Molecular Basis of CancerCarcinogenesis Dr. Raid Jastania
Molecular Basis of Cancer • Tumors are monoclonal proliferation • Tumors carry genetic defect that are not lethal (inherited or acquired) • Transformed cells acquire gene defects that allow them to form tumor
What are the genes involved in Cancer? • 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….
Molecular Basis of Cancer • 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
Molecular Basis of Cancer • 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
Independent Growth (Growth Autonomy) • 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 CDK’s
Independent Growth Growth Autonomy by Oncogenes • 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
Independent Growth (Growth Autonomy) • 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
Independent Growth (Growth Autonomy) • Transcription factors: • MYC: in Burkitt lymphoma • Cyclins and CDK: • Cyclin D: in breast cancer, liver cancer, lymphoma
Insensitivity to growth Inhibition • 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
Insensitivity to growth Inhibition • 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) • 2nd hit occurs and adenoma appear • With time more adenoma 100’s and 1000’s • Cancer develop when other genes affected eg. RAS, P53
Insensitivity to growth Inhibition • 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
Resistance to Apoptosis • 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
No Aging (continuous dividing) • 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
Angiogenesis • Tumors cannot grow more than 2 mm with no vascular supply • Hypoxia induces angiogenesis • Tumor associated angiogenic factors • VEGF • bFGF • P53 inhibits angiogenesis
Ability to invade and metastasize • 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
Genomic Instability • 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
Multistep Carcinogenesis • Colon Cancer: • APC – RAS – P53 • Hyperplasia – Adenoma – Carcinoma • Tumor progression and heterogeneity
Etiology of Cancer • Genetic Damage • 1. Chemicals • 2. Radiation • 3. Microbes
Etiology of Cancer • Heredity: • Inherited cancer syndromes • Familial cancer • Autosomal recessive syndromes of defective DNA repair
Etiology of Cancer • 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
Etiology of Cancer • 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)
Etiology of Cancer • 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
Etiology of Cancer • Radiation: • Ultraviolet sun light, x-ray, nuclear radiation • Chromosome breakage, translocation, mutation, genomic instability • Ultraviolet light causes skin cancer, common in Australia.
Etiology of Cancer • 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
