cancer (biokimia)

Cancer

• Cancer is a group of diseases in which genetically damaged cells proliferate autonomously

• The genetic damage consists of mutations (eg.point mutation, deletion, insertion) and chromosomal rearrangements or losses

• Such changes result in the loss or altered function of molecules involved in cell growth or proliferation.

Genes in Cancer

• Mutations could affect Protooncogenes or Tumorsuppressor genes.

• Protooncogenes code for a variety of growth factors, growth factor receptors, enzymes or transcription factors that promote cell growth and/or cell division.

• Mutated version of Protooncogenes (erbB, ras, jun, fos, myc, etc) are called Oncogenes

Genes in Cancer

• Proto-oncogenes are activated to oncogenes by various mechanisms.

• 1. Promoter insertion

• 2. Enhancer insertion

• 3. Chromosomal translocations

• 4. Gene amplification

• 5. Point mutation

Oncogen Cancer

• abl Translocation CML • myc Translocation Burkitt’s Lymphoma• erb B Amplification Epithelcarcinoma,

Astrocytoma,

Ca Oesophagus• neu Amplification Adeno Ca (Mammae,

Ovarium, Gaster)• myc Amplification Ca- Mammae, Lung,

Uterus, Oes • N-myc Amplification Neuroblastoma,

Ca.Paru • Int-2 Amplification Ca-Oesophagus

Apoptosis

• Programmed cell death

• Intracellular machinery responsible for apoptosis is called caspases.

• Caspases• Synthesized in the cell as inactive precursor called

procaspases• Usually activated by cleavage at aspartic acids by

other caspases.

Tumor suppressor genes

• Play an important role in tumorigenesis.

• Involved in the control of abnormal cell proliferation.

• Loss or inactivation : association with the development of malignancy.

Tumorsuppressor genes

• The majority of p53 mutations (80%) in breast cancer are missense, while 20%: nonsense mutations, deletions, insertions

• P53 protein (21kD) normally inhibits Cdk (Cyclin dependent kinase) enzymes.

• Recent evidence indicates that other damaged or deleted Tumorsuppressor genes may code for enzymes involved in DNA Repair mechanisms.

• If DNA repair mechanisms are incomplete, a complex mechanism involving P53 leads to programmed cell death or Apoptosis

Carcinogenics

• Radiant energy • Chemical compounds• Viruses ( DNA virus,RNA virus, Adeno

virus)• These act by causing mutations or by

introducing novel genes into cells

• Familial conditions (Tumor suppressor genes)

• Oxidative damage to DNA increase the mutations rate

Photodimerization

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thyminedimer

UV lightExposure to UV lightcan cause adjacentthymines to covalently link.

This results in adistortion of the DNAmolecule and breaks the hydrogenbonding with theadenine.

Tumor metastasis

• Metastasis is the most dangerous property of tumor cells

• The cell grow as secondary tumors• Many changes have been documented at

the surfaces of malignant cells

• Some are: alterations in transport property, diminished adhesion, loss of certain antigens etc.

The invasion-metastasis cascade

Chiang A and Massague J. N Engl J Med 2008;359:2814-2823

Tumor Initiation and Metastasis

Patterns of Metastatic Spread of Solid Tmors

Patterns of metastatic spread of solid tumor

Genes, Functions, and Cellular Players in Organ-Specific Metastasis

Genes,functions and cellualr players in organ specific metastasis

Angiogenesis

• Angiogenesis is the growth of new vasculature from pre-existing vessels.

• Involving 4 main steps :– Degradation of basement membrane– Migration of endothelial cells out of the vessels– Further proliferation and differentiation of the endothelial cells to

elongate the sprout and form the lumen of new vessel.– Secretion of growth factors by the endothelial cells, which attract

supporting cells that ‘s essential to the functioning and stability of new vessel.

• Primary factor controlling angiogenesis is :– Hypoxia .– Low oxygen tension triggers the secretion of

proangiogenic factors principally VEGF ( Vascular Endothelial Growth Factor), and stimulates new vessel formation to supply the need.

– Principal pro-angigenic regulators:• VEGF• FGF• TGF• IL8, leptin and angiogenin.

Angiogenesis Therapy

• Angiostatin (derived from plasminogen) and Endostatin (a collagen fragment) could prevent the growth of certain cancer in mice

• Some other new cancer therapies: Antisense therapy, Apoptosis promoters, Cell cycle inhibitors and Monoclonal antibodies.