- All cells have mechanisms regulating their growth, differentiation
and death
- Cancer develops when cells escape from the normal control mechanism
- Proliferation is uncontrolled
- Cells develop ability to invade and metastasise
- Carcinogenesis is a multi-step process
- Cells accumulate succession of gene mutations
- Each mutation overcomes natural anti-cancer defence mechanisms
- Growth regulation is lost
- Most cancers result from series of genetic errors
Cancer genes
- Genes related to cancer development may be divided into
- Oncogenes
- Tumour suppressor genes
- In health, activity of these genes is closely regulated
- Allows differentiated growth of normal tissues
- In cancer, balanced control of growth is lost
Oncogenes
- Oncogenes are regulatory genes
- Activity is abnormally increased after a genetic alteration
- Oncogene activation may occur after
- Chromosomal translocation
- Gene amplification
- Mutation within coding sequence of oncogene
- Oncogenes act in a dominant fashion
- Examples of oncogenes include:
- ras on chromosome 11 - mediates signal transduction
- erbB2 on chromosome 7 - growth factor receptor
- src on chromosome 20 - tyrosine kinase
- myc on chromosome 8 - transcription factor
Tumour suppressor genes
- Code for inhibitory proteins
- Normal function is to prevent cell growth
- In cancer, suppressor function is lost
- Most tumour suppressor genes are recessive
- Inactivation of tumour suppressor genes can occur by
- Gene mutation causing loss of gene product
- Prevention of binding of a gene product to its target site
- Inactivation by other proteins
- Examples of tumour suppressor genes include
- Rb on chromosome 13 - control of cell cycle
- p53 on chromosome 17 - DNA repair and apoptosis
- Bcl2 on chromosome 18 - apoptosis
- APC on chromosome 5 - regulation of co-transcriptional activators
- Mutation of tumour suppressor genes is seen in many familial cancers
- Rb - childhood retinoblastoma
- p53 - Li-Fraumeni syndrome
- APC - familial colon cancer
- BRCA1/2 - familial breast cancer
Cell growth
- In health growth factors are made by one cell type to stimulate
another
- Malignant cells generate their own stimulatory growth factors
- Positive feedback cycle occurs by two mechanisms
- Alteration to growth factors or receptors
- Alteration to intracellular signalling pathways
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