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