not affect DNA
- -> reversible
describe direct acting chemical carcinogens
- do not require chemical transformation for their carcinogenicity
- react with electron-rich sites in cells –> attach DNA
- ex: chlorambucil, busulfan, melphalan
describe indirect acting compounds/pro-carcinogens
- requires metabolic conversion in vivo in order to become a carcinogen
- most carcinogens are metabolized by cytochrome P-450 dependent mono-oxygenases
- ex: polycyclic aromatic hydrocarbons
what are the source and effects of polycyclic aromatic hydrocarbons
SOURCE - combustion of tobacco (cigarette smoking) - smoked meats and fish EFFECT - lung and bladder cancers - skin painting --> skin cancers - subcutaneous injection --> sarcomas - introduced into a specific organ --> local cancer
describe aromatic amines and azo dyes
- carcinogenicity mainly in liver (hepatocellular carcinoma)
- ultimate carcinogen is formed by action of cytochrome P-450 oxygenase system
describe Beta-naphthylamine
- bladder cancer in heavily exposed worked in aniline dye and rubber industries
Describe aflatoxin B1
SOURCE = mycotoxin produced by fungus aspergillus flavus in improperly stored corn, rice and peanutes
EFFECT = potent hepatic carcinogen
–> leads to Hepatocellular carcinoma due to p53 mutations*
