Molecular Basis of Cancer

Question 1

List the 7 major classes of genes involved in carcinogenesis

Answer 1

1. growth promoting proto-oncogenes
2. growth inhibiting tumor suppressor genes
3. genes that regulate DNA repair
4. genes that regulate apoptosis
5. genes that regulate telomere function
6. genes that regulate angiogenesis
7. genes that promote invasion and metastasis

Question 2

caretaker genes vs. gatekeeper genes

Answer 2

both are genes susceptible to mutation:

Caretaker genes = genes that regulate DNA repair; a mutation makes them unable to fix problems

Gatekeeper genes = suppress tumor formation by regulating cell growth

Question 3

What happens if mutations activate telomerase?

Answer 3

Telomerase allows cells to replicate indefinitely

Question 4

List 5 major targets for genetic alterations in cancer

Answer 4

1. Chromosomes
   
   1. abberant copy number, translocations, deletion, telomere extension, Loss of heterozygosity
2. DNA
   
   1. point mutations, micosatellite alterations, promoter hypermethylation, viral sequences
3. RNA
   
   1. over/underexpression, point mutations, miRNAs
4. Protein
   
   1. structural alterations/modifications, changes in enzymatic activity, mislocalization, altered expression
5. Mitochondria
   
   1. DNA mutations

Question 5

What are the 6 major skills a cancer cell needs to survive?

Answer 5

1. self sufficiency in growth signals (control of accelerator)
2. insensitive to anti-growth signals (brakes)
3. able to evade apoptosis (preventing car from driving off cliff)
4. limitless proliferative potential (continue forever)
5. sustained angiogenesis (enough fuel supply)
6. tissue invasion and metastasis

Question 6

What do normal cells need in order to move from quiescence to an active proliferating state?

Answer 6

Mitogens! (growth signals)

Question 7

What are the four classes of proto-oncogenes? (activating growth)

Answer 7

1. growth factors
2. growth factor/intracellular receptors
3. intracellular transducers
4. transcription factors

Question 8

How do growth factors work in normal cells? Provide 3 examples of GFs

Answer 8

Most soluble mitogenic growth factors are made by one cell in order to stimulate proliferation of another cell

examples: PDGF, EGF, TFG-a
* Platelet makes PDGF, binds receptor on fibroblast, stimulates cell to undergo round of replication, produces 2 daughter cells *
(note: GF = growth factor….)

Question 9

Autocrine stimulation

Answer 9

Process where cancer cells in tumors are able to synthezie growth factors that stimulate THEMSELVES–> signal continues to drive itself and you get unregulated cell divisions

Question 10

Explain how growth factor receptors work as a class of proto-oncogenes

list two examples of them

Answer 10

Mutation in receptors generates proliferative signal to a cell all by itself without the binding of an extracellular signal.

Overexpression of receptors –> hyperresponsive cancer cells

examples: EGFR/erbB, HER2/neu

Question 11

integrins - growth factor/intracellular receptors

Answer 11

Integrin is an example of how cancer cells can switch the TYPES of receptors they express, favoring ones that transmit PRO-GROWTH signals

integrins loosen binding (decrease affinity) to ECM, allow cells to move, proliferate, and metastasize

ex. mutation in H-ras leads to decreases in integrin affinity for the ECM

Question 12

How to intracellular transudcers act as a proto-oncogene, and provide an important example

altered form of signaling pathway protein allows them to release mitogenic signals with no stimulation by their upstream regulators

ras mutations (SOS-Ras-Raf-MAPK cascade)

Question 13

What is the signaling action of ras, and what part of the cycle is blocked in a mutant ras? What is a mutation of ras an example of?

Answer 13

growth factor binds GF receptor –> inactive RAS is activated by converting GDP to GTP –> activation of MAP-kinase pathway –> transcription –> cell cycle progression

active RAS gets inactivated by hydrolysis of GTP (lose a phosphate). this part is blocked in a mutant ras.

example of intracellular transudcers, a class of proto-oncogenes

Question 14

How do transcription factors act as a proto-oncogene? Give 3 examples

Answer 14

a mutation in TF results in inapprorpriate transcription that can UP REGULATE growth promoting genes, or, DOWN REGULATE growth inhibitory genes

(encourage the ones helping them out, block the ones slowing them down)

Examples: c-jun, c-fos, c-myc

Question 15

Myc-Max-Mad relationship: what is this an example of

Answer 15

example of transcription factors as class of proto-oncogenes:

