10- Cancer and Aging

Question 1

Neoplasm

Answer 1

Tumor, abnormal mass or growth uncoordinated with normal tissue

Question 2

How many different mutations are generally seen in cancer?

What type of mutations are tumor suppressants and oncogenes?

Answer 2

At least 5

Recessive for tumor suppressant, can also be silenced.

Oncogenes are Dominant

Question 3

How is epigenetic changes a part of cancer?

Answer 3

More heterochromatic portions (silenced) which is passed on to future cells in the tumor.

Silence of genes that block tumor progression

Question 4

What happens in shortening telomere cells if p53 (or rb) are mutated?

Answer 4

It will not halt the cell cycle, Non homologous end joining will join chromosomes which will be pulled apart.

Cancer cells activate telomerase activity.

Question 5

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?

Answer 5

Cytochrome P 450

Bulky lesions, NER should fix

Question 6

What type of repair should fix UV damage?

Answer 6

NER- pyrimidine dimers

ds break repair.

Question 7

What is Ras?

What is the most common inducing mutation?

Why is Ras usually activated in cancer cells.?

Answer 7

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.

Question 8

What is Myc?

Most common mutations?

Answer 8

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)

Question 9

What cancer is BCL2 related to?

How?

Answer 9

Diffuse Large B cell lymphoma (DLBC), non hodgkins lymphoma

Can cause chromosomal translocations, seen with gene rearrangements of Bcl2 and c Myc

Question 10

Li-Fraumeni Syndrome **

Common cancers?

Answer 10

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

Question 11

How is a p53 mutation affecting and leading to cancer/

How common is it?

Answer 11

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%

Question 12

What are the reasons that a loss of p53 is so detrimental?

4 reasons

Answer 12

1. Allow cells with DNA damage to progress through the cycle
2. Allows cells to escape apoptosis
3. allows division of cells with damaged chromosomes which can promote further cancer-promoting mutations to accumulate during divisions.
4. Allows resistance to chemotherapy and irradiation

Question 13

What does Apc stand for and what pathway is it associated with?

Answer 13

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.

Question 14

Wnt pathway? Where is APC in that pathway?

Answer 14

Wnt binds to frizzled receptor > inhibit APC complex (binding B-catenin) > B-catenin acts as transcription factor

APC is tumor suppressant

Question 15

What are the three proto-oncogenes to remember?

Answer 15

1. Bcl2
2. Myc
3. Ras

Question 16

What three tumor suppressants we should know?

Answer 16

1. p53
2. Rb
3. APC

Question 17

What is VHL?

Answer 17

Involved with Angiogenesis. Induced by hypoxia

Considered a tumor suppressor.

Question 18

VHL pathway?

Answer 18

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.

Question 19

What types of cells are in the microenvironment?

Answer 19

Tumor, stroma (connective tissue), white blood cells.

Question 20

What is the two way paracrine exchange for angiogenesis?

Answer 20

1. Tumors have to secrete angiogenic proteins that induce new vascular sprouts in the direction of the tumor
2. Endothelial cells secrete chemoattractants induce tumor cell migration toward blood supply. Also secrete mitogen and antiapoptotic proteins.

Question 21

Warburg Effect

Answer 21

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)

Question 22

Characteristics of vessels around tumor.

Answer 22

Irregular, tortorous, leaky

More hypoxic ( which selects for mutant cells that are able to survive)

Question 23

What is required for a cell to become metastatic?

Answer 23

Breack cell to cell and cell to basement adhesions.

Basement membrane remodeling

Angiogenesis

Question 24

Direct v indirect acting drugs towards angiogenesis

Answer 24

Direct: Inhibits epithelial cells from responding to angiogenic proteins.

Indirect: inhibits tumor cells synthesis of angiogenic proteins (ex. VEGF)

Question 25

How does oxidative stress hurt cells?

Answer 25

Protein modification: oxidate peptide backbones, damage 3D confirmation, enhance protein degradation.

DNA lesions: ss ds breaks, cross linking, base adducts,

Question 26

What is mitochondrial disease theory of aging?

Answer 26

Mitochondria creates free radicals, and if not enough antioxidants it will build up and cause damage

H2O2 and O2 in mito increase with age

Could be due to oxidative damage to mito DNA or lack of antioxidants

Question 27

What are the two theories of mtDNA mutations?

Clonal expansion and Viscous Cycle Theory

Answer 27

1. Clonal expansion: when # of wt molecules within cell decrease due to mutation, the cell responds by replicating all mtDNA
2. Viscous cycle: age related decline in respiratory efficiency due to mutations leads to increase in ROS which leads to further respiratory chain dysfunction.

Question 28

Interventions to aging?

Answer 28

Caloric restriction. Decrease of 30-60% of calories increased rodents life by 40%
—- mitohcondria put under less stress

Chronic exercise: gives modest increase in avg lifespan
– acute could increased oxidative stress.