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MOLECULAR PATHOGENESIS OF CANCER(GENES AND CANCER)

MOLECULAR PATHOGENESIS OF CANCER(GENES AND CANCER). GENETIC THEORY OF CANCER. CELL GROWTH OF NORMAL AS WELL AS ABNORMAL CELL IS UNDER GENETIC CONTROL. MOLECULAR PATHOGENESIS OF CANCER(GENES AND CANCER).

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MOLECULAR PATHOGENESIS OF CANCER(GENES AND CANCER)

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  1. MOLECULAR PATHOGENESIS OF CANCER(GENES AND CANCER) GENETIC THEORY OF CANCER.CELL GROWTH OF NORMAL AS WELL AS ABNORMAL CELL IS UNDER GENETIC CONTROL

  2. MOLECULAR PATHOGENESIS OF CANCER(GENES AND CANCER) IN CANCER ABNORMALITY MAY BE INHERITED OR AQUIRED-INDUCED BY CHEMICALS,VIRUSES OR RADIATION. MUTATED CELL TRANSMIT THEIR CHARACTERS TO THE NEXT PROGENY OF CELLS AND RESULT IN CANCER.

  3. GENETIC REGULATION OF NORMAL AND ABNORMAL MITOSIS NORMAL CELL GROWTH REGULATORY GENES CONTROL MITOSIS AS WELL AS CELL AGING

  4. GENETIC REGULATION OF NORMAL AND ABNORMAL MITOSIS REGULATORY GENES ARE 1.PROTO-ONCOGENES- GROWTH PROMOTING GENES. 2.ANTI-ONCOGENES- GROWTH SUPPRESSOR GENES

  5. GENETIC REGULATION OF NORMAL AND ABNORMAL MITOSIS 3.APOPTOSIS REGULATORY GENES 4.DNA REPAIR GENES- REPAIR DNA DAMAGE THAT HAS OCCURED DURING MITOSIS AND ALSO CONTROL THE DAMAGE TO PROTOONCOGENES AND ANTIONCOGENES

  6. ABNNORMALITIES OF GENES IN CANCER a.ACTIVATION OF GROWTH PROMOTING ONCOGENES.

  7. ABNORMALITIES OF GENES IN CANCER MUTANT FORM OF NORMAL PROTOONCOGENE IN CANCER IS TERMED ONCOGENE.

  8. ABNORMALITIES OF GENES IN CANCER b. INACTIVATION OF CANCER SUPPRESSOR GENES-PERMITTING CELLULAR PROLIFERATION OF TRANSFORMED CELLS.

  9. ABNORMALITIES OF GENES IN CANCER c. ABNORMAL APOPTOSIS REGULATING GENES WHICH MAY ACT AS ONCOGENES d. FAILURE OF DNA REPAIR GENES.

  10. ABNORMALITIES OF GENES IN CANCER CANCER GROWTH AND PROGRESSION IS A MULTISTEPPROCESS INVOLVING MANY GENERATIONSOF CELLS.VARIOUS CAUSES MAY ACT ON THE CELL ONE AFTER ANOTHER (MULTIHIT PROCESS).

  11. ABNORMALITEIS OF GENES IN CANCER THE CELLS SO FORMED ARE GENETICALLY AND PHENOTYPICALLY TRANSFORMED CELLS HAVING PHENOTYPIC FEATURES OFMALIGNANCY- EXCESSIVE GROWTH, INVASIVENESS, AND DISTANT METASTASIS.

  12. CANCER RELATED GENES AND CELL GROWTH MAJOR GENETIC PROPERTIES OR HALL MARKS OF CANCER ARE. 1.EXCESSIVE AND AUTONOMOUS GROWTH:GROWTH PROMOTING ONCOGENES. 2.REFRACTORINESS TO GROWTH INHIBITORY- GROWTH SUPPRESSING ANTIONCOGENES.