• mad-max = growth inhibitory complex, promots differentiation = good guy
• myc-max = strong growth signal = cancer
• competition of these exist in equilibrium normally, but overexpression of c-myc can shift the balance, promoting growth and impairing differentiation

Question 16

Strongest anti-growth signal

Answer 16

RB1 pathway: regulates the transit of cells through the G1/S transition, can shut down process even if there’s a strong growth signal

“I **R **Blocking u!!”

this is what cancer cells want to eliminate

Question 17

How do cancer cells acquire insensitivity to anti-growth signals, speciically RB1? Describe a few mechanisms and examples

Answer 17

1. inhibition of RB via phosphorylation (TGF-B), protein interaction, mutation
2. miRNAs can bind single stranded RNA and suppress it-does the opposite action of what the body wants to regulate oncogenes
   
   • specifically miRNA bind to _complementary sequences _ on target mRNAs –> translational repression, RNA degradation, and gene silencing
   • in cancer: up regulates oncogenes (by silencing a suppressor) or down regulates tumor suppressor genes (by silencing the tumor suppressor)

Question 18

ability of tumor cell to expand is determined by these two factors. Apoptosis is the major source for which factor?

Answer 18

1. cell proliferation
2. rate of cell attrition (reduction in size) << apoptosis

Question 19

What is the major mediator of intracellular stress signals?

Answer 19

Bcl2 family

Question 20

p53- its job and what happens if you lose it

Answer 20

• acts like RB
• also a pro apoptotic regulator
• if you inactivate p53, you can’t regulate apoptosis, and a cell wont commit suicide when its damaged

Question 21

What are the 2 common methods for evading apoptosis?

Answer 21

1. mutation of p53 (proapoptotic regulator)
2. deregulation of the PI3 kinase-AKT/PKB pathway

usually from loss of PTEN, negative regulator of AKT

Question 22

Limitless proliferative potential

• what normal cells have this? what makes them capable?
• how do cancer cells acquire it?

Answer 22

• normally, end of chromosomes (telomeres) cant be duplicated or read by DNA polyermase, resulting in shorter ends with each replication round
• only stem cells have limitless proflieration due to TELOMERASE (adds a whole series of 6 nucleotide repeats to maintain length)
• 90% of cancer cells activate telomerase by upregulating expression of telomerase system

Question 23

How might cancer stem cell targetd therapies work?

Answer 23

• develop chemotherapies that attack stem cells
• kills those off, remaining differentiated cells will have limited proliferative ability
• tumor loses capacity to generate cancer cell progeny, tumor regresses

conventional therapies kill only the differentiated cancer cells, and the CSCs remain, allowing the tumor to grow

Question 24

• What is the limit to tumor size without new vasculature
• What are the 4 positive signals for sustained angiogenesis?
• What are 2 important negative signals?
• how do tumors activate angiogenesis?

Answer 24

• 110 um is the limit
• Soluble facctors and their receptors:
  
  • vascular endothelial growth factor (VEGF)
  • basic fibroblast growth factor (bFGF)
  • acidic fibroblast growth factor
  • transforming growth factor alpha
• Negative signals / angiogenesis inhibitors
  
  • thrombospondin 1 (TSP)
  • ß- interferon
• tumors change the balance of angiogenic inducers and inhbiiters by altering **gene transcription **

Question 25

Tissue invasion and metastasis: several classes of genes are needed to tethor the tumor cell to its surroundings. List 7

Answer 25

1. cadherins
2. NCAM
3. MMP (to get out of vessels)
4. Met
5. HGF
6. Semaphorins
7. Chemokine receptors

Question 26

Where do the following usually spread?

1. bone cancers
2. breast cancers
3. lung tumors

Answer 26

1. bone cancers –> lung
2. breast cancers –> bone
3. lung tumors –> liver

Question 27

Li-Fraumeni syndrome

what are the requirements and implications

what type of inheritance

Answer 27

born with only one functional copy of p53 gene

sarcoma under the age of 40, with two first degree relatives with sarcoma or another cancer before age 40

autosomal dominant

carry increased risk for development of multiple cancers (only need “1 hit” to their normal p53 gene to fully lose the protection it provides)

Question 28

What are the 3 main actions of the p53 protein

Answer 28

1. activates temporary cell cycle arrest (quiescence)
2. arrest cell cycle permanently (senescence)
3. trigger programmed cell death (apoptosis)

all in response to damaged DNA

Question 29

HPV oncoprotein E6

Answer 29

binds p53, diables the protein, prevents apoptosis of cervical epithelial cells that have developed DNA damage