Dr. Subodhini Abhang

Cell that is transformed .

Recognized by population of abnormal cells within the

normal tissue causing destruction of normal cell

population & behave like parasite.

A simplified hypothesis for development of cancer

Inactive anti-oncogenes Diminish regulation by

apoptosis gene

Oncogenic Mutations viruses

Environmental factors( physical and chemical)

Oncogene Activation

Carcinogenesis

Characteristics of differentiated cell

Lack contact inhibition . Trap for nitrogen compounds.

Site of growth.

Loss of control on cell division.

Decreased protein degradation as compared to synthesis.

Transfer modified characters to daughter cells & subsequent progeny.

Loss of anchorage.

Causes of cancer

• Physical

• Chemical

• Biological

Effects of radiation

UV Rays X Rays Gama Rays

Mutagenic & Carcinogenic

Damage to DNA.Pyrimidine dimers to formFormation of apurinic or apyrimidinic sites.Single & double strand break & cross linkingFree radical formation.( OH ͘ , super oxide)

Effects of radiation

Pyrimidine dimers

Chemical carcinogens

• 80% of cancer caused by chemicals

• Organic eg. benzo pyrine,

• Organic eg. benzo pyrine,

• chemicals

dimethylnitrosamine

Inorganic eg. Cadmium , Arsenic

How carcinogens enter in the body ?

Occupation ==== Asbestos, benzene

Diet --------------- Aflatoxin produced by fungus (Aspergillus flavous) contamination with peanuts.

Drugs-------------- Diethylstilbestrol

Life style-----------Cigarette smoking

Two types ---- Direct

Procarcinogens

Role of initiator & promoter

Initiator Carcinogenbenzopyrene

PromotorCroton oil

Potential tumor cellsProliferating cancer cells

Release & migration of cancer cells

Promotors

Promotor

• Cyclomates

• saccharin

• Metabolites of Tyrosine :

Phenol & cresol

Tryptophan: Indol & Indol

acetate

Tissue

• Tumor of Bladder

• Tumor of Gastrointestinal tract.

Mechanism of action of chemical carcinogen

Pro -carcinogen proximate carcinogen

ultimate carcinogen

(highly reactive)

Electrophiles (deficient in electrons)

Enzyme responsible for activation-----Cytochrome P450

Some chemical carcinogens

Class• Polycyclic aromatic

hydrocarbons.

• Azo dyes (Aromatic amines)

• Nitrosamines

• Various drugs ( alkylating & acetylating agents)

• Aflatoxins(fungus AspergillusFlavus)

Compound

• Benzo pyrene present in cigarette smoke.

• An aniline azo dye Used in rubber industry: ca.bladder.

• Synthesized in gut from ingested nitrites or derived from digested proteins: gastric cancer

• Stilbesterol.

• Mold.-- potent hepatic carcinogen.

Oncogenes

Genes of viral origin which causes transformation of target cell.

Rous 1911 ------ got Nobel prize in 1966 Sarcoma virus

DNA RNA –mostly of retroviruses

Oncogenes play a crucial role in carcinogenesis

Oncogenes of Rous sarcoma virus:

gag pol env src

gag: Codes for group specific antigen

Pol: Reverse transcriptase

Env: certain glycoprotein of viral envelop

Src: protein tyrosine kinase

Mechanism of infective retrovirus formation

C DNA or provirus

Retrovirus

Reverse transcriptase

Cell

Viral DNA

1.

Host DNA

Becomes a part of host DNA

1a.Process of integration of viral genes into cellular DNA

Viral DNA

Mechanism by which proto-oncogene become oncogene

Proto-oncogene is the normal non mutated cellular analog of oncogene.

1.

LTR

myc

myc

LTR

Provirus

Myc mRNA

e.g. Avian leukemia virus

Promotor insertion:

myc

myc

LTR LTR

provirus

2. Enhancer Insertion

Myc mRNA

3. Translocation

Chromosome 4

Chromosome 4

Chromosome 20

Chromosome 20

Before After

In chronic granulocytic leukemia: Translocation between 9th and 22nd chromosome.

Break

Break

Gene for H –Chains

myc gene

myc gene

Burkitt’s Lymphoma: chromosomal translocation

8 8 8

14 14 14

Heavy chainsOf immunoglobulin

5. Gene amplification:

Observed in many tumors.

e.g . Methotrexate administration : leukemia

Inhibitor of dihydrofolate reductase

Dihydrofolate Tetra hydrofolate

- ---- required for sythesis of purines & thymine

Tumor cells become resistant to this drug

Gene for dihydrofolate reductase becomes amplified

resulting in 400 fold increase in activity.

5. Single point mutation

V-ras oncogene --------murine retrovirus

polypeptide related to G protein

modulates the activityadenylate cyclase

role in cellular responses of hormones & drugsC- ras oncogene -------DNA sequencing of C-ras protooncogene

Normal human bladder cells cancer of human bladder cells

Substitution of amino acid in 12 or 61 position results in GTPase

Chronic stimulation on adenylate cyclase

Mechanism of action of oncogenes:

1. Autocrine mechanism--- oncogene product is growth factor*

*Over stimulation

2. Oncogene alters the receptor---- receptor is permanently turn on without growth factor binding.

3. Transducer alteration: Transduction –change in genetic make up of a cell

by transfer of viral DNA to cell.Change in GTPase stimulatory protein Permanently turn on

results in uncoupling of normal ligand receptor binding.

Tumor suppressor genes OrAntioncogenes

Protect an individual from getting cancer. Deletion removes the growth control of cells and

Believed to be a key factor in the development of tumor.

P⁵³ ----Absent in most tumors

RB gene ( retinoblastoma gene) located in chromosome 13

DCC gene--- Ca colon

Tumor markers.

The biochemical indicators employed to detect the presence of cancer are collectively referred to as tumor markers.

- Abnormally produced molecules by tumor cells .Eg. Surface antigens

cytoplasmic proteins EnzymesHormones

Tumor markers.

Marker Associated cancer(s)

Oncofetal antigens

carcinoembryonic antigen(CEA)------------Colon, Stomach, Breast, Lung and Pancreasalpha fetoprotein (AFP) ------------Liver and germ cells of testisCancer antigen ( CA 125) ------------Ovarian cancer of epithelial origin.Prostate specific antigen ------------Prostate cancer

HormonsCalcitonin ------------CA of medullary thyroidCatecholamines and their metabolites (VMA) -------------Neuroblastoma

EnzymesProsthetic acid phosphatase ------------ Prostate cancerNeuron specific enolase ------------NeuroblastomaAlkaline phosphatase(ALP) ------------Bone secondary's

Specific ProteinsImmunoglobulin ----------- multiple myeloma