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Molecular Basis of Cancer

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Molecular Basis of Cancer

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  2. 2. Presented By: Mohsin Shad (2013-Bc-005) 2
  3. 3. What is cancer ?  Cancer is defined as when abnormal cells divide In an uncontrolled way. 3
  4. 4. Types of cancer  There are more than 200 types of cancer.  Skin cancer  Lung cancer  Liver cancer  Blood cancer  Bone cancer  Brain cancer 4
  5. 5. Cellular Basis of Cancer  Cancer is a collection of diseases characterized by abnormal and uncontrolled growth  Cancer arises from a loss of normal growth control  In normal tissues, the rates of new cell growth and old cell death are kept in balance  In cancer, this balance is disrupted  This disruption can result from 1) uncontrolled cell growth or 2) loss of a cell's ability to undergo apoptosis 5
  6. 6. 6 Cancer Cell Do Not Grow Faster Than Normal Cells Rather, Their Growth is Just Uncontrolled
  7. 7. How cancer spread?  The cancer spread in the body by two mechanisms.  Invasion  Metastasis 7
  8. 8. Invasion and Metastasis  Abnormal cells proliferate and spread (metastasize) to other parts of the body  Invasion - direct migration and penetration into neighboring tissues  Metastasis - cancer cells penetrate into lymphatic system and blood vessels 8
  9. 9. Different terms used in cancer  Benign tumor  Malignant tumor  Metastases  Carcinomas  Sarcomas  Leukemias 9
  10. 10. 10 • Benign tumors generally do not spread by invasion or metastasis • Malignant tumors are capable of spreading by invasion and metastasis Malignant versus Benign Tumors
  11. 11. Metastases: If cancer cell enter in the blood stream or lymphatic vessels and form secondary tumor. Carcinomas: Cancer arising from epithelial cells. Sarcomas: Cancer arising from connective tissue or muscle cells. Leukemias: Cancer that derived from Hemopoietic cells. 11
  12. 12. What causes Cancer?  Cancer is caused by alterations or mutations in the genetic code  Can be induced in somatic cells by:  Carcinogenic chemicals  Radiation  Some viruses  Heredity - 5% 12
  13. 13.  What is the molecular basis of cancer?  Cancer is a genetic disease.  Mutations in genes result in altered proteins  During cell division  External agents  Random event  Most cancers result from mutations in somatic cells  Some cancers are caused by mutations in germline cells 13
  14. 14.  Theories of cancer genesis Standard Dogma  Proto-oncogenes (Ras – melanoma)  Tumor suppressor genes (p53 – various cancers) Modified Dogma  Mutation in a DNA repair gene leads to the accumulation of unrepaired mutations (xeroderma pigmentosum) Early-Instability Theory  Master genes required for adequate cell reproduction are disabled, resulting in aneuploidy (Philadelphia chromosome) 14
  15. 15. 15 CANCER AND GENETICS • Cancer: genome disease • Causes of genomic changes • Effects of genomic changes •Revolution in cancer treatment: ‘Smart Bullets Period’
  16. 16. 16 CANCER: GENOME DISEASE • Loss of DNA • Gain of DNA • Changes in nucleotides • Epigenetic effects
  17. 17. 17 Signs for Genomic Changes in Cancer • Changes in chromosome numbers - Aneuploidy • Chromosomal changes - Increase in DNA copy number -15 different region - Loss in chromosomal -200.000 regions • Micro changes - Microsatellite changes Mikrosatellite - 100.000 - Nucleotide changes
  18. 18. 18 Carcinogenic chemicals UV Replication Errors Radiation Viruses Rearrangements (translocation, deletions, amplifications) Point mutations Alters DNA of genes controlling cell proliferation. (Proliferation becomes abnormal) Cancer cell Normal cell Damaged DNA THE CAUSES OF GENOMIC CHANGES IN CANCER
  19. 19. 19 • Approximately 90-95% of all cancers are sporadic. • 5-10% are inherited. CANCER AND GENETICS
  20. 20. Viruses Associated with human cancer  DNA Viruses  RNA Viruses  An Example of DNA virus is Hepatitis B Virus that cause Liver Cancer  An Example of RNA virus is HIV virus and its associated tumor is Kaposi’s sarcoma 20
  21. 21. 21 • Oncogenes • Tumor suppressor genes • DNA repair genes GENES PLAYING ROLE IN CANCER DEVELOPMENT
  22. 22. Factors that promote cancer 22 There are two types of factors that promote cancer 1: Tumor initiator 2: Tumor promoter A carcinogen that sows the seed of cancer in the skin and initiate the cancer is tumor initiator. Tumor promoter (which are not mutagenic) cause cancer selectively in skin previously exposed to tumor initiator.
  23. 23. ONCOGENES  Oncogenes are mutated forms of cellular proto-oncogenes.  Proto-oncogenes code for cellular proteins which regulate normal cell growth and differentiation. 23
  24. 24. 24 Class I: Growth Factors Class II: Receptors for Growth Factors and Hormones Class III: Intracellular Signal Transducers Class IV: Nuclear Transcription Factors Class V: Cell-Cycle Control Proteins Five types of proteins encoded by proto-oncogenes participate in control of cell growth:
  25. 25. 25 Oncogenes are usually dominant (gain of function) • cellular proto-oncogenes that have been mutated (and “activated”) • cellular proto-oncogenes that have been captured by retroviruses and have been mutated in the process (and “activated”) • virus-specific genes that behave like cellular proto- oncogenes that have been mutated to oncogenes (i.e., “activated”)
  26. 26. RAS GENE  RAS gene is an example of oncogene that stimulates or inhibits cell division  kills tumor cells  destroys DNA  repels bacteria that can cause cancer 26
  27. 27. The result:  Overproduction of growth factors  Flooding of the cell with replication signals  Uncontrolled stimulation in the intermediary pathways  Cell growth by elevated levels of transcription factors 27
  28. 28. Tumor suppressor genes  Normal function - inhibit cell proliferation  Absence/inactivation of inhibitor --> cancer  Both gene copies must be defective 28
  29. 29. Rb gene  Rb protein controls cell cycle moving past G1 checkpoint  Rb protein binds regulatory transcription factor E2F  E2F required for synthesis of replication enzymes  E2F - Rb bound = no transcription/replication  Growth factor --> Ras pathway --> G1Cdk-cyclin synthesized  Active G1 Cdk-cyclin kinase phosphorylates Rb  Phosphorylated Rb cannot bind E2F --> S phase  Disruption/deletion of Rb gene  Inactivation of Rb protein --> uncontrolled cell proliferation --> cancer 29
  30. 30. p53  Phosphyorylated p53 activates transcription of p21 gene  p21 Cdk inhibitor (binds Cdk-cyclin complex --> inhibits kinase activity)  Cell cycle arrested to allow DNA to be repaired  If damage cannot be repaired --> cell death (apoptosis)  Disruption/deletion of p53 gene  Inactivation of p53 protein --> uncorrected DNA damage --> uncontrolled cell proliferation --> cancer 30
  31. 31. 31 These are genes that ensure each strand of genetic information is accurately copied during cell division of the cell cycle. Mutations in DNA repair genes lead to an increase in the frequency of mutations in other genes, such as proto-oncogenes and tumor suppressor genes. i.e. Breast cancer susceptibility genes (BRCA1 and BRCA2) Hereditary non-polyposis colon cancer susceptibility genes (MSH2, MLH1, PMS1, PMS2) have DNA repair functions. Their mutation will cause tumorigenesis. DNA REPAIR GENES
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