Chapter 19

1. Chapter 19 Cancer RISK versus BENEFIT

2. OUTLINE • Introduction • Normal Cells • Regulation of Cell Division • Tumor Suppressor Genes and Apoptosis • Normal Cell Characteristics • Cancer Cell Characteristics • Angiogenesis • Metastasis • Causes of Cancer • Diagnosis and Treatment of Cancer

3. Introduction • The study of cancer is called? • Oncology. • The medical specialist for cancer? • Oncologist. • 1/3 Americans will deal with cancer in their lifetime! • > 50% will survive their cancer. • The critical factor is early detection. • The earlier the cancer is detected, the more likely it can be effectively treated. • With cancer, FEAR can kill you. . . . .

4. Normal Cells • With few exceptions, cells within a tissue adhere to one another and are joined by various junctions. • Chemical signals between cells tell them whether they should be dividing or not dividing. • Stimulatory growth factors. • Inhibitory growth factors.

5. Regulation of Cell Division • Two sets of genes control cell division. • Proto-oncogenes. • Code for transcription factors that control gene expression. • When mutated they become Oncogenes. • “tumor genes”, “lump genes”. • Tumor suppressor genes. • Some are transcription factors that control the expression of proto-oncogenes, while others prevent molecules in the stimulatory pathway from working.

6. Cell Cycle Regulation

7. From the following article: Cancer: Drivers and passengers Daniel A. Haber and Jeff Settleman Nature 446, 145-146(8 March 2007)

8. Tumor Suppressor Genes and Apoptosis • Certain tumor suppressor genes (TSG) also control the occurrence of apoptosis. • “Cell death”. • Enzymes that carry out apoptosis are always present in a cell, but are held in check by inhibitors. • Gene p53 brings about apoptosis when DNA is damaged. • Apoptosis protects the body from cells with abnormal chromosomes or “run away” cell division.

9. Function of p53

10. Replicative Potential • After cells become fully differentiated they can no longer divide. • Chromosomes in human cells end with repetitive DNA sequences, telomeres. • Telomeres get shorter after each cell cycle. • Cells can undergo 60 – 70 divisions.

11. Normal Cell Characteristics • Genetically stable. • Differentiate and adhere to other cells. • Respond appropriately to growth signals. • Undergo apoptosis when DNA repair fails. • Undergo a limited number of cell cycles.

13. Cancer Cells • Carcinogenesis - Development of cancer or “cancer beginnings”. • Cancer is over 100 different diseases……… • Cancer (“crab”) is a “genetic disease” requiring a number of mutations (at least ten), each propelling cells toward tumor development  benign, malignant. • Each tumor is composed of cells that are experiencing uncontrolled growth. • Cancer cells are non-specialized and do not contribute to body functioning.

14. Cancer Cell Characteristics • Genetically unstable. • Not differentiated - Do not adhere to other cells (no “contact inhibition”). • Insensitive to inhibitory growth signals. • No apoptosis when DNA repair fails. • Unlimited number of cell cycles (immortal). • Induce and sustain angiogenesis. • Invade and metastasize.

15. Cancer Cells

16. Carcinogenesis • Takes many years because it requires many mutations that occur over time. • 3 Phases (Steps): • Initiation. • Promotion. • Progression.

18. Regulation of Cell Cycle • Approximately 100 oncogenes discovered that can cause increased cell growth (by producing proteins) and lead to tumors, ie. “gas pedal”. • Genes “turned on” which should be off / “gain-of-function” mutations. • Form when mutations occur in proto-oncogenes. • Most frequent are in ras gene family –> ras protein which causes cells to no longer respond to inhibitory growth factors and grow out of control. • Tumor suppressor genes undergo mutations. • Approximately half-dozen identified. • Genes “turned off” which should be on / “loss-of-function” mutations. • Most common in cancer development is p53.

19. Normal Cells

20. Cancer Cells

21. Unlimited Replicative Potential • Cancer cells have unlimited replicative potential because all division restraints, including apoptosis and telomere shortening (telomerase), have been removed. • In other words, they are essentially immortal.

22. Angiogenesis • Angiogenesis is the formation of new blood vessels. • Cancer cells release signals, such as vascular endothelial growth factor (VEGF), that bind to receptors on the epithelial cells of blood vessels. • New blood vessels branch and send capillaries into the center of a tumor. • Occurs when cell mass is ~1 million cells. • Essential to provide oxygen/nutrients, to remove carbon dioxide/wastes. . . . .

