Neoplasia 6-3-2011

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Neoplasia 6-3-2011

  1. 1. Neoplasia<br />Dr Omar Chughtai<br />
  2. 2.
  3. 3. Cancer<br />Uncontrolled growth of abnormal cells<br />
  4. 4.
  5. 5.
  6. 6. The Study of Cancer<br /><ul><li>Research:
  7. 7. Pathologists
  8. 8. Molecular Biologists and Geneticists
  9. 9. Diagnose:
  10. 10. Pathologists
  11. 11. Radiologists
  12. 12. Treat:
  13. 13. Oncologists
  14. 14. Surgeons</li></li></ul><li>Nomenclature<br />Neoplasm: new growth<br />Tumor: swelling caused by inflammation; now almost always used to refer to neoplastic masses<br />
  15. 15. Nomenclature<br />Metaplasia Dysplasia<br />
  16. 16. Characteristics of Neoplasms<br />Differentiation and Anaplasia<br />Rate of Growth<br />Invasion of Surrounding Tissue<br />Metastatic Potential<br />
  17. 17. Differentiation and Anaplasia<br />Differentiation: How similar tumor cells are to normal cells <br />Benign Tumors: Well-differentiated<br />Malignant Tumors: Range of differentiation<br />Anaplasia: The lack of differentiation<br />
  18. 18.
  19. 19.
  20. 20.
  21. 21. Differentiation and Anaplasia<br />Pleomorphism: <br />Variable cell size / shape<br />
  22. 22. Differentiation and Anaplasia<br />Abnormal Nuclear Morphology: <br />Variable nuclear size / shape<br />dark (hyperchromatic)<br />prominent nucleoli<br />clumped chromatin<br />
  23. 23. Differentiation and Anaplasia<br />Mitoses: Increased in number, abnormal in shape <br />
  24. 24. Differentiation and Anaplasia<br />Loss of Polarity: No longer arranged neatly<br />
  25. 25. Differentiation and Anaplasia<br />Tumor Giant Cells: <br />
  26. 26. Differentiation and Anaplasia<br />Tumor Necrosis: <br />
  27. 27. Rate of Growth <br />Tumors are clonal<br />
  28. 28. Rate of Growth<br /><ul><li>Cell Proliferation:
  29. 29. Doubling Time is same as normal tissue or even longer
  30. 30. Growth Fraction:
  31. 31. Very high initially
  32. 32. Decreases as tumor size grows
  33. 33. Cell Loss:
  34. 34. Apoptosis, Lack of nutrients, Necrosis </li></li></ul><li>Rate of Growth <br />Fast Growing Tumors have high cell turnover<br />High cell proliferation<br />High cell loss<br />Susceptible to chemotherapy<br />
  35. 35. Rate of Growth <br />Slow Growing Tumors<br />Low cell proliferation<br />Low cell loss<br />Resistant to chemotherapy<br />
  36. 36. Local Invasion<br />Benign Tumors: <br />Discrete, well-circumscribed mass<br />Don’t infiltrate surrounding tissue<br />Fibrous capsule<br />
  37. 37. Local Invasion<br />Malignant Tumors: <br />Poorly demarcated<br />Infiltrate surrounding tissue<br />No capsule<br />
  38. 38. Metastasis<br />Tumor implants discontinuous from the primary tumor<br />
  39. 39. Metastasis – Peritoneal Cavity<br />
  40. 40. Metastasis – Hepatic Metastasis<br />
  41. 41. Metastasis – Lymph Node<br />
  42. 42. Nomenclature<br />BENIGN<br /><ul><li>Relatively harmless
  43. 43. Will remain localized
  44. 44. Local surgical removal
  45. 45. Epithelial:
  46. 46. Adenoma
  47. 47. Papilloma
  48. 48. Mesenchymal
  49. 49. Fibroma
  50. 50. Leiomyoma</li></ul>MALIGNANT<br /><ul><li>Harmful
  51. 51. Potential to spread widely
  52. 52. Surgical removal is not enough
  53. 53. Epithelial: carcinoma
  54. 54. Adenocarcinoma
  55. 55. Squamous cell carcinoma
  56. 56. Mesenchymal: sarcoma
  57. 57. Fibrosarcoma
  58. 58. Leiomyosarcoma</li></li></ul><li>
  59. 59. Epidemiology<br />Second most common cause of death <br />In the United States, one in five deaths is due to cancer<br />In Pakistan, . . . .<br />
  60. 60. Most Common Cancers<br />Men<br />Prostate<br />Lung<br />Colorectal<br />Women<br />Breast<br />Lung <br />Colorectal<br />
  61. 61. Cancer Mortality Trends<br />Decreased deaths in men from<br />Ca Lung: Decreased smoking<br />Prostate: PSA screening<br />Ca Colon: Colonoscopy screening<br />Decreased deaths in women from <br />Ca Breast: Self exam, Mammography<br />Ca Cervix: Pap Smear<br />
  62. 62. Cancer Mortality Trends<br />Increased deaths in men and women from <br />Hepatocellular Ca: Hepatitis C <br />Increased deaths in women: <br />Ca Lung: Smoking<br />
