(inherited or acquired) Transformed cells acquire gene defects that allow them to form tumor
A lot of genes! Like what? Genes promote growth eg. RAS Genes inhibit growth eg. P53 Genes control apoptosis eg. Bcl-2 Genes of DNA repair And others. Targeted genes: 1. Proto-oncogenes (oncogenes) 2. Tumor suppressor genes 3. Genes controlling apoptosis 4. Genes regulating DNA repair Other genes involved: Genes regulating angiogenesis Genes enhancing invasion and metastasis Carcinogenesis is a multistep process At both genetic and phenotypic levels Progression results from accumulation of genetic defects
What does a cell need to be cancer? Independent growth (growth autonomy) Insensitive to inhibition of growth Resistant to apoptosis No aging (continuous dividing) Sustained angiogenesis Ability to invade and metastsize
By the action of oncogenes (from protooncogenes) Promote growth, no control
Normal growth (dividing) Growth factor Growth factor receptor Signal transduction Transcription factors Entry of the cell cycle by cyclins and CDKs
Growth factors PDGF in Glioblastoma multiforme TGF-alpha in Sacroma Growth factor receptors EGF (epidermal growth factor) ERBB1 in squamous cell carcinoma of lung ERBB2 in breast cancer Signal transducing proteins RAS: colon cancer, pancreatic cancer ABL: (BCR-ABL) in Chronic myologenous leukemia (CML) Gleevec is a drug used to inhibit ABL action and used in the treatment of CML Transcription factors: MYC: in Burkitt lymphoma
Cyclins and CDK: Cyclin D: in breast cancer, liver cancer, lymphoma Retinoblastoma gene RB Two-hit hypothesis (Knudson) Mutated in many cancer including retinoblastoma TGF-beta pathway Act through RB Mutated in colon cancer, stomach and endometrial cancer APC beta catenin pathway APC in cytoplasmic protein that regulates the level of beta-catenin Beta-catenin activates cell proliferation APC binds to Beta-catenin and enhance degradation Inherited mutation of APC in FAP (familial adenomatous polyposis) 2 nd hit occurs and adenoma appear With time more adenoma 100s and 1000s Cancer develop when other genes affected eg. RAS, P53 P53: Common in human cancer 70% Tumor suppressor gene
DNA damage P53 activation by release from MDM2 P53 results in arresting the cell cycle by increasing P21. P53 enhance repair of the DNA damage by GADD45 P53 induces apoptosis by increasing level of Bax Li-Fraumeni Syndrome: inherited mutated P53 Bcl-2 family Level of Bcl-2 vs. BAX, BAD Bcl-2 prevents apoptosis by preventing the release of cytochrome C Bcl-2 overexpressed in lymphoma Normal cells have 60-70 replication possible, then the cells cannot divide (aging) This is done by shortening of Telomere Tumors have telomerase activity and prevent cell aging Tumors cannot grow more than 2 mm with no vascular supply Hypoxia induces angiogenesis Tumor associated angiogenic factors VEGF bFGF P53 inhibits angiogenesis 1. Loosening of intercellular junction E-cadherin mutation 2. Attachment to matrix Cancer cells have high number of receptors to ECM like laminin receptor 3. Degradation of ECM By secreting metalloproteinases 4. Migration By the action of cytokines and chemokines 5. Homing Expression of adhesion molecules DNA mismatch repair genes: hereditary non-polyposis colon cancer DNA excision repair gene: Xeroderma pigmentosum Ataxia telangiectasia (ATM) gene senses the DNA damage BRCA1, BRCA2: involved in DNA repair Colon Cancer: APC RAS P53 Hyperplasia Adenoma Carcinoma Tumor progression and heterogeneity Genetic Damage 1. Chemicals 2. Radiation 3. Microbes
Heredity: Inherited cancer syndromes Familial cancer Autosomal recessive syndromes of defective DNA repair Heredity: Inherited cancer syndromes Autosomal dominant Eg. Familial Adenomatous Polyposis (FAP) Retinoblastoma, MEN, Neurofibromatosis, von Hipple- Lindau Familial cancer Not clear transmission pattern Cancer at early age, multiple, affecting relatives BRCA1, BRCA2 Autosomal recessive syndromes of defective DNA repair: Xeroderma pigmentosum, ataxia telangiectasia Chemicals: Scrotal cancer in chimney sweepers Direct or indirect action Natural or synthetic Alkylating agents, hydrocarbons, smoking, Azo dyes, Aflatoxin B1 Mechanism: mutation of genes (promoters and initiators)
Carcinogens Smoking: causes lung cancer, pancreatic cancer, bladder cancer Asbestos: found in construction, roofing papers, fire- resistant textile, causes lung cancer, mesothelioma, GI cancer Benzene: found in light oil, printing, paint rubber, dry cleaning, adhesive, causes leukemia and lymphoma Cadmium: found in batteries, metal plating, causes prostate cancer Vinyl chrolride: found in refrigerant, adhesive, causes liver cancer Radiation: Ultraviolet sun light, x-ray, nuclear radiation Chromosome breakage, translocation, mutation, genomic instability Ultraviolet light causes skin cancer, common in Australia.
Viruses and microbes Acute transforming viruses contain viral oncogenes Slow transforming viruses cause insertional mutation HTLV-1 causes T-cell lymphoma HPV: cervical cancer EBV: lymphoma HBV: Liver cancer Helicobacter pylori: gastric cancer