COH603: Public Health Biology

1. Class 6: Wednesday, June 19 2013 COH603: Public Health Biology

2. Chronic Disease • Cancer • Type II Diabetes

3. Cancer • Unregulated cell growth • Genetic Instability is a hallmark of cancer

4. DNA Facts • There are 3 billion letters in your DNA code in every cell of your body. • This would fill a stack of books 200ft high. • End to end it would extend to the moon and back ~500 times • At 1 base/second, this would take you 100yrs to finish • If you and a friend read your own DNA code per second, it would take 8.5 minutes before you found a difference!

6. Genetic Instability • Lost of structural integrity of the genome • About 50% of the proteins encoded by the genome play a role in the structural integrity of the genome. • Two major forms of Genetic Instability • Chromosome Instable (CIN or MSS) • Microsatellite Instable (MSI)

7. Microsatellites in DNA • Microsatellites are repeated sequences of DNA. • maintained by the MMR proteins • These sequences can be made of repeating units of 1-6 base pairs in length. • The length of these microsatellites is highly variable from person to person each individual has microsatellites of a set length.

8. Microsatellite Instability • Five markers have been recommended by the National Cancer Institute to screen for MSI in HNPCC tumors. • MSI detection in two of the markers is considered a positive result or high probability of MSI (MSI-H). • Microsatellite instability is the condition of genetic hypermutability that results from impaired DNA Mismatch Repair (MMR)

9. Mismatch Repair Pathway

10. Chromosome Instability • Microsatellite Stable by definition • Hallmark signature is loss of heterozygosity

11. Common Pathways to Cancer: MSS(CIN)

12. Common Pathways to Cancer: MSI

13. Senescence Proliferation Stem cell Apoptosis Quiescence Differentiation Stem cells have Multiple Choices

14. Senescence Proliferation Cancer cell Apoptosis Quiescence Differentiation Cancer “exploits” these choices

15. The Hallmarks of Cancer

16. Self-Sufficiency in Growth Signals • Normal cells require mitogenic growth signals (GS) before they can move from a quiescent state into an active proliferative state.

17. Insensitivity to Antigrowth Signals • Within a normal tissue, multiple antiproliferative signals operate to maintain cellular quiescence and tissue homeostasis

18. Evading Apoptosis • The ability of tumor cell populations to expand in number is determined not only by the rate of cell proliferation but also by the rate of cell attrition. • Programmed cell death—apoptosis

19. Limitless Replicative Potential • Growth signal autonomy, insensitivity to antigrowth signals, and resistance to apoptosis—all lead to an uncoupling of a cell’s growth program from signals in its environment.

20. Sustained Angiogenesis • The oxygen and nutrients supplied by the vasculature are crucial for cell function and survival, obligating virtually all cells in a tissue to reside within 100μm of a capillary blood vessel • angiogenesis • the growth of new blood vessels

21. Tissue Invasion and Metastasis • Primary tumor masses spawn pioneer cells that move out, invade adjacent tissues, and travel to distant sites where they may succeed in founding new colonies. • metastasesare the cause of 90% of human cancer deaths

22. Hallmarks are functions of Gene Expression • Elaborate, integrated circuit operates within normal cells and are reprogrammed to regulate hallmark capabilities within cancer cells

24. Inflammation – The 7th Hallmark • Inflammatory conditions in selected organs increase the risk of cancer. • An inflammatory component is present in the microenvironment of tumors that are not epidemiologically related to inflammation. • In the tumor microenvironment, inflammation contributes to proliferation and survival of malignant cells, angiogenesis, metastasis, subversion of adaptive immunity, reduced response to hormones and chemotherapeutic agents. • cancer-related inflammation (CRI) can induce genetic instability by inflammatory mediators, leading to accumulation of random genetic alterations in cancer cells.

25. A Seventh Hallmark

27. The Three E’s of Cancer Immunoediting

28. Cancer Immunosurveillance • Functional cancer immunosurveillance acts as an extrinsic tumor suppressor • Cancer Immunoediting • Elimination • Equilibrium • Escape

29. Immunity is a double-edge sword

30. Factors to Consider in a Polarized Immune Response Tumor Promoting Immunity Tumor Suppressing Immunity Immune Coordination Sustained Immune Memory Cytotoxicity and Apoptosis Reduced Inflammation Anti-angiogenesis Reduced Metastasis Reduced Recurrence Increased Disease Free Survival • Chronic Inflammation • Immune Suppression • Tissue remodeling • Angiogenesis • Hyper-proliferation • Metastasis • Increased Recurrence • Reduced Disease Free Survival

31. Factors to Consider in a Polarized Immune Response Tumor Promoting Immunity Tumor Suppressing Immunity Immune Coordination Sustained Immune Memory Cytotoxicity and Apoptosis Reduced Inflammation Anti-angiogenesis Reduced Metastasis Reduced Recurrence Increased Disease Free Survival • Th2: IL-4, -13, -10 • Th17: IL-23, -6, -17, TNF-α • B cells • TAMs • T regs • MDSC • TGF-β • VEGF, IDO, PGE2

32. Factors to Consider in a Polarized Immune Response Tumor Promoting Immunity Tumor Suppressing Immunity Th1: IL-2, IFN-γ NK cells NKT cells CD8+ T cells Cytotoxic T cells Effector memory T cells Perforin Granzyme B • Th2: IL-4, -13, -10 • Th17: IL-23, -6, -17, TNF-α • B cells • TAMs • T regs • MDSC • TGF-β • VEGF, IDO, PGE2

33. The Dual Role of the Immune Response in Tumorigenesis Immune Strength and Coordination Tumor Escape High Immune Infiltration Low Immune Infiltration Strong Immune Coordination Loss of Immune Coordination Strong Tumor Antigenicity Weak Tumor Antigenicity Limited Inflammation Chronic Inflammation

34. Increased Tumor recurrence Reduced disease-free survival Reduced Tumor recurrence and Increased disease-free survival Reduced Metastasis Anti-angiogenesis Tumor Metastasis Immune Strength and Coordination Tumor Escape Tissue Remodeling Angiogenesis Hyper-proliferation Cytotoxicity Apoptosis Reduced Inflammatory Chronic Inflammation Immune Suppression Immune Coordination Sustained Immune Memory

36. Emerging Hallmarks • Uncontrolled cell proliferation that represents the essence of neoplastic disease include: • Deregulated control of cell proliferation • Adjustments of energy metabolism in order to fuel cell growth and division.

37. Landmarks in Cancer Epidemiology

38. Landmarks in Cancer Epidemiology

41. Cancer Incidence Males -White

42. Cancer Incidence Males -Black

43. Death Rates – White Men

44. Death Rates – Black Men

45. Cancer Incidence Females -White

46. Cancer Incidence Females -Black

47. Death Rates – White Female

48. Death Rates – Black Female

49. Break • Papers on Cancer

50. Type II Diabetes • A metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency.