hallmarks of cancer

Question 1

10 hallmarks of cancer

Answer 1

1. growth signal autonomy
2. insensitivity to growth inhibitory signals
3. evasion of apoptosis
4. unlimited replicative potential
5. angiogenesis
6. invasion and metastasis
7. avoiding immune destruction
8. reprogramming energy metabolism
9. genetic instability
10. tumour-producing inflammation

give indian elephants upumma and indian ants roti, grapes, tumour

Question 2

growth signal autonomy

Answer 2

proto-oncogenes to oncogenes

signalling of oncogenes independent of growth signals

mechanisms
- amplification
- change in structure to constitutively active

1. increase in growth factor (amplificaton)
   eg glioblastoma overexpress PDGF
2. increase in growth factor receptors
   amplification -> eg increase in human epidermal growth receptor 2 (HER2) which causes breast cancer (test for HER2: fluorescence institu hybridisation FISH)
   point mutation -> eg structural change to EGFR tyrosine kinase -> constitutively activated -> 40-50% of lung adenocarcinoma (female non-smokers) + 15% in western population
3. cell signalling molecules
   (point mutation)
   eg RAS: mutation blocks conversion of active GTP to GDP -> continuous signalling
   BRAF: downstream transcription factor for cellular proliferation
   eg melanoma, hairy cell leukaemia
4. transcription factors (amplification)
   eg chromosomal translocation from 8 to 14 causes MYC gene to go to IgG promoter (Burkitt’s lymphoma, neuroblastoma)
5. cell cycle components (amplification and translocation)
   eg cyclin + cyclin dependent kinase

Question 3

insensitivity to growth inhibitory signals

Answer 3

loss of function mutation of TSG

1. Retinoblastoma (Rb) protein/cyclin dependent kinase (CDK) pathway dysregulation

normal cell cycle: G0 - G1- S - G2 - Mitosis

normal Rb activity:
Rb is the regulator of G1 to S and inhibits progression by binding to E2F transcription factor, preventing transcription of genes needed for DNA replication (cell cycle arrest at G1)

normal cyclin-dependent kinase activity: upon growth factory signalling, cyclin bind to CDK to form cyclin-CDK complex. Cyclin-CDK complex phosphorylates Rb, inactivating it so RB cannot cause cell cycle arrest

Rb inhibits mitosis -> TSG
CyclinCDK promote mitosis-> proto-oncogene

2. p53 mutation (guardian of the genome)

normal p53 activity: when DNA damage detected, upregulates expression of CDK inhibitor for temporary arrest at G1-> S

eg FAP, Li Fraumeni Syndrome

Question 4

evasion of apoptosis

Answer 4

• deletion of p53 gene
• translocation of BCL2 to the position next to IgH -> up-regulation of BCL2
  (BCL2 gene prevents apoptosis)

Question 5

unlimited replicative potential

Answer 5

reactivation of telomerase to lengthen telomeres -> replicative immortality

Question 6

angiogenesis

Answer 6

1. oncogenes upregulate vascular endothelial growth factor (VEGF)
   - triggered by upregulation of oncogenes

Question 7

invasion and metastasis

Answer 7

epithelial mesenchymal transition

Question 8

avoiding immune destruction

Answer 8

• increase expression of PD-L1
  PD-L1 on macrophage binds to PD1 receptor on T cell, inhibiting T cell and suppressing T cell mediated immune response
• increase expression of CTLA-4 (have greater binding affinity to B7 than CD28)
  + induce low levels of B7 protein on APC -> preferential binding of CTLA 4

Treg suppress anti-tumour immune response

Question 9

reprogramming energy metabolism

Answer 9

Warburg effect
- increase glucose uptake + ferment glucose to lactate even in the presence of oxygen and despite functional mitochondria
- cancer cells’ adaptation for survival -> can divide rapidly under many conditions

Question 10

genetic instability

Answer 10

caused by mutations in genes coding for mismatch repair proteins (MMR) -> MSH2, MSH6, MLH1, PMS2

normal function of MMR proteins:
mutations in YSG or PCG can be repaired by MMR

• mutation in MMR proteins can lead to micro satellite instability where the errors in tandem repeat sequence are not repaired
  (microsatellites-> short tandem repeating sequences)
• do not directly cause cancer but failure to repair mutations in TSG or proto-oncogene due to mutation in both alleles of MMR can cause cancer

eg HNPCC

Question 11

tumour-producing inflammation

Answer 11

inflammation brings bioactive molecules like growth factors, pro-angiogenic factors, ECM modifying agents etc to tumour, promoting tumour growth, angiogenesis and malignant conversion

Question 11

types of mutations in genes

Answer 11

1. gene amplification
2. point mutation
3. deletion/insertion
4. chromosomal translocation