Carcinogenesis

1. Carcinogenesis Patricia Jakel, RN,MN,OCN

2. What Is Cancer?

3. What is cancer? • A series of cellular, genetic aberrations that cause abnormal cell proliferation. • Unchecked local growth (tumor formation) and invasion of surrounding tissue. • Ability to metastasize (e.g. spread in a contiguous fashion to form secondary sites).

4. Changing Approach and Outcomes • Cancer as disease change from acute to chronic • 20th Century Model: “Seek and Destroy” • 21st Century Model : “Target and Control”

5. Essential Aberrations of Malignancy • Proliferation • Evading Apoptosis-avoiding programmed cell death • Cellular Differentiation • Motility and Invasion • Recruitment of Blood Vessels and Angiogenesis • Metastatic Spread • Cancer cells must compete successfully at each event to go forward.

6. Mechanism of Cancer • Apoptosis- is programmed cell death-that is, it is an active process controlled by cellular signaling. It may be triggered by the absence of a required growth factor:intercellular signals that indicate DNA damage or other injury to the cell; harmful external agents; or other intra- and extracellular events.

7. Mechanism of Cancer • Angiogenesis- or the formation of new blood vessels, critical step in tumor growth. Without tumors must obtain oxygen and nutrients by diffusion and therefore cannot grow larger. • The tumor remains dormant until it can stimulate blood vessel growth from nearby capillaries. • Malignant cells can release growth factors and enzymes that stimulate rapid formation of blood vessels. These chemical include VEGF- Targeted therapy.

8. Carcinogenesis • Refers to the process by which cancer arises. Likely involves a series of multiple steps or cellular changes over time. This three-stage theory is the most widely used explanation of the process by which a normal cell is transformed into a cancer cell.

9. Pathology-cancer arsies due to cumulative alteration in a cell’s genes 1. Proto-oncogenes- the genetic portion of the DNA that regulates normal cell growth and repair: mutation may allow cell to proliferate beyond normal body needs.

10. Pathology • 2.Tumor suppressor gene- the genetic portion of the DNA that stops cell division; mutation may allow cells to proliferate beyond normal body needs. • 3. Oncogenes- abnormal, mutated genes responsible for the transformation of a normal cell into a cancer cell. May arise from mutations in proto-oncogenes, tumor suppressor genes, or other genes.

11. 3. Oncogenes continued- • Different types of oncogenes may act together to induce cancers. • 1.p53 tumor suppressor gene-normally functions to stop cell proliferation, which allows DNA damage to be repaired. • When mutated, p53 restraint on cell proliferation is lost. • p53 mutations occur in about half of all human cancers: most common in colorectal, lung, and breast cancer.

12. 3. Oncogene continued • 2. Ras family of proto-oncogens-normally function to promote cellular growth • When mutated ras oncognes may allow cells to proliferate unrestrainted. • Ras oncogene are the most frequently detected oncogenes in human cancers; most common in pancreatic, colorectal, and thyroid cancers

13. Clinical Implications • Presence of certain oncogenes may have diagnostic and prognostic value. • Prevention of gene mutation is one focus of chemoprevention clinical trails. • Understanding of genetic changes may result in new targets for treatment

14. Genes and Cancer • Proto-Oncogenes- normal genes that participate in in normal tissue repair. Molecular “bucket brigade.” • Oncogenes- mutated proto-oncogenes. Excessively active • Secreted growth factor • Cell-surface growth-factor receptors • Membrane associated G protein • Tumor-Suppressor Genes- normal tell the cell to stop growing, role in cell cycle activity, helps with apoptosis

15. Relationship between genes and cancer • Cancer is a disease if genes gone awry. Genes that control the orderly replication of cells become damaged, allowing the cell to reproduce without restraint and eventually to spread into neighboring tissues and set up growths throughout the body.

16. Cancer Tends to Involve Multiple Mutations Benign tumor cells grow only locally and cannot spread by invasion or metastasis Malignant cells invade neighboring tissues, enter blood vessels, and metastasize to different sites Time Mutation inactivates suppressor gene Cells proliferate Mutations inactivate DNA repair genes Proto-oncogenes mutate to oncogenes More mutations, more genetic instability, metastatic disease

17. Cancer and Genetics • All cancer is genetic, in that it is triggered by altered genes. However, just a small portion of cancer is inherited: a mutation carried in reproductive cells, passed on from one generation to the next, and present in cells throughout the body.

18. Cancer and Genetics • Most cancer is random mutations that develop in body cells division during one’s lifetime- either as a mistake when cells are going through cell division or in response to injuries from environmental agents such as radiation or chemicals.

19. 1. Initiation • A cancer causing agent damages the DNA, this gene may then: • Undergo repair • Become permanently changed (mutated)but not cause cancer unless exposed to threshold levels of cancer promotors. • Become mutated and produce a cancer cell line.

20. Promotion- a process by which carcinogens are subsequently introduced, resulting in one of the following changes: • Reversible damage to the proliferation mechanism of the cell; the effects of the promoting factors may be inhibited: • Cancer-reversing agent. • Host Characteristics • Time and dose limits.

