Molecular Basis of Cancer Carcinogenesis

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 CDKs

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 100s and 1000s 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, fireresistant 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