Carcinogenesis Flashcards
List at least 5 of 7 properties of malignant cancer cells
- unresponsive
- Dedifferentiated
- Invasive
- Metastatic
- Clonal in origin
- Anchorage Independence
- Growth factor Independence
How are malignant cancer cells unresponsive?
they are unresponsive to normal signals for proliferation control.
–> ability to proliferate indefinitely (immortalization!)
What is senescence?
The normal finite lifespan of a cell
How are malignant cancer cells de-differentiated?
lack many specialized structures/functions (with rounded morphology)
How are malignant cancer cells invasive?
Loss of contact inhibition (ability to grow over one another)
How are malignant cancer cells metastatic?
they are capable of shedding cells. These cells can drift thru circ. system and proliferate at different sites in body.
What does it mean for a malignant cancer cell to be clonal in origin?
derived from a single cell
Describe conversion of normal cells to metastatic cells
normal cell -> early neoplasia -> progressive neoplasia -> carcinoma -> metastasis
For normal cells to change into neoplastic cells, what must take place?
Change in cellular hereditary must take place
Mutagenic events in gametic/somatic cells will produce tumors years later.
somatic cells (ie. UV)
-somatic mut produced by environmental factors.
What is the multistep process for carcinogenesis?
- tumor initiation
- promotion
- conversion
- progression
proto-oncogenes are critical for what?
growth
repair
and homeostasis
what do tumor suppressor genes code for?
anti-proliferation signals,
proteins that suppress mitosis and growth
3 different types of cytogenic abnormalities associated with malignancy?
- translocations and gene deletions
- LOH
- Aneuploidy
HPV
what is it?
What does it make?
virus that wants to push cells into S phase.
Makes E6 and E7 oncoproteins
What does E6 and E7 do?
E6: inactivates p53
E7: inactivates Rb
Both E6+7 are made by HPV
What does the 1st and 2nd hit usually consist of?
1st: a pt mut
- inactivates 1 copy of TSG
2nd: a large del
- that results in loss of functional TSG allele (the last one)
retinoblastoma (Rb) tumors show what in ch?
partial or complete deletion of Rb gene in ch14q14
How does Rb inhibit txn initiation?
Rb can bind to E2F TF
How does Rb get inactivated? (process)
- GF+EGFR binds CDK 4,6 and CYCD1-3
- CDK 4,6 and CYCD1-3 bcomes protein kinase
- protein kinase activates 2nd protein kinase (CDK2 and CYC E)
- Both protein kinases together inactivate Rb protein (phosphorylates it)
- Rb cannot bind E2F
Hallmark of TSG
tumor cells have descended as clone from single cell that acquired homozygosity for susceptibility to malignancy gene.
Non malignant cells:
-heterozygous loss of TSG
Malignant cells
-homozygosity loss of TSG
Familial adenomatous polyposis (FAP) is caused by what??
Autosomal dominant fashion
-LOH of WT APC gene on ch5q
in cells of adenomatous polyps of colon
Indiv. who inherit 1 defective APC gene have ___% higher risk of developing colon cancer by 50
90%
APC function
- encodes cytoplasmic protein that regulates phosphorylation which controls localization of beta-catenin
- cause degredation of unbound cytoplasmic beta-cathenin
Breast and Ovarian Cancer mut in what genes?
BRCA1 + BRCA2
Functions of BRCA1+2?
- Scaffold
- DNA Repair
- checkpoint
Heterozygous mut of BRCA1 + BRCA2?
Breast/Ovarian cancer -
5% of women with breast cancer are hetero
Homozygous BRCA2?
Fanconi’s Anemia:
-bc BRCA2 is allelic with FAND1
75% of p53 mutations - what type?
Missense
50% of APC mutations - what type?
Frameshift
56 % of ATM mutations - what type?
Frameshift
Fanconi’s anemia will result in what?
pts get bone marrow failure ~5yrs recessive disease (both copies of BRCA2 mut)
54 % of BRCA1 mutations - what type?
Frameshift
Majority of mutations in cancer due to what type of mut?
Frameshift - (inactivates protein)
P53 protein is what? Why is mutation in p53 so damaging?
A txn factor (4 subunits)
- Dominant negative mutation: prevents WT prot from acting as TXN factor
- —>”spoiler” effect: 1 mutated p53 subunit = bad txn factor
mut 175 in p53 gene results in what type of cancer?
lung cancer
What is the function of beta catenin?
if not P by APC gene –> nucleus and activates txn of oncogenes (C-MYC)
If APC is lost, what happens to c-myc?
overexpression of cmyc = cancer
What is the function of APC complex (and also E-Cadherin)?
phosphorylates beta catenin, preventing it from entering nucleus
HPV: E6 has what type of activity?
Ubiquitin ligase activity -> ubiq p53 -> degredation of p53
if E6 present —> inhibits apoptosis —>(normally want p53 for apop)
HPV: E7 has what type of activity?
Competes with RB (TSG) and pushes cell cycle foward to S phase
Retroviruses are single/double strand viruses
single
How were oncogenes discovered?
ALV virus: normal (doesnt cause tumor devel)
RSV virus: oncogenic
- found chicken with Src gene next to other genes (gag, pol, env)
- Saw that the chicken had tumors
- took out Src and put in healthy chicken
- Other chicken also devel tumors.
-cellular component must be present: Src was incorporated into host genome
List 4 viral oncogenes and its oncoproteins
- Rous sarcoma virus (RSV) : v-src
- avian erythroblastosis virus (aev) : v-erb
- abelson leukemia virus (alv) : v-able
- random fused oncogene w/ gag : v-myc
v-src function
causes fibrosarcomas in birds
v-erb function
causes erythroblastomas in chickens
v-abl function
causes abelson leukemia in mice
v-myc function
elicits neoplastic transformation of cells
List useful oncogenes that can be used as molecular markers for prognosis in cancer
- c-ras
- N-Myc
- HER2/erbB2
-detection = poor prognosis
c-ras gene mutation causes? Model type?
mutation in hu bladder cells
—> production of unregulated ras protein
- qualitative
N-myc gene mutation causes? Model type?
mutation in neuroblastoma
quantitative
HER2/erbB2 oncogenic activity? Model type?
gene is amplified in breast cancer
—-> causes increased numbers in tyrosine kinase rcptrs
quantitative
What antibody is used against erbB2/HER2?
herceptin
Function of herceptin?
its an antibody that binds to erbB2/HER2 receptor and blocks activity of rcptr.
—->extends life of breast cancer pts
What drug is used against chronic myelogenic leukemia?
GLEEVAC!!!!!
Function of gleevac?
beesh: its an ATP analog (mimics ATP) - binds to active site of ABL tyrosine kinase in pts w/ BCR-ABL translocation
- —> prevents phosphorylation —> treats CML