  63. 63. Cancer Incidence<br />
  64. 64. Cancer Mortality - Men<br />
  65. 65. Cancer Mortality - Women<br />
  66. 66. Geography and Environment<br />Ca Stomach deaths are 7-8 times higher in Japan than in the US<br />Ca Lung deaths are higher in the US than in Japan<br />
  67. 67. Geography and Environment<br />
  68. 68. Obesity and Cancer<br />
  69. 69. Age and Cancer<br />
  70. 70. Genetic Predisposition to Cancer<br />Cancers are caused by genetic mutations<br />Sporadic<br />Inherited<br />
  71. 71. Inherited Cancer Syndromes<br />Person inherits one autosomal dominant mutant gene<br />Carriers of the mutated gene have a significantly increased risk of developing cancer<br />Familial Adenomatous Polyposis<br />Retinoblastoma<br />
  72. 72. Defective DNA Repair<br />Autosomal recessive<br />Cells have decreased ability to recover from DNA damage<br />Xeroderma pigmentosum<br />Ataxia-Telangiectasia<br />
  73. 73. Familial Cancers<br />Clustering of certain cancers in families<br />Early age at onset<br />Two or more first-degree relatives with the same cancer<br />Siblings: 2-3 X risk of cancer<br />Multiple / Bilateral tumors<br />Multiple low-penetrance genes<br />
  74. 74. Precancerous Conditions<br />
  75. 75. Molecular Basis of Cancer<br />Nonlethal Genetic Damage<br />Clonal Expansion of Mutated Cell<br />Accumulation of Mutations<br />
  76. 76. Nonlethal Genetic Damage<br />Proto-oncogenes<br />Tumor Suppressor Genes<br />Genes that regulate Apoptosis<br />Genes involved in DNA repair<br />
  77. 77.
  78. 78.
  79. 79. Tumor Progression<br />
  80. 80. Accumulation of Mutations<br />
  81. 81.
  82. 82.
  83. 83. Growth Factors<br />Normal: Paracrine stimulation<br />Cancer cells: Synthesize the same growth factors to which they are responsive (Autocrine loop)<br />
  84. 84. Growth Factor Receptors<br />Normal: Receptors are transiently activated<br />Mutated: Constitutive activation without the need for Growth Factor binding!<br />
  85. 85. Signal Transducing Proteins<br />Located on inner surface of plasma membrane<br />Receive signals from Growth Factor Receptor<br />Transmit signals to the cell nucleus<br />Two most important members of this group: <br />RAS<br />ABL <br />
  86. 86.
  87. 87. RAS<br />Most commonly mutated oncogene<br />One of a family of small GTP/GDP binding Proteins<br />Normal activation is transient<br />Upon Activation, GDP is replaced by GTP<br />GTP is hydrolyzed to GDP by intrinsic GTPase<br />GTPase activity is accelerated by GTPase- Activating Proteins<br />
  88. 88. RAS<br />Point mutations interfere with hydrolysis of GTP<br />RAS is trapped in the activated state<br />Cell ends up in a state of continuous proliferation<br />
  89. 89. BCR-ABL Translocation<br />
  90. 90. BCR-ABL Translocation<br />ABL proto-oncogene:<br />Limited tyrosine kinase activity<br />Localizes to nucleus and promotes apoptosis in cells with DNA damage <br />BCR-ABL Hybrid Protein:<br />Much higher, uncontrolled tyrosine kinase activity<br />Can’t move into nucleus, thus can’t cause apoptosis in cells with damaged DNA<br />Chronic Myeloid Leukemia<br />
  91. 91. Signal Transducing Proteins<br />
  92. 92. The Cell Cycle<br />
  93. 93. Transcription Factors<br />MYC proto-oncogene: <br />Induced rapidly upon signal to divide<br />Activate CDK’s<br />Inhibits CDKI’s<br />Levels decline to baseline when cell cycle begins<br />
  94. 94. Transcription Factors<br />Mutated MYC oncogene: <br />Persistent expression / overexpression<br />Leading to sustained proliferation<br />
  95. 95. Transcription Factors<br />
  96. 96. Cell Cycle Regulators<br />Cyclins D, E, A and B appear sequentially and bind to various CDK’s<br />Cyclin-CDK complexes drive the cell through the cel cycle<br />CDKI’s exert negative control over the cell cycle<br />
  97. 97.
  98. 98. Cell Cycle Regulators<br />
  99. 99. Summary<br />Cancer Progression<br />Oncogenes<br />Growth Factor<br />GF Receptors<br />Signal Transducing Proteins<br />Transcription Factors<br />Cell Cycle Regulators<br />

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