23. Metastasis • A benign tumor is a disorganized, usually encapsulated, mass that does not invade adjacent tissue. • Malignancy (malignant tumor) is present when metastasis establishes new tumors distant from the primary tumor. • Due to mutations, cancer cells tend to be motile because they have a disorganized internal cytoskeleton and lack intact actin filament bundles.

27. Based on what we know about cancer and the processes surrounding it, • cancer cells might be viewed as normal cells • which have reverted to their “embryonic state” • by activation of oncogenes and inactivation of tumor suppressor genes • and, therefore, demonstrate characteristics normally seen in cells during the early stages of embryonic development which . . .

28. Types of Cancer by Origin: • Carcinomas (Adenocarcinomas). • Arise from epithelial cells (glandular epithelial cells). • Sarcomas. • Arise from connective / muscle tissue. • Leukemia and lymphomas. • Arise from bone marrow (blood cancer) and from lymphatic tissue.

29. The Top 4 Cancers in the United States Population (by death rate): • #1 - Lung cancer • #2 – Colon cancer • #3 – Breast cancer • #4 – Prostate cancer

30. Causes and Prevention of Cancer

32. Causes of Cancer • Heredity. • Certain cancers, such as breast, lung, and colon cancers, run in families. • Some childhood cancers are inherited as a dominant gene. • Examples: BRCA1, BRCA2, RB. RET, WT1. • EnvironmentalCarcinogens. • “cancer generator”, an environmental agent that can trigger cancer, ie. radiation and organic chemicals. • Mutagen increases chances of DNA mutation. • Carcinogens contribute to cancer development.

33. Causes of Cancer • Radiation. • Skin cancers – U.V. radiation in sunlight and tanning beds. • Radon gas can lead to lung cancer. • X rays and nuclear radiation.

34. Causes of Cancer • Organic chemicals. • Tobacco smoke - contains carcinogens that can lead to cancers of the lung, mouth, larynx, bladder, kidney, and pancreas. • Foods – rich in saturated fats and low in fiber are correlated with increased cancer rates for the colon, rectum, and prostate. • Pollutants – industrial chemicals, pesticides, and herbicides are mutagenic and can lead to cancer.

36. Causes of Cancer • Viruses. • Have been linked to liver cancer, cervical cancer, form of lymphoma, and nasopharyngeal cancer. • Only 6 viruses implicated in human cancer. • Examples: HBV (HCV), HPV, EBV, HIV, KSHV, HTLV.

37. HEALTH FOCUS “Prevention of Cancer” • Protective behaviors…….. • The right diet……… • What vitamins are associated with cancer prevention? • A and C

38. Diagnosis of Cancer • Warning Signs. • Change in bowel or bladder habits. • A sore that does not heal. • Unusual bleeding or discharge. • Thickening or lump (in breast/elsewhere). • Indigestion or difficulty swallowing. • Obvious change in wart or mole. • Nagging cough or hoarseness.

39. Routine Screening Tests • Cervical Cancer • Pap smears • Used since 1938, one of most effective screens. • New vaccine!? • Breast Cancer. • Monthly self-exam. • Annual examination by physician. • Mammography. • Melanoma……………

41. Health Focus Shower Check for Cancer

46. Routine Screening Tests • Colon Cancer. • Digital rectal examination. • Flexible sigmoidoscopy. • Stool occult blood test. • Colonoscopy. • (CEA blood test). • SeeTable 19.1 in text, “Recommendations for the Early Detection of Cancer in Average-Risk Asymptomatic People”.

47. Routine Screening Tests • Tumor Marker Tests. • Blood tests for tumor antigens/antibodies produced against tumors. • Used to detect first-time cancers and cancer relapses. • PSA (prostate specific antigen): prostate cancer. • CEA: colon cancer relapse. • CA-125: ovarian cancer. • AFP: liver cancer.

48. Routine Screening Tests • Genetic Tests. • Test for genetic mutations in proto-oncogenes and tumor suppressor genes by testing DNA. • When an individual tests positive for the presence of marker genes. . . . . • The individual should be vigilant for signs of cancer. • Examples: ras gene for colon cancer, BRCA1 for breast cancer, RET – thryoid, p16 – melanoma, “microsatellites” – bladder, telomerase.

49. Routine Screening Tests • Confirming Diagnosis. • Surgery. • Needle biopsies. • Imaging techniques such as CAT scans, MRI, radioactive scans (using administered radioisotopes), ultrasound.

50. Prognosis • The predicted outcome of a disease (cancer). • Depends on: • (1) Whether the tumor has spread to surrounding tissue. • (2) Whether there is lymph node involvement. • (3) Whether distant tumors have begun.