18. Molecular basics of carcinogenesis
- DNA damage to normal cell -> mutations in genome -> altered gene product -> Tumor suppressors ↓ or oncogenes ↑
- Protective mechanisms against carcinogenesis
- DNA repair enzymes
- Tumor suppressors
- Characteristics of cancer cells
- Inhibition of apoptosis + lack of response to inhibitory factors -> capable of self-maintained replication, long survival
- Mutagenic agents/defective DNA repair -> genetic instability -> more mutations
- Capable of angiogenesis
- Capable of invasion and metastasis
- Theories of carcinogenesis
- Somatic mutation theory (classic theory): cancer results from accumulation of mutations in susceptible cells
- Process
- Chemical, radiation, virus, etc. exposure to the cell causes mutations
- Mutations causes activation of proto-oncogenes and inactivation of tumour suppressor genes
- Cell transforms from healthy -> pre-cancerous -> cancerous
- Counterarguments
- 1: the stroma of the cancer is not mutated but highly influences tumor development, either positively or negatively
- Healthy cells transplanted to certain cancer stromas will become cancerous
- Cancer cells transplanted to other cancer stromas will not become more malignant
- 2: Many cancers acquire mutations first after they become cancerous
- Process
- Cancer stem cell theory
- Cancer cells arise from stem cells that accumulate damage as they divide
- Somatic mutation theory (classic theory): cancer results from accumulation of mutations in susceptible cells
- Gene dysfunction is not necessarily due to gene mutation – it can also be due to epigenetic malfunction
- Epigenetic malfunctions are reversible
- “Epigenetic drugs” reverse these malfunctions
- Tumour types can be subclassified according to their gene expression
- These subtypes have different biological properties and diagnosis
- Examples
- HER2 positive and negative breast cancer
- ALK positive and negative lung cancer