Molecular Basis of Carcinogens Flashcards
What are 5 properties of malignant cancer cells?
- Unresponsive to proliferation control signals
- DE-Differentiated: do not have specialized structures /function of tissue where they are growing
- Invasive: can grow into neighboring healthy tissue, extending the boundaries of the tumor
4; Malignant: can shed cells that travel through circulatory system and proliferate at other sites - Clonal in origin: all cells from same single cell origin
- Resistance to apoptosis
- limitless replication potential
What is the multistep process for carcinogenesis?
cancer is the result of the accumulation of somatic mutations produced by environmental factors
Important steps are: Tumor initiation promotion conversion progression
What is the relative importance of heredity in carcinogenesis? The environment?
Heredity:
- susceptibility to cancer is heritable
- cancer is caused by changes in cellular heredity
- Cancer is not inherited as a single gene (mendelian inheritance)
Environment:
- mutagenic events early in life can be associated with cancer later
What types of early mutations are associated with later cancer?
UV light exposure
mutations to DNA repair genes
How do mutations in DNA repair genes cause later cancers?
increases rate of future mutations
Ex: p53, BRCA1, BRCA2
What 2 types of genes are usually mutated in tumor initiation?
- Oncogenes: encourage cell proliferation -> activated
2. Anti-oncogenes: inhibit cell proliferation -> inactivated
What are at least 2 cytogenetic abnormalities associated with malignancy?
- translocations/ deletions
ex: CML- Philadelphia chromosome - Loss of heterozygocity (LOH)
ex: retinoblastoma - Aneuploidy
What events can lead to a loss of heterozygocity?
Classic 2 Hit hypothesis of tumorgenesis (Kundson)
1st hit: pont mutation in activating tumor supressor gene
2nd hit: deletion resulting in loss of WT copy
Both are necessary because 1 good copy is enough for normal function
What are some dominantly inherited susceptibilities to cancer?
familial Adenomatous Poluposis Familial retinoblastoma Familial breast and ovarian cancer Wilms tumor syndromw von hippel lindau
What are some recessively inherited susceptibilities to cancer?
xeroderma pigmentosa
ataxia-telegiectasia
bloom’s syndrome
fanconi’s congenital aplastic anemia
How was the retinoblastoma gene identified?
many tumors had abnormal structure on chromosome 13 near q14 -> some completely deleted, some partial deletions, some rearrangements
-> in most patients, heterozygosity for Rb gene
=> tumor descends from single cell that has become homozygous for susceptibility gene
What are 3 functions of the normal Rb protein?
- Prevent excessive cell growth by inhibiting cell cycle
- recruits chromatin remodeling enzymes
- Has a “pocket” for function binding of other proteins -> can be targeted by pathologies like HPV and become inactivated
How doe Rb function during the cell cycle
inhibits cell proliferation -> anti oncogene
- hypophosphorylation of Rb protein prevents cells from entering S phase
- if Rb protein hyperphosphorylated -> cell proceeds to S
What happens during the cell cycle if Rb is lost/ nonfunctional?
Cells cannot down regulate their division and growth is out of control
What is a hallmark of tumor suppressor genes?
protects a cell from one step on the path to cancer
ex) Rb prevents cell from entering s phase
their loss may be more important than oncoactivation in many cancers
