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Neoplasia IV Biology of Tumor Growth

Neoplasia IV Biology of Tumor Growth. Husni Maqboul, M.D. Molecular Basis Of Cancer. Principles Non lethal genetic damage lies at the heart of carcinogenesis Targets of genetic damage are : Protooncogenes Antioncogenes ( Cancer suppressor genes )

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Neoplasia IV Biology of Tumor Growth

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  1. Neoplasia IVBiology of Tumor Growth Husni Maqboul, M.D

  2. Molecular Basis Of Cancer • Principles • Non lethal genetic damage lies at the heart of carcinogenesis • Targets of genetic damage are : • Protooncogenes • Antioncogenes ( Cancer suppressor genes ) • Genes of programmed cell death ( Apoptosis genes ) • DNA repair genes

  3. Molecular Basis Of Cancer • No single oncogene can fully transform cells • Every human Cancer shows activation of several oncogenes, and loss of two or more suppressors • Multistep process at phenotypic and genetic levels

  4. Evolution of Colorectal Cancer

  5. Tumor Development and Growth • Transformation • Growth of transformed cells • Invasion of tumor cells into the surrounding tissues • Metastasis of tumor cells to distant sites

  6. Transformation and Growth • By the time a tumor is clinically detectable ( 1gr. or 10 *9 cells, it has completed a major portion o f its life cycle • Growth fraction : By the time of detection, 10 - 30% of tumor cells are in the replicative pool • Rate of growth determined by growth fraction, and excess of cell production, over cell loss • 1cell 1 gr. of cells needs 30 cell cycles ( theoretically 90 days ) but actually it needs much longer time , moths or even years

  7. Clonality of Neoplastic Cells • Most tumor cells are monoclonal • Identical glucose-6-phosphate isoenymes in tumors of female patients (an X-linked enzyme). • All tumor cells may possess a specific chromosomal abnormality. • Unique rearrangement of immunoglobulin or T-cell receptor genes in lymphoid tumors. • Tumor cell heterogeneity is common • Clinical behavior is the best definition of malignancy

  8. Tumor Monoclonality

  9. Tumor Angiogenesis • Tumors cannot enlarge beyond 1-2mm in thickness unless they are vascularized • Neovasculrization promotes growth by nutrient and oxygen supply, and by secretion of many GF by newly formed endothelial cells • Angiogenesis is also a requisite for metastasis • Most human tumors do not produce angiogenesis, and remain in situ for moths or years

  10. Tumor Angiogenesis • Tumor-associated angiogenic factors • Vascular endothelial growth factor • Controlled by RAS, and induced by hypoxia (hypoxia-inducible factor I) • Basic fibroblast growth factor • Growth balanced by antiangiogenesis factors • Thrombospondin I ( induced by wild-type TP53) • Angiostatin, endostatin ( being tested in treatment of Ca ), and vasculostatin

  11. Tumor Progression and Heterogeneity • Biologic phenomenon related to sequential appearance of subpopulations of cells different in several phenotypic attributes such as invasiveness, rate of growth, metastatic ability, karyotype, hormonal responsiveness, and susceptibility to antineoplastic drugs • Multiple mutations because of genetic instability

  12. Tumor Progression and Heterogeneity

  13. Properties of Transformed Cells In Vitro • Decreased contact inhibition • Decreased requirement for growth factors • Anchorage independence • Failure to differentiate • Immortality • Transplantability • Reduced cohesiveness

  14. Tumor Cell Invasion • Detachment from other tumor cells. • Adhesion to the extracellular matrix. • Proteolytic degradation of the extracellular matrix. • Motility and migration into the extracellular matrix.

  15. Cell-Cell Adhesion molecules that function in tumor cell invasion and metastasis • Detachment • E-cadherin linked to β catenins ( inactivation of of E-cadherin genes, or by activation of β catenin genes) • Integrins: A family comprising many heterodimeric cell-surface molecules that mediate cell adhesion to different extracellular matrix molecules. A switch to poorly adhesive forms may take place in some tumors

  16. Cell-Extracellular matrix adhesion molecules involved in invasion and metastasis • Attachment to ECM • Laminin ( of B.M ) receptors - Up regulation with irregular distribution • CD44: Mediates tumor cell attachment to hyaluronate.

  17. Structural Proteins of Extracellular Matrix • Basement membrane • Type IV collagen • Laminin • Proteoglycans • Interstitial Stromal Matrix • Type I collagen • Type II collagen • Fibronectin • Proteoglycans

  18. Enzymes that Mediate Tumor Cell Degradation of Extracellular Matrix • Matrix metalloproteinases (MMP) • Type IV collagenases (Gelatinase) • Interstitial collagenases • Stromelysins • Plaminogen Activator/Plasmin • Cathepsins • Glycosidases • Tumor cell-Endothelial cell adhesion • Sialyl Lewis X-E-selectin • VLA-4-VCAM

  19. Migration • Tumor-cell derived motility factors • Autocrine motility factors • Thymosin beta 15 (e.g in prostatic Ca but not in BNH) • Hepatocyte GF • Cleavage products of matrix components • Have growth promoting, angiogenic and chemotactic activities

  20. Host Factors Affecting Tumor Cell Growth • Blood Supply • Tumor cell production of angiogenic factors such as fibroblast growth factor. • Hormones • Hormonally dependent tumors occur that proliferate more rapidly with increased hormone. • Immunological • Host immune response to the tumor versus tumor cell resistance to the immune response.

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