Self-sufficiency in growth, evasion of death, limitless replication, angiogenesis, invasion and metastasis
Mnemonic
The Hanahan and Weinberg hallmarks, most usefully grouped:
Growth
- Sustaining proliferative signalling (oncogenes such as RAS, HER2)
- Evading growth suppressors (p53, Rb)
- Enabling replicative immortality (telomerase)
- Resisting cell death (BCL-2)
Spread and support
- Inducing angiogenesis (VEGF)
- Activating invasion and metastasis
Enabling characteristics
- Genome instability
- Tumour promoting inflammation
Emerging
- Deregulating cellular energetics (the Warburg effect)
- Avoiding immune destruction (the basis of checkpoint inhibitors)
“Grow, ignore the brakes, live forever, refuse to die, build a blood supply, invade, and hide from the immune system.”
p53 is the guardian of the genome and the most commonly mutated gene in human cancer; its germline loss causes Li-Fraumeni syndrome.
Expansion
The core capabilities a cell must acquire to become malignant:
- Self-sufficiency in growth signals: oncogene activation, as with RAS and HER2
- Insensitivity to growth inhibition: loss of tumour suppressors, as with Rb and p53
- Evasion of apoptosis: BCL-2 overexpression, p53 loss
- Limitless replicative potential: telomerase reactivation
- Sustained angiogenesis: VEGF secretion
- Invasion and metastasis: loss of E-cadherin, matrix metalloproteinases
Later additions: reprogrammed metabolism (the Warburg effect, aerobic glycolysis), immune evasion, genomic instability and tumour-promoting inflammation.
Each maps to a therapy: HER2 to trastuzumab, VEGF to bevacizumab, immune evasion to checkpoint inhibitors targeting PD-1 and CTLA-4, and defective DNA repair to PARP inhibitors.
Carcinogenesis is multistep: several mutations must accumulate, which explains the long latency, the rise in incidence with age, and the adenoma to carcinoma sequence in colorectal cancer where the specific order of APC, KRAS and p53 mutations has been mapped.