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cancer and health

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  1. 1. M.Prasad Naidu MSc Medical Biochemistry, Ph.D.Research Scholar
  2. 2. Introduction Cancer cells are characterized by three properties : 1. Diminished or unrestrained control of growth , 2. Invasion of local tissues , 3. Spread or metastasis to other parts of the body . • Nearly all cancers originate from a single cell this clonal origin is critical discriminating feature between neoplasia & hyperplasia .
  3. 3. contd  Physical , chemical , & biological agents can cause cancer .  Agents causing cancer fall into 3 broad groups : 1. Radiant energy , 2. Chemical compound , 3. Viruses .  Spontaneous mutations  Oxidative damage to DNA .
  4. 4. Carcinogenic chemicals
  5. 5. Both organic & inorganic molecules are carcinogenic . Carcinogens do not share structural similarity .
  6. 6. Ultimate carcinogens are electrophiles ( molecules deficient in electrons ) they readily attack nucleophilic groups ( electron rich ) in DNA , RNA , & proteins . Metabolism of procarcinogens involves cytochrome P 450 system . Procarcinogen Proximate carcinogen Ultimate carcinogen
  7. 7. contd  Carcinogens interact covalently with cellular macro molecules .  Carcinogens found to interact with purine , pyrimidine , or phosphodiester groups of DNA .  The most common site of attack is guanine & addition of various carcinogens to N2 , N3 , N7 , O6 , O8 atoms of this base .
  8. 8. contd  Persistant unrepaired lesions are important in generating mutations critical for carcinogenesis.  Ames assay is used to detect the mutagenecity of the chemical carcinogen .  Ames assay uses specially constructed strain of salmonella typhimurium , that has a mutation in gene that codes for one of the enzyme involved in synthesis of histidine .
  9. 9.  S .typhimurium of the above strain can not synthesize histidine , needs histdine added to the medium for it’s growth .  Chemical carcinogen by its mutagenic nature restore synthesis of histidine in the S . Typhimurium .  S .typhimurium along with mitochondrial supernatant provides activation by monooxygenases .
  10. 10. Initiation & promotion • In organs such as skin & liver carcinogenesis has 2 stages 1. Intiation ( rapid & irreversible stage ), 2. Promotion . • Most carcinogens are capable of acting as both intiating & promoting agents .
  11. 11. DNA the critical macromolecule in carcinogenesis Cancer cells beget cancer cells that is essential changes responsible for cancer are transmitted from mother to daughter cells .  Both irradiation & chemical carcinogens damage DNA & are capable of causing mutations in DNA .  Many tumor cells exhibit abnormal chromosomes .
  12. 12.  Transfection experiments indicate that purified DNA ( oncogens ) from cancer cells can transform normal cells into ( potential )cancer cells .  Genes that increase susceptibility to cancer have been isolated .  Epigenetics is defined as changes that alter the pattern of gene expression that persists across at least one cell division eg: methylation of CpG dinucleotides , histone acetylation .
  13. 13. Oncogenes play a crucial role in carcinogenesis  An oncogene is a gene that, when mutated or expressed at high levels, turn a normal cell into a tumor cell.  Oncogenes were first recognized as unique genes of tumor causing viruses that are responsible for the process of transformation.
  14. 14. Oncogenes of Rous Sarcoma virus Rous sarcoma virus is retrovirus containing 4 genes named gag , pol , env , src .
  15. 15. contd  gag gene encodes for group specific antigens of the virus .  pol for reverse transcriptase that characterizes retro viruses .  env for certain glycoproteins of viruses .  src ( sarcoma causing gene ) produces a protein tyrosine kinase .
  16. 16. contd  The abnormal phosphorylation of vinculin a protein in focal adhesion plaques could help explain the rounding - up of cells & their diminished adhesion to substratum & to one another during transfromation .  Certain glycolytic enzymes appear to be target proteins for src tyrosine kinases .
  17. 17. contd  The products of src interact with the kinase catalyzing phosphorylation of phosphotidyl inositol to phosphotidyl inositol 4 , 5 bis phosphate .  Inositol triphosphate releases calcium from intracellular storage .
  18. 18. Contd  Diacyl glycerol activates protien kinase C which inturn phosphorylates number of proteins some of which are ion pumps .  Mild alkalinization of the cell brought about by activation Na+ / H+ antiport system could play a role in stimulating mitosis .
  19. 19. Protein tyrosine kinase in normal & transformed cells Insulin , PDGF , EGF found in both normal & transformed cells have tyrosine kinase activity .  The amount of phosphotyrosine in most normal cells is low but is usually elevated in cells transformed by oncogenic virus containing protein tyrosine kinase .
  20. 20. contd  The product of ras oncogene of murine sarcoma virus binds GTP , has GTPase activity & regulate activity of adenylyl cyclase .  myc oncogen encodes a DNA binding protein .  abl , src , sis , erb – B , oncogene products have tyrosine kinase activity .
  21. 21. Proto - Oncogene A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression .  Products of proto – oncogenes believed to play important roles in normal differentiation & other cellular process.