21. Promotion continued. • Irreversible damage to the proliferation mechanism, resulting in cancer cell transformation.

22. Progression • Invasion -cells continue to divide; increase in bulk, pressure, and secretion of enzymes result in local spread and invasion of surrounding structures. • Neovascularization-formation of new blood vessels.

23. Metastasis-the production of secondary tumors at distant sites. • Routes of metastasis • Sites • Clinical Implication • Metastasis is the major cause of death from cancer. • Most tumors have begun to metastasize at the time of detection.

24. Invasion and Metastasis 1 Cancer cells invade surrounding tissues and blood vessels 2 Cancer cells are transported by the circulatory system to distant sites 3 Cancer cells reinvade and grow at new location

25. Carcinoma in Situ Normal Hyperplasia Milddysplasia Carcinoma in situ (severe dysplasia) Cancer(invasive)

26. Neoplasm vs Tumor • Interchangeable terms • Refers to abnormal growth of tissue that serves no function and continues to grow unchecked. • Can be benign or malignant • Cancer- common term for all malignancies

27. Tumor Nomenclature • Hematologic Malignancies • Lymphomas • Malignancies of the lymphocyte • Subclassified as: • Hodgkin's • Non-Hodgkin's • Multiple myeloma-arises from the plasma cell (B lymphocyte) line.

28. Tumor Nomenclature • Hematologic Malignancies • Leukemias • Arises from hematopoietic cells • Classified according to cell type and maturity. • Lympho-denotes leukemia of lymphoid origin. • Myleo-denotes leukemia of myeloid origin

29. Different Kinds of Cancer Leukemias: Bloodstream Some common carcinomas: Lung Breast (women) Colon Bladder Prostate (men) Lymphomas: Lymph nodes Some common sarcomas: Fat Bone Muscle

30. Naming Cancers Cancer Prefixes Point to Location Prefix Meaning adeno- gland chondro- cartilage erythro- red blood cell hemangio- blood vessels hepato- liver lipo- fat lympho- lymphocyte melano- pigment cell myelo- bone marrow myo- muscle osteo- bone

31. Why Cancer Is Potentially Dangerous Brain Melanoma cells travel through bloodstream Liver Melanoma(initial tumor)

32. Tumor Grading General Relationship Between Tumor Grade and Prognosis 100% Low grade Patient Survival Rate High grade 1 2 3 4 5 Years

33. Tumor Staging Five-Year Survival Rates forPatients with Melanoma (by stage) 100% 50% I II III Stage at Time of Initial Diagnosis

34. What Causes Cancer? Some viruses or bacteria Some chemicals Radiation Heredity Diet Hormones

35. Population-Based Studies Regions of Highest Incidence U.K.: Lung cancer JAPAN: Stomach cancer CANADA: Leukemia U.S.:Colon cancer CHINA: Liver cancer BRAZIL: Cervical cancer AUSTRALIA: Skin cancer

36. Heredity? Behaviors? Other Factors? Colon Cancer(Number of new cases per 100,000 people) Stomach Cancer (Number of new cases per 100,000 people) 100 50 5 0 100 70 7 0 Japan Japanese familiesin U.S. U.S. Japan Japanese familiesin U.S. U.S.

37. Tobacco Use and Cancer Some Cancer-Causing Chemicals in Tobacco Smoke

38. Low-Strength Radiation High Dallas Skin Cancer Incidence Pittsburgh Detroit Low Least Most Annual Sunshine (UV radiation)

39. High-Strength Radiation High Leukemia Incidence Low Least Most X-ray Dose(atomic radiation)

40. Ultraviolet radiation-a complete carcinogen • Sources of UVR • Sunlight • Tanning salons • Industrial sources-welding arcs

41. Viruses- • Infect DNA, resulting in proto-oncogene changes and cell mutation. • Effects modified by: • Age • Immunocompetence

42. Viruses Virus inserts and changes genes forcell growth Cancer-linked virus

43. Examples of Human Cancer Viruses Some Viruses Associated with Human Cancers

44. AIDS and Kaposi’s Sarcoma Without disease HIV infection Depressed immune system KSHV infection Kaposi’s sarcoma

45. Bacteria and Stomach Cancer Patient’s tissue sample H. pylori

46. Heredity Can Affect Many Types of Cancer Inherited Conditions That Increase Risk for Cancer

47. Mutations and Cancer Genes Implicated in Cancer

48. What causes cancer??? • Exposure to carcinogens-chemical, or viral, or physical or familial • Exposure to radiation-cellular DNA damage by physical release of energy. • Ionizing radiation • Damage to the cell by this source; • Is usually repaired and no mutation results. • May give rise to a malignancy when damage affects proto-oncogenes or tumor suppressor genes. • Depends on numerous factors.

49. Cancer Prevention Carcinogenic chemicals Carcinogenic radiation Cancer viruses or bacteria

50. Avoid Tobacco Lung Cancer Risk Increases with Cigarette Consumption 15x 10x 5x Lung Cancer Risk 0 15 30 Non-smoker Cigarettes Smoked per Day