  13. CANCER RELATED GENES AND CELL GROWTH 3.ESCAPING CELL DEATH BY APOPTOSIS - GENES REGULATING APOPTOSIS. 4.AVOIDING CELLULAR AGING- TELOMERES AND TELOMERASE 5.CONTINUED PERFUSION -CANCER ANGIOGENESIS

  14. MAJOR GENETIC PROPERTIES AND HALL MARKS OF CANCER 6. INVASION AND DISTANT METASTASIS-CANCER DISSEMINATION. 7. DNA DAMAGE AND FAILURE OF REPAIR SYSTEM

  15. MAJOR GENETIC PROPERTIES AND HALL MARKS OF CANCER 8. CANCER PROGRESSION, TUMOUR HETEROGENEITY AND CLONAL AGGRESSIVENESS.

  16. MAJOR GENETIC PROPERTIES OR HALL MARKS OF CANCER

  17. MECHANISM OF ACTIVATION OF GROWTH PROMOTING ONCOGENES IN HUMANTUMOURS 1. POINT MUTATION ( SINGLE BASE SUBSTITUTION) EXAMPLE –RAS ONCOGENE IN HUMAN TUMOURS SUCH AS BLADDER CANCER, PANCREATIC ADENOCARCINOMA.

  18. MECHANISM OF ACTIVATION OF GROWTH PROMOTING ONCOGENES IN HUMANTUMOURS 2. CHROMOSOMAL TRANSLOCATION TRANSFER OF A PORTION OF ONE CHROMOSOME TO ANOTHER IS IMPLICATED IN THE PATHOGENESIS OF LEUKEMIAS AND LYMPHOMAS

  19. MECHANISM OF ACTIVATION OF GROWTH PROMOTING ONCOGENES IN HUMAN TUMOURS (TRANSLOCATION) PHILADELPHIA CHROMOSOME IN CHRONIC MYELOID LEUKEMIAS- ABL PROTOONCOGENE ON CHROMOSOME 9 IS TRANSLOCATED TO CHROMOSOME 22(95% OF CML).

  20. PHILADELPHIA CHROMOSOME

  21. MECHANISM OF ACTIVATION OF GROWTH PROMOTING ONCOGENES IN HUMAN TUMOURS (TRANSLOCATION) BURKITTS LYMPHOMA- TRANSLOCATION OF C-MYC PROTOONCOGENE FROM IT’S SITE ON CHROMOSOME 8 TO CHROMOSOME 14

  22. MECHANISM OF ACTIVATION OF GROWTH PROMOTING ONCOGENES IN HUMAN TUMOURS (TRANSLOCATION) 3. GENE AMPLIFICATION- INCREASE IN NUMBER OF COPIES OF A GENE FOUND IN SOME SOLID HUMAN TUMOURS.

  23. HOW ONCOGENES ACT ? BY SIGNAL TRANSDUCTION FOR CELL PROLIFERATION.

  24. STEPS IN SIGNAL TRANSDUCTION FOR CELL PROLIFERATION BY ONCOGENES-IN RELATION TO MITOSIS. 1. GROWTH FACTORS IN CANCER. GFs ELABORATED BY MANY CELLS HAVING PARACRINE ACTION,BUT IN CANCER THEY HAVE AUTOCRINE ACTION AS WELL.

  25. STEPS IN SIGNAL TRANSDUCTION FOR CELL PROLIFERATION BYONCOGENES 2.RECEPTORS FOR GROWTH FACTORS.-ARE CODED BY ONCOGENES-

  26. STEPS IN SIGNAL TRANSDUCTION FOR CELL PROLIFERATION BYONCOGENES HER2(ERB2) – GFRECEPTOR OVEREXPRESSED IN BREAST CANCER, CARCINOMA LUNG,OVARY AND STOMACH

  27. STEPS IN SIGNAL TRANSDUCTION FOR CELL PROLIFERATION BY ONCOGENES IN RELATION TO MITOSIS- SIGNAL TRANSDUCTION PROTEINS 3 .SIGNAL TRANSDUCTION PROTEINS -TRANSDUCE SIGNALS FROM GF RECEPTORS ON THE CELL SURFACE TO THE NUCLEUS OF THE CELL- MUTATED IN SOME CANCERS.

