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Caecinogenesis The Molecular Basis Of Cancer Fadwa Jameel Altaf Layalh S. Ab dullah Osama Nassif Ali Sawan Types of Normal Cellular Genes 3 Normal regulatory genes; Growth promoting protooncogene Growth inhibiting tumor suppressor gene Gene regulate apoptosis 4 the category is DNA repair gene Molecular Basis Of Cancer Nonlethal genetic damage lies at the heart of carcinogenesis Genetic hypothesis of cancer implies that a tumor mass result from the clonal expansion of a single progenitor cell that incurred the genetic damage Clonality of Neoplastic Cells Most tumor cells are monoclonal 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 Principles of Carcinogenesis Neoplastic transformation is a progressive process involving multiple “hits” or genetic changes. Alterations in DNA cause changes in one or both of the following types of genes: Proto-oncogenes----Oncogene--(dominant) Tumor suppressor genes---TSG---- (recessive) Genes regulate apoptosis (dominant or recessive) DNA repair genes Tumor Development and Growth Transformation Growth of transformed cells Invasion of tumor cells into the surrounding tissues Metastasis of tumor cells to distant sites Hallmarks of Cancer Six fundamental changes of cell Physiology 1. 2. 3. 4. 5. 6. Self sufficiency in growth factors Insensitivity to growth-inhibitory signals Evasion of apoptosis Limitless replicative potential Sustained angiogenesis Ability to invade and metastasize Self-Sufficiency In Growth Signals Oncogenes promote autonomous cell growth in cancer cells by: Point Mutations Chromosomal Translocations Gene Amplification Activation of Oncogenes Point Mutations Chromosomal Translocations The RAS gene is an oncogene that becomes activated by a point mutation. Translocation of chromosome 9 and 22 in CML creating a fusion gene that produces an activated tyrosine kinase. Gene Amplification Specific oncogenes such as N-myc and C-neu are amplified in neuroblastoma and breast cancer respectively. Self-Sufficiency In Growth Signals Oncogenes promote autonomous cell growth in cancer cells Their product is called oncoproteins Devoid of important regulatory elements & their production does not depend on growth factors or other external signals Self-Sufficiency In Growth Signals (Oncogenes) Growth Factors Growth Factor Receptors Signal transducing Proteins Nuclear transcription factors Cyclins & cyclin- dependent kinases Growth Factors Many cancer cells acquire growth self-sufficiency, by acquiring the ability to synthesize the same GF to which they are responsive. The growth factor itself is not altered or mutant, but the product of other oncogenes cause overexpression of growth factors Self-Sufficiency In Growth Signals (Oncogenes) Growth Factors Growth Factor Receptors Signal transducing Proteins Nuclear transcription factors Cyclins & cyclin- dependent kinases Growth Factor Receptors Mutations & pathologic overexpression of normal forms of GFR have been detected in several tumors. Overexpression of GFR render tumor cells hyperresponsive to normal level of GF EGF receptor seen in 80% of sq cell ca of lung HER2 is amplified in 25%-30% of adenocarcinoma of breast Self-Sufficiency In Growth Signals (Oncogenes) Growth Factors Growth Factor Receptors Signal transducing Proteins Nuclear transcription factors Cyclins & cyclin- dependent kinases 30% OF ALL TUMORS Activation of MAP kinase pathway BCR-ABL HYBRID GENE Potenttyrosine kinase activity Impaired apoptosis (Gleevec)ST1 571 is effective in treatment of CML Self-Sufficiency In Growth Signals (Oncogenes) Growth Factors Growth Factor Receptors Signal transducing Proteins Nuclear transcription factors Cyclins & cyclin- dependent kinases Self-Sufficiency In Growth Signals (Oncogenes) Growth Factors Growth Factor Receptors Signal transducing Proteins Nuclear transcription factors Cyclins & cyclin- dependent kinases Cyclins CyclinD overexpressed seen in -Breast, esophagaus, liver, lymphoma . Cyclin CDK4 amplification is seen in -Melanoma, sarcoma, glioblastoma. . Cyclin B,E,& CDKs occur in some malignant neoplasm but they are less frequant than cyclin D/CDK4.