Lecture 19: Neoplasia I

Question 1

Cell cycle and cancer

Answer 1

Loss of G1/S regulation marks all cancers; go/no go checkpoint

Question 2

Normal G1/S regulation paths

Answer 2

1. MAPK
2. PI3K

Question 3

MAPK G1/S pathway

Answer 3

1. RTK-Pi recruits MAPK
2. MAPK recruits Grb2
3. SOS (Ras GEF) recruitment -> Ras activation
4. Ras -> RAF, MEK, ERK Pi cascade
5. Cyclin D upreg.

Question 4

PI3K G1/S pathway

Answer 4

1. PI3K (RTK) auto-self-Pi recruits PI3K
2. PI3K converts PIP2 to PIP3 (Pi)
3. PIP3 activates MTOR downstream -> growth

Question 5

Cyclin D action

Answer 5

1. Cyclin D activates/recruits Cdk4/6
2. Cyclin D:Cdk complexes -> Pi of Rb
3. Rb releases sequestered E2F TFs
4. E2Fs -> S phase gene expression

Question 6

Possible oncogenes that can be activated for loss of G1/S control

Answer 6

Mx in:
- RTKs
- Ras (most common, 30%)
- PI3K
- AKT, mTOR, RAF, etc.
- Upreg. in Myc, Cyclin D/E, E2F

Question 7

Possible tumor suppressors that can be lost for loss of G1/S control

Answer 7

• Rb loss ( –| E2F)
• p53 loss (chkpt)
• p16 loss ( –| Cdk)
• PTEN loss (PI3K inhib.)

Question 8

Potential sources of gene abnormalities

Answer 8

1. Mx
2. Gene amplification/deletion
3. Epigenetic changes

Question 9

Possible causes of gene mutation

Answer 9

Exogenous: lifestyle, natural exposures (UV, virus), pollution, work/home
Endogenous: ROS dmg, DNA replication mistakes; 66% cancer Mx are random

Question 10

Gene amplification/deletion in cancer

Answer 10

• Caused by abnormal divisions, aneuploidy
• Near all tumors have CIN; amp. oncogenes or deplete suppressors
  e.g. trisomy 12 -> RAS
  e.g. Chr. 9 loss –| CDKN1A
• Occurs w/ mitotic defects; chr. segregation errors

Question 11

Epigenetic changes

Answer 11

e.g. methylation silencing
e.g. acetylation activation/overexpression

Question 12

Oncogenic viruses

Answer 12

EBV, HPV
- HPV -> E6, E7 oncogene incorporation inhibiting Rb, p53

Question 13

Multi-hit hypothesis

Answer 13

4-6+ gene changes req. for tumorigenesis
1. Activate oncogenes
2. Tumor suppressor loss
3. Replicative immortality
Add’l adaptations -> progression/mets

Question 14

Hallmarks of cancer

Answer 14

1. Sustained proliferative signals
2. Evading growth suppressors
3. Avoid immune destruction
4. Enable replicative immortality
5. Tumor-promoting inflammation
6. Invasion + mets
7. Inducing angiogenesis
8. Genome instability
9. Resist cell death
10. Energetics dysregulation

Question 15

Hallmark: sustained proliferative signals

Answer 15

• Targeting S phase, mitotic cells (e.g. mAbs, kinase/microtubule inhibs)
• EGFR (RTK), BRAF, PI3K, AKT inhibs.
• Anti-metabolites (disrupt DNA replicat.)

Question 16

Hallmark: evade growth suppressors

Answer 16

• Cdk inhibs; hard to target p53/Rb loss
• Peto’s Paradox: more p53 copies in large animals

Question 17

Hallmark: avoiding immune destruction

Answer 17

• Immune activating anti-CTLA4 mAb, anti-PD-L1
• Reactivating CTL immunotherapy

Question 18

Hallmark: enable replicative immortality

Answer 18

• Inhib. telomerase expression; too toxic usually

Question 19

Hallmark: tumor-promoting inflammation

Answer 19

• Immune cells release ROS mutagens, growth/angiogen. cytokines
• Reducing inflam. can slow growth

Question 20

Hallmark: invasion + mets

Answer 20

ID gene changes promoting mets

Question 21

Hallmark: inducing angiogenesis

Answer 21

• VEGF inhibs e.g. Bevacuzimab, Avastin

Question 22

Hallmark: genome instability

Answer 22

• Nearly all tumors are aneuploid, CIN
• Inducing more DNA dmg kills these cells (poor repair, pre-existing dmg)
  e.g. alkylating agents, topoisomerase inhibs., antibiotics

Question 23

Hallmark: resisting cell death

Answer 23

• Anti-apop. protein overexpression (MCL-1, BCL-2)
• Inhibitors of these proteins

Question 24

Hallmark: dysregulation of energetics

Answer 24

• Tumors have increased glucose uptake, increased aerobic glycolysis
• Glycolysis inhibs.