Hallmarks of Cancer: Next Generation PDF

The Hallmarks of Cancer: Next Generation  3- Resisting Cell Death (Apoptosis) ◦ BCL-2 ---controls apoptosis by maintaining the balance between the pro- apoptotic (BAX, BAK)and anti-apoptotic molecules (BCL-2) ◦ Apoptosis can be activated by intrinsic (mitochondrial) and extrinsic pathways...

The Hallmarks of Cancer: Next Generation  3- Resisting Cell Death (Apoptosis) ◦ BCL-2 ---controls apoptosis by maintaining the balance between the pro- apoptotic (BAX, BAK)and anti-apoptotic molecules (BCL-2) ◦ Apoptosis can be activated by intrinsic (mitochondrial) and extrinsic pathways, which in turn activate caspases that induce apoptosis. ◦ Mitochondrial membrane permeability is regulated by BCL2 ◦ In 85% of cases of follicular lymphoma, activation of anti-apoptotic BCL 2 gene protects tumor cells from apoptosis ◦ TP53 is a pro-apoptotic gene which induces apoptosis in cells with irreparable DNA damage The Hallmarks of Cancer: Next Generation  4- Activating Invasion and Metastasis Divided into three steps ◦ Invasion of extracellular matrix is an active process Detachment of tumor cells from each other (loss of E-cadherin functions) Basement membrane and interstitial matrix degradation is mediated by proteolytic enzymes secreted by tumor cells and stromal cells, such as MMPs and cathepsins) Attachment of tumor cells to new binding sites in ECM Migration/locomotion of tumor cells under the influence of cytokines ◦ Vascular dissemination ◦ Homing of tumor cells Mechanisms of invasion Vascular dissemination & Homing of tumor cells ◦ Intravasation/ extravasation involves adhesion to vascular endothelium and then entrance into other organ parenchyma ◦ Metastatic site can be predicted by location of primary tumor and its vascular and lymphatic drainage ◦ Many tumors arrest in the first capillary bed they encounter (lung and liver, most commonly). ◦ Organ tropism:  Some tumors show organ tropism, probably due to activation of adhesion or chemokine receptors whose ligands are expressed by endothelial cells at the metastatic site. The Hallmarks of Cancer: Next Generation  5- Inducing Angiogenesis ◦ Vascularization of tumor cells is essential for growth and metastasis. ◦ Hypoxia activates hypoxia induced factor 1α (HIF) which activates transcription of VEGF (vascular endothelial growth factor) genes. ◦ VEGF secreted by tumor cells leads to angiogenesis (new vessel formation) ◦ HIF is inactivated by VHL gene (tumor suppressor gene) von Hippel-Lindau protein ◦ Clinical significance: VEGF antibody is now approved for treatment of some cancer Inducing angiogenesis The Hallmarks of Cancer: Next Generation  6- Enabling Replicative Immortality ◦ After 60-70 cell doubling, cells lose the capacity to divide and enter senescence. ◦ This phenomenon is due to progressive shortening of telomeres at the ends of chromosomes. ◦ Short telomere recognized as DNA damage, leading to cell cycle arrest mediated by P53 and RB ◦ Cells with mutation in P53 and RB genes can not recognize DNA damage and keep dividing Cancer cells can reactivate telomerase (an enzyme which add up telomere segments in chromosomes) thus achieving immortality Telomeres and Telomerase The Hallmarks of Cancer: Next Generation  The Molecular Basis Of Cancer Carcinogenesis is a multistep process resulting from the accumulation of multiple genetic alterations that collectively give rise to the transformed phenotype. Thus even though most malignant tumors are monoclonal in origin, by the time they become clinically evident their constituent cells may be extremely heterogeneous. Tumor progression and associated heterogeneity are most likely to result from multiple mutations that accumulate independently in different cells, generating subclones with different characteristics such as; ability to invade, rate of growth, metastatic ability, karyotype, hormonal responsiveness, and susceptibility to antineoplastic drugs. Tumor progression and generation of heterogeneity. New subclones arise from the descendants of the original transformed cell by multiple mutations.With progression, the tumor mass becomes enriched for variants that are more adept at evading host defenses and are likely to be more aggressive. Environmental repair DNA hazards Cell Damage The Molecular Basis Of Failure to repair Cancer Inherited mutations DNA Damage in genes Mutation in gene Activate Inactivate tumor Mutation in gene of Oncogenes suppressor genes apoptosis Uncontrolled cell proliferation Decreased apoptosis Clonal expansion Additional Invasion mutations Progression Metastasis Angiogenesis Malignancy  Genomic Instability ◦ Normal cells are able to repair DNA damage. ◦ Individuals with inherited defects in DNA repair genes are at greater risk for the development of cancer ◦ Best examples are ◦ Hereditary non polyposis colon cancer syndrome (HNPCC), defective DNA mismatch repair ◦ Xeroderma pigmentosum; skin Ca on exposure of sun light due to defect in DNA repair ◦ BRCA1 and BRCA2, which are mutated in familial breast cancers, are involved in DNA repair.  Karyotopic Changes or Chromosmal Abnormalities in Tumors ◦ Genetic damage during carcinogenesis may be small (e.g. point mutations) or large enough to involve part of a chromosome and can be detected in a karyotype analysis ◦ Common types of structural abnormalities in tumor cells are - balanced translocation. - deletions. - gene amplification - aneuploidy: whole chromosome gain or loss  Karyotopic Changes in Tumors 1. Balanced translocations: ◦ exchange of segments between two chromosomes. ◦ common in hematologic malignancies ◦ Philadelphia (Ph) chromosome in chronic myelogenous leukemia (95%) exchange of segments between chromosomes 9 and 22 (BCR-ABL) (t(9:22) ◦ t(8:14) in Burkitt’s Leukemia/ lymphoma ◦ t(14:18) in Follicular B cell lymphoma 2. Deletions : ◦ removal of segment of chromosome. ◦ Common in solid tumors ◦ Deletions of chromosome 13q band 14 are associated with retinoblastoma. ◦ Delations of 17p, 5q and 18q in colorectal cancer. 3. Gene amplifications: ◦ increased production of a particular gene ◦ N-MYC and HER-2 genes in neuroblastoma & breast Ca 4. Aneuploidy: ◦ a number of chromosomes that is not a multiple of the haploid state; for humans that is a chromosome number that is not a multiple of 23. Translocation Amplification  EACH CANCER MUST RESULT FROM ACCUMULATION OF MULTIPLE MUTATIONS