Caecinogenesis The Molecular Basis Of Cancer

1. Caecinogenesis The Molecular Basis Of Cancer Fadwa Jameel Altaf Layalh S. Ab dullah Osama Nassif Ali Sawan

2. 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

3. 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

4. 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

5. 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

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

8. Hallmarks of Cancer Six fundamental changes of cell Physiology • Self sufficiency in growth factors • Insensitivity to growth-inhibitory signals • Evasion of apoptosis • Limitless replicative potential • Sustained angiogenesis • Ability to invade and metastasize

10. Self-Sufficiency In Growth Signals • Oncogenes promote autonomous cell growth in cancer cells by: Point Mutations Chromosomal Translocations Gene Amplification

11. Activation of Oncogenes • Point Mutations • The RAS gene is an oncogene that becomes activated by a point mutation. • Chromosomal Translocations • 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.

12. 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

14. Self-Sufficiency In Growth Signals (Oncogenes) • Growth Factors • Growth Factor Receptors • Signal transducing Proteins • Nuclear transcription factors • Cyclins & cyclin- dependent kinases

15. 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

16. Self-Sufficiency In Growth Signals (Oncogenes) • Growth Factors • Growth Factor Receptors • Signal transducing Proteins • Nuclear transcription factors • Cyclins & cyclin- dependent kinases

18. 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

19. Self-Sufficiency In Growth Signals (Oncogenes) • Growth Factors • Growth Factor Receptors • Signal transducing Proteins • Nuclear transcription factors • Cyclins & cyclin- dependent kinases

21. 30% OF ALL TUMORS

22. Activation of MAP kinase pathway

23. Potenttyrosine kinase activity Impaired apoptosis (Gleevec)ST1 571 is effective in treatment of CML BCR-ABL HYBRID GENE

24. Self-Sufficiency In Growth Signals (Oncogenes) • Growth Factors • Growth Factor Receptors • Signal transducing Proteins • Nuclear transcription factors • Cyclins & cyclin- dependent kinases

28. Self-Sufficiency In Growth Signals (Oncogenes) • Growth Factors • Growth Factor Receptors • Signal transducing Proteins • Nuclear transcription factors • Cyclins & cyclin- dependent kinases

31. 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.