Cancer…

Licentious division - prostate cancer cells during division.

Cancer

not a single disease; heterogeneous group of disorderscharacterized by the presence of cells that do not respond to the normal controls on division.

Normal cells

Cancer cells

Normal cells grow in monolayer Cancer cells grow in

clumps (foci)COURTESY OF G. STEVEN MARTIN.)

Angiogenesis

Metastasis

Why a greater number of cells do not give rise to cancerous tumors ….???

> malignant transformation requires more than a single genetic alteration(hits).

How is a normal cell transformed into a

cancerous cell?

Rather than lacking function, cancer cells reproduce

at a rate far beyond the normally tightly regulated

boundaries of the cell cycle.

occur due to an alteration of a normal biological

process — cell division.

MALIGNANT

TRANSFORMATION OF CELLS

Induction of malignant transformation with chemical or physical carcinogens appears to involve multiple steps and at least two distinct phases:

initiation and promotion.

The signals that regulate cell division fall into two basic types:

molecules that stimulate cell division and

those that inhibit it.

Genes that have been implicated in carcinogenesis are dividedinto two broad categories:

Tumor-suppressor genes and

Oncogenes.

Tumor-suppressor genes

Encode proteins that

restrain cell growth and

prevent cells from becoming

malignant.

Act recessively since both

copies must be deleted or

mutated before their

protective function is lost.

Oncogenes

> Encode proteins that promote the loss of

growth control and malignancy.

Oncogenes arise from

Proto-oncogenes—genes that

encode proteins having a role in a cell’s

normal activities.

Mutations that alter either the protein or

its expression cause the proto-oncogene to

act abnormally and promote the formation

of a tumor.

MESSAGE The proteins that oncogenes encode areactivated in tumor cells, whereas the proteins that tumor suppressorgenes encode are inactivated.

Tumor suppressor genes

Five broad classes of proteins are generally recognized as being encoded by tumor-suppressor genes

Intracellular proteinsthat regulate or inhibit progression through a

specific stage of the cell cycle (e.g., p16 and Rb)

Receptors or signal transducers for secreted hormones or developmental signals that inhibit cell proliferation (e.g., TGF)

Checkpoint-control proteins that arrest the cell cycle if DNA is damaged or chromosomes are abnormal (e.g., p53)

• Proteins that promote apoptosis

• Enzymes that participate in DNA repair

TP53 : the guardian of genome…

The product is a protein of 53 kilodaltons(hence the name).

>The p53 protein prevents a cell from completing the cell cycle if its DNA is damaged or the cell has suffered other types of damage.

Loss-of-Function Mutations in Tumor-Suppressor

Genes Are Oncogenic

• deletions or point mutations

• methylation of cytosine residues in the promoter or other control elements.

Loss of Heterozygosity

Subsequent loss or inactivation of the normal allele in a somatic cell, referred to as loss of heterozygosity (LOH),is a prerequisite for cancer to develop.

Tumor suppressor gene in cancer cells

[Micrographs by E. R. Fearon and K. Cho. From W. K. Cavanee and R. L. White, Scientific American, March 1995, pp. 78–79.]

Oncogenes

Proteins encoded by proto-oncogenes

Conversion of proto-oncogenes into oncogenes

Gain-of-Function Mutations ConvertProto-oncogenes into Oncogenes

• Point mutation(i.e., change in a single base pair) in a

proto-oncogene that results in a constitutively activeprotein product

• Chromosomal translocation that brings a growth regulatory

gene under the control of a different promoterthat causes inappropriate expression of the gene

Five broad classes of proteins are generally recognized as being encoded by tumor-suppressor genes

• Amplification (i.e., abnormal DNA replication) of a

DNA segment including a proto-oncogene, so thatnumerous copies exist, leading to overproduction of the encoded protein

Proto-oncogenes intoOncogenes

POINT MUTATION OF AN INTRACELLULAR SIGNAL TRANSDUCER

[Adapted from B. Vogelstein and K. W. Kinzler, 1993, Trends Genet. 9:138.]

Model of sequential genetic alterations leading to metastatic colon cancer.

Although oncogenes or mutated tumor-suppressor

genes or both are required to produce cancer,

mutations in DNA repair genes

can increase the likelihood of acquiring mutations

in these genes.

Cancer is currently treated by surgery, chemotherapy, and radiation.

Several other strategies are being tested; these include # immunotherapy,# inhibition of proteins encoded by oncogenes, # inhibition of angiogenesis.

REFERENCES

1. Molecular Cell Biology- Lodish, Baltimore et al, Freeman

and Co.

2. Cell and Molecular Biology- Concepts and Experiments-

Karp (2012) 5th edn.,

John Wiley and sons

3. www.youtube.com

4.http://www.biooncology.com/

RAHUL E M

BPS051416

SI

PLANT SCIENCE

CUK