  28. STEPS IN SIGNAL TRANSDUCTION FOR CELL PROLIFERATION BY ONCOGENES IN RELATION TO MITOSIS- SIGNAL TRANSDUCTION PROTEINS EXAMPLES a . RAS GENE- ONE THIRD OF ALL HUMAN TUMOURS CARRY MUTATED RAS- CARCINOMA COLON,LUNG,PANCREAS

  29. STEPS IN SIGNAL TRANSDUCTION FOR CELL PROLIFERATION BY ONCOGENES(SIGNAL TRANSDUCTION PROTEINS) NORMAL RAS PROTEIN IS INACTIVATED BY GTPase.BUT MUTATED FORM OF RAS GENE REMAIN UNAFFECTED BY GTPase,SO CONTINUE TO REMAIN ACTIVE TO SIGNAL FOR CELL PROLIFERATION.

  30. STEPS IN SIGNAL TRANSDUCTION FOR CELL PROLIFERATION BY ONCOGENES(SIGNAL TRANSDUCTION PROTEINS) b. BCR-ABL HYBRID GENE- ABL PROTO-ONCOGENE FROM IT’S NORMAL LOCATION ON CHROMOSOME 9 IS TRANSLOCATED TO CHROMOSOME 22 WHERE IT FUSES WITH BCR(BREAKPOINT CLUSTER REGION) GENE .

  31. STEPS IN SIGNAL TRANSDUCTION FOR CELL PROLIFERATION BY ONCOGENES(SIGNAL TRANSDUCTION PROTEINS) THIS HYBRID GENE IS MORE POTENT IN SIGNAL TRANSDUCTION PATHWAY-CML,CERTAIN ACUTE LEUKAEMIAS.

  32. SIGNAL TRANSDUCTION FOR CELL PROLIFERATION BY ONCOGENES IN RELATION TO MITOSIS 4. NUCLEAR REGULATORY TRANSCRIPTION PROTEINS - SIGNAL TRANSDUCTION PATHWAY REACHES NUCLEUS WHERE IT REGULATES DNA TRANSCRIPTION.

  33. SIGNAL TRANSDUCTION FOR CELL PROLIFERATION BY ONCOGENES IN RELATION TO MITOSIS MOST IMPORTANT REGULATORY TRANSCRIPTION PROTEIN IS MYC PROTEIN WHICH BINDS TO DNA REGULATES CELL CYCLE BY TRANSCRIPTIONAL ACTIVATION.

  34. SIGNAL TRANSDUCTION FOR CELL PROLIFERATION BY ONCOGENES IN RELATION TO MITOSIS OVEREXPRESSION OF MYC ONCOGENE CAUSES AUTONOMOUS CELL PROLIFERATION.

  35. SIGNAL TRANSDUCTION- NUCLEAR REGULATORY TRANSCRIPTION PROTEINS EXAMPLE-BURKITT’S LYMPHOMA-MUTATION IN MYC ONCOGENE IS DUE TO TRANSLOCATION 8:14 AMPLIFICATION OF MYC GENE IN CARCINOMA LUNG ,BREAST ,COLON

  36. SIGNAL TRANSDUCTION- NUCLEAR REGULATORY TRANSCRIPTION PROTEINS 5. CELL CYCLE REGULATORY PROTEINS- CYCLINS AND CYCLIN DEPENDENT KINASES(CDKs). MUTATIONS IN THESE PROTEINS ARE MOST IMPORTANT GROWTH PROMOTING SIGNALS IN CANCERS

  37. SIGNAL TRANSDUCTION- NUCLEAR REGULATORY TRANSCRIPTION PROTEINS EXAMPLES- OVEREXPRESSION OF CYCLIN-D IN CARCINOMA BREAST,LIVER,MANTLE CELL LYMPHOMA, AMPLIFICATION OF CDK4 IN MLIGNANT MELANOMA GLIOBLASTOMAS AND SARCOMAS.

