Molecular Basis Of Cancer Lecture PDF

The Molecular Basis Of Cancer Oncogenesis: the induction or formation of tumors ◦ Oncogenes: are the MUTANT forms of NORMAL genes called Proto-oncogenes ◦ Oncogenes code for Oncoproteins  Fundamental Principles Non-lethal genetic damage (MUTATION) lies at the heart of carcinogenesis. Such...

The Molecular Basis Of Cancer Oncogenesis: the induction or formation of tumors ◦ Oncogenes: are the MUTANT forms of NORMAL genes called Proto-oncogenes ◦ Oncogenes code for Oncoproteins  Fundamental Principles Non-lethal genetic damage (MUTATION) lies at the heart of carcinogenesis. Such damage is acquired by environmental agents (chemicals, radiation, viruses) or inherited in the germ line. Genetic hypothesis of cancer: A tumor mass results from the clonal expansion of a single progenitor cell that has incurred genetic damage “i.e. tumors are monoclonal” ◦ Carcinogenesis involves accumulation of mutations overtime as well as one-off cell catastrophic events Mutations in Cancer: 1. Driver mutations  located in cancer genes and confer a growth advantage on cells 2. Passenger mutations  do not confer a growth advantage Molecular Basis of Cancer What is NORMAL in a cell? ◦ Dependence on growth factors ◦ Cell and tissue specific signals ◦ Loss of these signals leads to apoptosis ◦ Anchorage dependent proliferation ◦ Requires interaction of transmembrane proteins (integrins) with components of the ECM ◦ Contact inhibition ◦ Contact with other cells inhibits proliferation and movement ◦ Limited proliferative capacity ◦ Normal somatic cells have a limited number of divisions before entering senescence The Hallmarks of Cancer: Next Generation Cell 2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013)  1- Sustaining proliferative signaling ◦ Proto-oncogenes are normal genes that promote cell proliferation and differentiation. ◦ Oncogenes are mutated form of proto-oncogenes, that promote cancer cell growth autonomously (without normal growth promoting signals) ◦ Oncoproteins (products of oncogenes) promote uncontrolled cell proliferation by these mechanisms 1. Stimulate independent secretion of growth factors, so cell starts replicating 2. Mutation/over expression of growth factor receptors 3. Mutation in the genes that encode signaling proteins from receptor to nucleus 4. Over expression of nuclear transcription factors promoting cell cycle 5. Mutations in cyclin genes that result in uncontrolled cell proliferation Oncogenes And Tumor Suppressor Genes  Mechanism of Self sufficiency in growth signals 1. Stimulus independent secretion of growth factor, so cell start replication 1. PDGF –PDGF receptors in brain tumor 2. Mutation/ over expression of growth factor receptors 1. Her2/NEU receptor (25-30% cases of breast cancer), sensitive to small amount of growth factor. ◦ Clinical significance: Antibodies to these receptors is use to treat breast Ca 3. Mutation in genes that encode signaling from the receptor to the nucleus 1. RAS – commonly mutated in human cancers 2. ABL tyrosine kinase, fuses with the BCR gene in Chronic Myeloid Leukemia (BCR-ABL; t9:22), inappropriate tyrosine kinase activity leads to growth autonomy and impaired apoptosis. ◦ Clinical significance: BCR-ABL inhibitor (imatinib mesylate) is used in treatment of CML 4. Over expression of nuclear transcription factors, promote cell cycle All cell growth signals enter into the nucleus to induce mitosis 1. MYC gene promote progression through the cell cycle, ◦ mutated MYC gene seen in Burkitt lymphoma/ leukemia 5. Mutations that activate cyclin genes result in uncontrolled cell proliferation ◦ CDK-cyclin complexes drive cells through the cell cycle. The Hallmarks of Cancer: Next Generation Cell 2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013)  2- Evading Growth Suppressors Growth inhibitory signals are generated by; tumor suppressor genes ◦ Tumor suppressor genes encode proteins that inhibit cellular proliferation by regulating the cell cycle. So mutation in this group leads to uninhibited cell proliferation ◦ Unlike Oncogenes, both copies of the gene must be lost for carcinogenesis to occur (autosomal recessive) ◦ In cases with familial predisposition for development of tumors, affected persons inherit one defective (nonfunctional) copy of a tumor suppressor gene and lose the second one through somatic mutation. In sporadic cases, both copies are lost through somatic mutations. ◦ E.g in retinoblastoma ( familial & sporadic) both alleles of the RB gene are lost. ◦ Because in retinoblastoma families only a single somatic mutation is required for expression of the disease, the familial transmission follows an autosomal dominant inheritance pattern. ◦ P53 is one of the most commonly mutated gene in human cancers. ◦ APC is a tumor suppressor gene lost in Adenomatous polyposis coli Oncogenes And Tumor Suppressor Genes  Mitosis Prepare for mitosis Cell prepares for DNA synthesis Synthesis and DNA replication Extremely important check point Cell can exit cycle---- Temporarily -----Quiescence Control by RB gene Permanently----- Senescence When cells have DNA damages they activate DNA damage checkpoint that arrests cell cycle and thereby allowing for DNA repair or Apoptosis.  TP53 Gene: Guardian of the Genome Tumor suppressor gene/ pro-apoptotic gene P53 maintain central role in maintaining integrity of genome P53 senses DNA damage and assist in DNA repair by Arresting cell cycle (G1 arrest) , and Induce DNA repair genes. If DNA damage can not be repaired then p53 works by three interlocking mechanisms as follows: Temporarily arresting the cell cycle---- Quiescence Permanently arresting the cell cycle ---- Senescence Triggering programmed cell death ----Apoptosis Li-Fraumeni syndrome: homozygous loss of p53, patient develop variety of tumors The role of p53 in maintaining the integrity of humane genome Normal Apoptosis Neoplasm DNA repair genes ◦ Disability of DNA repair genes predispose the cell to accumulating DNA mutations & thus to neoplastic transformation ◦ Genes that regulate apoptosis and DNA repair may act like proto-oncogenes (loss of one copy is sufficient) or tumor suppressor genes (loss of both copies). Excellent visual! https://prezi.com/zxl6ucvgx3l3/hallmarks -of-cancer-evading-growth-suppressors/ The Hallmarks of Cancer: Next Generation