10- Cancer and Aging Flashcards
Neoplasm
Tumor, abnormal mass or growth uncoordinated with normal tissue
How many different mutations are generally seen in cancer?
What type of mutations are tumor suppressants and oncogenes?
At least 5
Recessive for tumor suppressant, can also be silenced.
Oncogenes are Dominant
How is epigenetic changes a part of cancer?
More heterochromatic portions (silenced) which is passed on to future cells in the tumor.
Silence of genes that block tumor progression
What happens in shortening telomere cells if p53 (or rb) are mutated?
It will not halt the cell cycle, Non homologous end joining will join chromosomes which will be pulled apart.
Cancer cells activate telomerase activity.
Benzo-a-pyrene is a combustion product of tobacco smoke. What transforms it to benzo [a]pyrene-7,8,- idol?
What type of damage will this cause? and what should fix it?
Cytochrome P 450
Bulky lesions, NER should fix
What type of repair should fix UV damage?
NER- pyrimidine dimers
ds break repair.
What is Ras?
What is the most common inducing mutation?
Why is Ras usually activated in cancer cells.?
proto oncogene, signal transducing protein (GFs and MAPK pathway)
Most common: single point mutations in gene.
Mutated Ras form always activated because of inability to hydrolyze GTP.
What is Myc?
Most common mutations?
proto oncogene, acts as transcription factor, (also cell reprogramming to pluripotent)
Targets: cyclins, histone acetylation, increase motility, increase telomerase activity, change in metab and protein turnover
Mutations: translocations and amplifications (form a chromosome with many copies of gene)
What cancer is BCL2 related to?
How?
Diffuse Large B cell lymphoma (DLBC), non hodgkins lymphoma
Can cause chromosomal translocations, seen with gene rearrangements of Bcl2 and c Myc
Li-Fraumeni Syndrome **
Common cancers?
Patients with this have 25 fold greater chance of getting cancer before 50. Likely to develop early and have more than one primary.
Family has inherited one bad allele of p53, only needs one somatic mutation to lose
sarcoma, breast, brain, leukemia, carcinomas of adrenal cortex
How is a p53 mutation affecting and leading to cancer/
How common is it?
p53 can no longer bind to DNA to transcribe p21 which binds Cdk and blocks entry into cell cycle.
some form of mutation in almost every cell.
Mutation in p53 gene in 50%
What are the reasons that a loss of p53 is so detrimental?
4 reasons
- Allow cells with DNA damage to progress through the cycle
- Allows cells to escape apoptosis
- allows division of cells with damaged chromosomes which can promote further cancer-promoting mutations to accumulate during divisions.
- Allows resistance to chemotherapy and irradiation
What does Apc stand for and what pathway is it associated with?
adenomatous polyposis coli. Dominant, 100% penetrance
Wnt pathway
APC is a tumor suppressant and implicated in colon cancer
800 inactivating mutations exist within this gene.
Wnt pathway? Where is APC in that pathway?
Wnt binds to frizzled receptor > inhibit APC complex (binding B-catenin) > B-catenin acts as transcription factor
APC is tumor suppressant
What are the three proto-oncogenes to remember?
- Bcl2
- Myc
- Ras
What three tumor suppressants we should know?
- p53
- Rb
- APC
What is VHL?
Involved with Angiogenesis. Induced by hypoxia
Considered a tumor suppressor.
VHL pathway?
Marks Hif 1 for degradation (add ubiquitin groups) so it can’t turn on VEGF, which functions in formation of new blood vessels.
So if no VHL, Hif 1 (proto oncogene) can activate VEGF (proto oncogene) and form new vessels.
Hif1 is oxygen dependant, cancer cells can override that.
What types of cells are in the microenvironment?
Tumor, stroma (connective tissue), white blood cells.
What is the two way paracrine exchange for angiogenesis?
- Tumors have to secrete angiogenic proteins that induce new vascular sprouts in the direction of the tumor
- Endothelial cells secrete chemoattractants induce tumor cell migration toward blood supply. Also secrete mitogen and antiapoptotic proteins.
Warburg Effect
The core of the tumor is hypoxic so high amounts of anaerobic glycolysis
Causes: loss of tumor suppressors, activate oncogenes, natural selection, hypoxic environment stabilizes Hif1 (continues to signal VEGF for angiogenesis)
Characteristics of vessels around tumor.
Irregular, tortorous, leaky
More hypoxic ( which selects for mutant cells that are able to survive)
What is required for a cell to become metastatic?
Breack cell to cell and cell to basement adhesions.
Basement membrane remodeling
Angiogenesis
Direct v indirect acting drugs towards angiogenesis
Direct: Inhibits epithelial cells from responding to angiogenic proteins.
Indirect: inhibits tumor cells synthesis of angiogenic proteins (ex. VEGF)
