Acquired (Environmental)

DNA damaging agents:

* Chemicals

* Radiation

* Virus

Normal Cell

DNA damage

Mutations in the genome

of somatic cells

Alterations of genes

that regulate Apoptosis

Activation of growth

promoting oncogenes Inactivation of

cancer suppressor

genes

Successful

DNA repair

Failure of DNA repair

Expression of altered gene products

and loss of regulatory gene products Clonal expansion

Additional mutations

Heterogeneity.

Inherited Mutations:

-DNA repair

-Cell growth

- Apoptosis

MULTISTEP PROCESS,

INVOLVES “NONLETHAL” GENETIC DAMAGE,

TUMOURS are -- MONOCLONAL,

TUMOURS ARE MONOCLONAL

•All the tumor cells derived from single mutated cell.

•All the cell in one tumor will express the same genetic

change.

•Tumor is formed by –the Clonal expansion of single

precursor cell that has incurred genetic damage.

Properties of cancer cells

They keep growing

And growing

And growing

And growing

1. Self-sufficiency in growth signals

2. Insensitivity to growth-inhibitory signals

3. Evasion of apoptosis

4. Limitless replicative potential

5. Sustained angiogenesis

6. Ability to invade and metastasis

7. Escape from immunity and rejection.

Orderly progression of cells through the various stages of

cell cycle is orchestrated by cyclins and cyclin dependent

kinases (CDKs) and by their inhibitors.

By phosphorylation CDK’s will drive the cell cycle—cells will

proceed to the next stage of proliferation.

CDK’s are normally in inactive form.

They become activated by phosphorylation after binding to

the family of proteins called Cyclins.

They are inactivated by ubiquitin - proteosome pathway after

their action.

Cyclins: main function is to activate the CDK’s.

E.g., cyclins D, E, A & B

CDK’s: cdk 4, cdk 2, cdk 1.

G1 S G2 M

Cyclin D/cdk4

Cyclin E/cdk2

Cyclin A/cdk2

Phosphorylation of RB gene is ON-OFF switch of cell

cycle.

In hypophosphorylated state, RB gene prevents cells

from replication by forming tight, inactive complex with

transcription factor E2F.

Phosphorylation of RB gene eliminates main barrier to

cell cycle progression and promotes cell replication.

G1 / S Phase: 1st checkpoint.

G2/ M Phase: 2nd checkpoint.

It is “point of no return” in the cell cycle

Before cell makes its final commitment to replicate, the

G1/S check point checks for DNA damage.

If DNA damage is present, the cell repair machineries will

repair it and arrests the cell cycle.

They provide some time for DNA repair; irreversible

damage—Apoptosis—Cell death.

Monitors the completion of DNA replication and checks

whether cell can safely initiate mitosis.

Defect in this checkpoint can give rise to various

chromosomal abnormalities.

To function properly, checkpoints take the help of many

‘sensors’—which will senses the damage.

Protooncogenes are physiological regulators of the cell cycle—control cell proliferation and differentiation.

Oncogenes –are characterized by ability to promote cell growth in the absence of normal mitogenic signals.

Oncoproteins –are products of oncogenes: the production of which is independent of growth factors.

Definitions:

1. PROTO-ONCOGENES,

[ ONCOGENES ]

2. TUMOUR SUPPRESSOR GENES,

3. GENES THAT REGULATE APOPTOSIS,

4. DNA REPAIR GENES.

GENES AFFECTED IN CANCER:

Molecular Basis of Neoplasia:

Proto-oncogene

Oncogene

Promote autonomous cell growth,

Cell growth in the absence of mitogenic

signals,

Their products – oncoproteins,

VARMUS & BISHOP: 1989: Nobel prize;

ACUTE TRANSFORMING RETROVIRUSES

Oncogenes And Cancer:

V - oncVIRAL ONCOGENE

Animals TUMOURS

Molecular analysis of viral genome

-

PDGF - beta chain :

== Astrocytoma

== Osteosarcoma,

FGF : == Stomach cancer

== Bladder cancer

== Breast cancer,

== Melanoma,

Can be:

Overexpressed by tumor cells : E.g., as in case of

Astrocytomas and Osteosarcomas—PDGF is

Overexpressed.

Amplification : e.g., in case of Stomach and Breast Ca—

FGF is amplified.

“Many cancer cells develop

growth self-sufficiency

by acquiring the ability to synthesize

the same growth factors

to which they are responsive”!

Overexpression of growth factor genes.

Proto-oncogenes Oncogenes

… Insertional mutagenesis,

… Point mutations,

… Chromosomal translocations,

… Gene amplification

“Extensive cell proliferation

increases the chance of

spontaneous or induced mutation

in cell population”

“Any cell----which is dividing rapidly…..,is susceptible for

developing point mutations..hence and malignancies ”