  38. 11.REFRACTORINESS TO GROWTH INHIBITION GROWTH SUPRESSING ANTIONCOGENES. MUTATED ANTIONCOGENES BEHAVE LIKE GROWTH PROMOTING ONCOGENES.

  39. 11.REFRACTORINESS TO GROWTH INHIBITION MAJOR ANTIONCOGENES IMPLICATED IN HUMAN CANCER ARE ARE 1.RB GENE-NUCLEAR TRANSCRIPTION GENE PRESENT IN EVERY HUMAN CELL.

  40. 11.REFRACTORINESS TO GROWTH INHIBITION MUTANT FORM OF RB GENE PROMOTE CELL CYCLE – RETINOBLASTOMA.

  41. 11.REFRACTORINESS TO GROWTH INHIBITION SPORADIC CASES OF RETINOBLASTOMA- MUTATION OF BOTH ALLELS IN RETINAL CELLS OCCUR AFTER BIRTH

  42. 11.REFRACTORINESS TO GROWTH INHIBITION IN INHERITED CASES ALL SOMATIC CELLS INHERIT ONE MUTANT RB GENE FROM A CARRIER PARENT, WHILE OTHER ALLELE GETS MUTATED LATER(TWO HIT HYPOTHESIS OF KNUDSON).

  43. 11.REFRACTORINESS TO GROWTH INHIBITION MUTANT RB GENE IN OSTEOSARCOMA,CARCINOMABREAST, COLON ,LUNGS

  44. II .REFRACTERINESS TO GROWTH INHIBITION-GROWTH SUPPRESSING ANTIONCOGENES- 2.TP53 GENE –A GROWTH SUPPRESSOR ANTIONCOGENE. TWO MAJOR FUNCTIONS OF TP53 ARE a.BLOCKING MITOTIC ACTIVITY b.PROMOTING APOPTOSIS.

  45. II .RFRACTERINESS TO GROWTH INHIBITION-GROWTH SUPPRESSING ANTIONCOGENES- ACTS TOGETHER WITH RB GENE IDENTIFIES CELLS WITH DAMAGED DNA,DIRECTS SUCH CELLS TO APOPTOSIS BY ACTIVATING APOPTOSIS INDUCING BAX GENE.

  46. GROWTH SUPPRESSING ANTIONCOGENES TP53 IS CALLED THE PROTECTOR OF GENOME. MUTATED FORM OF TP53 ACT LIKE A ONCOGENE

  47. GROWTH SUPPRESSING ANTIONCOGENES 3.TRANSFORMING GROWTH FACTOR BETA. – ACT ON CELL CYCLE –INHIBITS CELL PROLIFERATION. MUTATED FORM PERMITS CELL PROLIFERATION-CARCINOMA COLON,PANCREAS, STOMACH

  48. GROWTH SUPPRESSING ANTIONCOGENES 4. ADENOMATOUS POLYPOSIS COLI (APC) GENE -INHIBITS MITOSIS-THROUGH CYTOPLASMIC PROTEIN - BETA CATENIN WHICH BLOCKS THE SIGNAL TO THE NUCLEUS.

  49. GROWTH SUPPRESSING ANTIONCOGENES IN COLONIC CANCER APC GENE IS LOST, THUS THE CANCER CELLS CONTINUE TO UNDERGO MITOSIS WITHOUT THE INHIBITORY INFLUENCE OF BETA CATENIN

  50. GROWTH SUPPRESSOR ONCOGENES 5 .OTHER ANTIONCOGENES WILMS’ TUMOUR GENE-(WT)-NORMALLY INHIBITS PROLIFERATION OF CELLS IN EMBRYONIC KIDNEY.MUTATED WT GENES(WT1 AND 2) ARE SEEN IN HEREDITORY WILMS’ TUMOUR.

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