1. Molecular Perspectives In Oncogenesis Marigold D.R. Majarucon-Ferrolino, MD , FPCP, FPSMO Department of Biochemistry & Nutrition Our Lady of Fatima University College of Medicine

3. CANCER CELLS AND NORMAL CELLS CANCER CELLS NORMAL CELLS Loss of contact inhibition Increase in growth factor secretion Increase in oncogene expression Loss of tumor suppressor genes Oncogene expression is rare Intermittent or co-ordinated growth factor secretion Presence of tumor suppressor genes Normal cell Few mitoses Frequent mitoses Nucleus Blood vessel Abnormal heterogeneous cells

10. The Cell Cycle G1/S checkpoint G2/M checkpoint DEATH DIFFERENTIATION DNA content = 2n Mitosis M S DNA synthesis G 2 G 1 G 0 DNA content = 4n

11. CYCLIN, CDK,CDKI: PHOSPHORYLATION

15. Rb Gene Activation

22. INVASION AND METASTASIS

27. ONCOGENE FAMILY Classification of Oncogenes A. Secreted Growth Factors B. Cell Surface Receptors C. Intracellular Transducers D. DNA-binding Nuclear Proteins E. Regulators of the Cell Cycle Components of signal transduction pathways c-sis, hst erb B, fms, ret, trk, fes, fms c-src, c-abl, mst, ras myc, jun, fos bcl, bax, bad

28. SIGNAL TRANSDUCTION

29. ONCOGENE FAMILY Mechanisms of Oncogene Activation 1. Point Mutation H-ras [codon 12] Normal C G C  Gly Bladder ca C T C  Val H-ras GTP Perpetual cell division 2. Gene Amplification Double minutes HSRs Normal copy Multiple copies

30. ONCOGENE FAMILY Mechanisms of Oncogene Activation 3. Gene Translocation Ex. Burkitt’s Lymphoma

31. ONCOGENE FAMILY Mechanisms of Oncogene Activation 3. Gene Translocation Ex. Chronic Myelogenous Leukemia [CML]

32. ONCOGENE FAMILY Mechanisms of Oncogene Activation 4. Viral Gene Integration promoter Viral promoter

34. TUMOR SUPPRESSOR GENE FAMILY KNUDSON’S Two-Hit Hypothesis 1st Hit : TS mutation or Inherited mutation 2nd Hit : gross chromosomal loss

37. TUMOR SUPPRESSOR GENE FAMILY p53 protein

38. p53 in action

40. In summary ….. ONCOGENES TS GENES MUTATOR GENES

41. Re-cap of Molecular Carcinogenesis Proto-oncogene Gain-of-function TS gene Loss-of-function Mutator gene Loss-of-function CANCER

49. CARCINOGEN METABOLISM Three Main Categories: I. Chemical Carcinogens II. Physical Carcinogens III. Viral Agents Carcinogens Mutations Cancer Environmental factors ?

50. CHEMICAL CARCINOGENESIS Stages: Initiation - primary exposure Promotion - transformation Progression - Cancer growth Frank Cancer

56. PHYSICAL CARCINOGENESIS Ultraviolet Rays UV-A = 320 - 400 nm UV-B = 280 - 320 nm UV-C = 200 - 280 nm

57. PHYSICAL CARCINOGENESIS Ultraviolet Rays UV-C  filtered by ozone UV-B Inhibition of cell division inactivation of enzymes induction of mutations cell death at high doses Squamous cell cancer Basal cell cancer Melanocarcinoma

60. Viral Oncogenes RETROVIRUS Oncogene Viral RNA Viral DNA NUCLEUS DNA Oncogene REVERSE TRANSCRIPTASE INSERTION TRANSCRIPTION Oncogene Viral RNA CELL MEMBRANE CYTOPLASM Viral genome RNA messenger TRANSCRIPTION Oncogene protein

63. VIRAL AGENTS: DNA viruses Human Papillomavirus [HPV types 16, 18, 31, 33 & 35] Interruption of the E1/E2 ORF E2 is not expressed Over-expression of E6 & E7

67. SIGNAL TRANSDUCTION

71. PROLIFERATION

73. The Cell Cycle G1/S checkpoint G2/M checkpoint DEATH DIFFERENTIATION DNA content = 2n Mitosis M S DNA synthesis G 2 G 1 G 0 DNA content = 4n

77. CYCLIN, CDK,CDKI: PHOSPHORYLATION

79. Rb Gene Activation

82. p53 in action

83. CELL-CYCLE PROGRESSION

88. IMMORTALIZATION

96. EVADING APOPTOSIS

103. ANGIOGENESIS

105. INVASION AND METASTASIS

107. PROCESS OF METASTASIS

112. METASTASIS AND INVASION

113. THANK YOU !