Other Mechanisms of

Molecular Pathogenesis of

Cancer

-Reshma Ann Mathew

Molecular Basis of Cancer

Monoclonality of tumoursField theory of cancerMulti-Step process of cancer growth and progressionGenetic theory of cancerGenetic regulators of normal and abnormal mitosis

EVASION OF APOPTOSISApoptosis in normal cell is guided by cell death receptor CD95/Fas (extrinsic pathway) & by DNA damage (Intrinsic pathway).

The integrity of the outer mitochondrial membrane is regulated by pro-apoptotic and anti-apoptotic members.

The BH3 only proteins(BID) regulate balance between them.

Reduced CD95 level

Binding of FLIP inactivates death-induced signalling complex

Loss of P53 leading to reduced levels of BAX

Reduced cytochrome c from mitochondria due to increased BCL2Loss of APAF-1

IAP inhibits caspases

*FADD- Fas associated via death domain, *IAP-inhibitors of apoptosis*APAF-1- Apoptotic peptidase activating factor-1

Defects in DNA repairNormally p53 gene is responsible for

detection and repair of DNA damage.

Defects in 3 types of DNA-repair systems-

Mismatch repair, nucleotide excision repair and recombinant repair,

they contribute to different types of cancers.

In inherited mutations(Mutator genes), this system of DNA repair is defective, it is seen in-

1) Hereditary non-polyposis colon cancer(Lynch Syndrome)-

It is a familial carcinoma of the colon.There is a defect in genes involved in

DNA-mismatch repair.

2) Xeroderma Pigmentosum-Defect in Nucleotide excision

repair system.

3) Ataxia telangiectasia- Hypersensitivity to DNA damaging agent such as ionizing agents

4) Bloom Syndrome- Hypersensitivity to DNA damaging agent such as ionizing agents

5) Hereditary breast cancer

6) Fanconi anemia- Hypersensitive to DNA cross linking agents such as chemotherapeutic agents.

Limitless Replicative Potential:Telomerase

After each mitosis(cell doubling) there is progressive shortening of telomeres which are the terminal tips of chromosomes.

However , it has been seen that after repetitive mitosis for a maximum of 60-70 times, telomeres are lost in normal cells and the cells cease to undergo mitosis.

Replication of somatic cells, which do not express telomerase, leads to shortened telomeres.-In the presence of competent checkpoints, cells undergo arrest and enter nonreplicative senescense.

-In the absence of checkpoints, DNA repair pathways are inappropriately activated, leading to the fomation of dicentric chromosomes. At mitosis, the dicentric chromosomes are pulled apart at anaphase, resulting in new double stranded DNA breaks.

This Bridge-fusion breakage cycle repeats and produces mitotic catastrophe and cell death.

-Re-expression of telomerase allows the cells to escape the bridge-fusion-breakage cycle, thus promoting their survival and tumorigenesis.

MicroRNAs in CancerMiRNAs control cell growth,

differentiation and cell survival but they also play a role in carcinogenesis.

It can participate in neoplastic transformations by-

Increasing the expression of oncogenes

(or)Reducing the expression of tumor

supressor genes

1)Reduced activity of a miRNA that inhibits translation of an oncogene gives rise to an excess of oncoprotein

2)Overactivity of a miRNA that targets a tumor supression gene reduces the production of the tumor supressor protein

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