Carcinogenesis PDF

Dr.Rabie M.Elbadry CARCINOGENESIS CARCINOGENESIS  Carcinogenesis is a multistep process at both the phenotypic and the genetic levels.  It starts with a genetic damage:  Environmental  Chemical  Radiation  Viral  Inhereted Carcinogenesis  Genetic damage lead to “ mutation”  single c...

Dr.Rabie M.Elbadry CARCINOGENESIS CARCINOGENESIS  Carcinogenesis is a multistep process at both the phenotypic and the genetic levels.  It starts with a genetic damage:  Environmental  Chemical  Radiation  Viral  Inhereted Carcinogenesis  Genetic damage lead to “ mutation”  single cell which has the genetic damage undergoes neoplastic proliferation ( clonal expansion) forming the tumor mass Carcinogenesis  Where are the targets of the genetic damage??  Four regulatory genes are the main targets:  Growth promoting protooncogenes  Protooncogene > mutation > oncogene  Growth inhibiting (supressors) genes  Genes regulating apoptosis  DNA repair genes Carcinogenesis  Main changes in the cell physiology that lead to formation of the malignant phenotype:  Self-sufficiency in growth signals  Insensitivity to growth-inhibitory signals  Evasion of apoptosis  Limitless replicative potential  Sustained angiogenesis  Ability to invade and metastsize Carcinogenesis A - Self-sufficiency in Growth signals:     Oncogene: Gene that promote autonomous cell growth in cancer cells They are derived by mutations in protooncogenes They are characterized by the ability to promote cell growth in the absence of normal growthpromoting signals Oncoproteins : are the products Carcinogenesis  Remember the cell cycle !!  Binding of a growth factor to its receptor on the     cell membrane Activation of the growth factor receptor leading to activation of signal-transducing proteins Transmission of the signal to the nucleus Induction of the DNA transcription Entry in the cell cycle and cell division Carcinogenesis  HOW CANCER CELLS ACQUIRE SELF- SUFFICIENCY IN GROWATH SIGNALS?? Carcinogenesis 1- Growth factors:  Cancer cells are capable to synthesize the same growth factors to which they are responsive  E.g. Sarcomas ---- > TGF-a Glioblastoma-----> PDGF Carcinogenesis 2-Growth factors receptors:   Receptors --- mutation ----continous signals to cells and uncontroled growth Receptors --- overexpression ---cells become very sensitive ----hyperresponsive to normal levels of growth factors Carcinogenesis 3- Signal-transducing proteins :  They receive signals from activated growth factors receptors and transmitte them to the nucleus. Examples :  RAS  ABL Carcinogenesis  Main changes in the cell physiology that lead to formation of the malignant phenotype: A- Self-sufficiency in growth signals B- Insensitivity to growth-inhibitory signals C- Evasion of apoptosis D- Limitless replicative potential E- Sustained angiogenesis F- Ability to invade and metastsize Carcinogenesis 2. Insensitivity to growth-inhibitory signals  Tumor supressor genes control ( apply brakes) cells proliferation  If mutation caused disruption to them  cell becomes insensitive to growth inhibition uncontrolled proliferation  Examples: RB, TGF-b, APC, TP53 Carcinogenesis  RB ( retinoblastoma ) gene :  First tumor supressor gene discovered  It was discovered initially in retinoblastomas  Found in other tumors, e.g. breast ca  RB gene is a DNA-binding protein  RB is located on chromosome 13 Carcinogenesis  TP53 ( P53 )  It has multiple functions  Mainly :  Tumor suppressor gene ( anti-proliferative )  Regulates apoptosis Carcinogenesis  With loss of TP53, DNA damage goes unrepaired  Mutations will be fixed in the dividing cells, leading to malignant transformation Carcinogenesis  Main changes in the cell physiology that lead to formation of the malignant phenotype: A- Self-sufficiency in growth signals B- Insensitivity to growth-inhibitory signals C- Evasion of apoptosis D- Limitless replicative potential E- Sustained angiogenesis F- Ability to invade and metastsize Carcinogenesis  Evasion of apoptosis:  Mutations in the genes regulating apoptosis are factors in malignant transformation  Cell survival is controlled by genes that promote and inhibit apoptosis Carcinogenesis  Main changes in the cell physiology that lead to formation of the malignant phenotype: A- Self-sufficiency in growth signals B- Insensitivity to growth-inhibitory signals C- Evasion of apoptosis D- Limitless replicative potential E- Sustained angiogenesis F- Ability to invade and metastsize Carcinogenesis  Limitless replicative potential :  Normally there is progressive shortening of telomeres at the ends of chromosomes  Telomerase is active in normal stem cells but absent in somatic cells  In tumor cells : activation of the enzyme telomerase, which can maintain normal telomere length Carcinogenesis  Main changes in the cell physiology that lead to formation of the malignant phenotype: A- Self-sufficiency in growth signals B- Insensitivity to growth-inhibitory signals C- Evasion of apoptosis D- Limitless replicative potential E- Sustained angiogenesis F- Ability to invade and metastsize Carcinogenesis  Sustained angiogenesis  Neovascularization has two main effects:  Perfusion supplies oxygen and nutrients  Newly formed endothelial cells stimulate the growth of adjacent tumor cells by secreting growth factors, e.g : PDGF, IL-1  Angiogenesis is required for metastasis Carcinogenesis  Main changes in the cell physiology that lead to formation of the malignant phenotype: A- Self-sufficiency in growth signals B- Insensitivity to growth-inhibitory signals C- Evasion of apoptosis D- Limitless replicative potential E- Sustained angiogenesis F- Ability to invade and metastsize Carcinogenesis  Ability to invade and metastsize:  Two phases :  Invasion of extracellular matrix  Vascular dissimenation and homing of tumor cells Carcinogenesis  Vascular dissemination and homing of tumor cells:  May form emboli  Most travel as single cells  Adhesion to vascular endothelium  extravasation Carcinogenesis  Main changes in the cell physiology that lead to formation of the malignant phenotype: A- Self-sufficiency in growth signals B- Insensitivity to growth-inhibitory signals C- Evasion of apoptosis D- Limitless replicative potential E- Sustained angiogenesis F- Ability to invade and metastsize