  22. 22. Oncogenes from tumor cellsDNA isolated from tumor cell added Recipient cells often a line of mouse fibroblasts NIH/3T3 microscopic observation for1-2 wk Foci of transformed cell
  23. 23. contd  The procedure is repeated several times using DNA extracted from transformed cells ,thus reducing the amount of DNA not involved in transformation , that was transfected & facilitating identification by southern blot technique using suitable probe .
  24. 24. Activation of Proto - oncogenes  5 mechanisms of activation : 1. Promoter insertion , 2. Enhancer insertion , 3. Chromosomal translocation , 4. Gene amplification , 5. Point mutations .
  25. 25. Promoter Insertion  Certain retro viruses lack oncogenes ( eg : avian leukemia viruses ) but may cause cancer over a long period of time .  Retroviruses infect cells a DNA copy ( cDNA ) of their RNA genome is synthesized by reverse transcriptase & the cDNA is integrated into the host genome .
  26. 26. Enhancer Insertion
  27. 27. Chromosomal translocation
  28. 28. Mechanism of action of oncogens Oncogens act on key intracellualr pathways involved on growth control , uncoupling them from the need fro an exogenous stimuli .  Products of src acting as tyrosine kinase , products of ras acting to stimulate adenylyl cyclase act by phosphorylating key regulatory proteins of cell cycle .
  29. 29.  Elevations of various cyclins , decrease of kinase inhibitory proteins ( KIP : p21 ,p27, p57 ) & decrease of inhibitors of CDK4 ( INK4 : p16 )has been documented in cancers .
  30. 30. Growth factors  Polypeptide growth factors are mitogenic .  Growth factors act in an endocrine , paracrine , or autocrine manner .  Growth factors act on the cell cycle & mitosis via transmembrane signal transduction.
  31. 31. Growth factors & oncogenes interact in several ways The products of several oncogenes are either growth factors or parts of the receptors for growth factors .  Product of sis oncogene truncated B chain of PDGF .  B chain is biologically active as homodimer without involvement of A chain .
  32. 32. contd  Autocrine stimulation by PDGF gives a chronic mitogenic stimulus could be an imporatnt factor in transformation of cell .  The product of erb – B is truncated EGF with much of deletion of external domain of EGF but retaining the tyrosine kinase part .  This abnormal form is continuously active tyrosine kinase when present in cells causing chronic mitogenic stimulus .
  33. 33. Transforming growth factor β  TGFβ known to inhibit the growth of most cell types except fibrobalsts .  In fibroblast TGFβ promotes growth by activating sis gene .  TGFβ inhibitory effect is on cell cycle progression is by phosphorylating pRB , reduction of the levels of mRNA s of cyclin E & A , inhibition of cyclin E & cyclin A dependent kinases .
  34. 34. The p53 tumor suppressor gene acts as a guardian of the genome  Mutations in p53 occurs frequently in many human tumors .
  35. 35.  Selenium has cancer preventive action .  Selenomethionine the main form of selenium in our diets , participates in a redox reaction resulting in the reduction of 2 cysteine residues within p53 leading to an induction of p53 DNA – binding activity .  HPV proteins E6 & E7 bind & inactivate cellular tumor suppressors p53 & pRB respectively .
  36. 36. Genetic model of colorectal cancer suggest poly gene etiology for its development Multiple cumulative mutational events are invariably required for the progression from normal to fully malignant phenotype .
  37. 37. Telomerase  DNA polymerase is unable to replicate the ends of chromosomes , resulting in loss of DNA at specialized ends of chromosomes called telomere.  Telomeres composed of tandem repeates of six nucleotide sequences ( TTAGGG ) .
  38. 38. contd  Telomere binds with specialized telomere binding proteins to form a T loop structure that prevents the ends of chromosomes from being recognized as broken or damaged DNA.  Loss of telomere repeats with each cell division cycle causes gradual telomere shortening leading to growth arrest.
  39. 39. contd  Critically short telomere triggers a p53 regulated DNA damage check point , this is called replicative senescence .  Cells can bypass this growth arrest if pRB or p53 are nonfunctional .
  40. 40. contd  The ability to bypass telomere based growth limitations is thought to be a critical step in the evolution of most malignancies .  This occurs by the expansion of telomerase in cancer cells .  Telomerase is an enzyme that adds TTAGGG repeats onto the 3’ end of chromosome .
  41. 41. Contd More than 90% of human cancers express high levels of telomearse .  Most normal do not express sufficient telomerase to prevent telomere attrition with each cell division .  Stems cell have high telomerase activity .
  42. 42. Malignancy of tumor cells tends to progress Once a cell becomes tumor cell , the composition & behavior of it’s progeny do not remain static , there is tendency for malignancy to increase .  The important phenomenon of progression appears to reflect a fundamental instability of the genome of tumor cells .
  43. 43. Metastasis is the most dangerous property of tumor cells Metastasis is spread of cancer cell from primary site of origin to other tissue where they grow as secondary tumors .  There is failure of cell - cell interaction much attention is on comparison of the biochemistry of normal & malignant cells .