2. Carcinogenesis Patricia Jakel, RN,MN,OCN

3. What Is Cancer?

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

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

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

7. 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. 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.

8. 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. 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. 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. Malignant cells can release growth factors and enzymes that stimulate rapid formation of blood vessels. These chemical include VEGF- Targeted therapy.

9. 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. 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.

10. 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.

11. 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. 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. 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.

12. 3. Oncogenes continued- Different types of oncogenes may act together to induce cancers. 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. 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. 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. p53 mutations occur in about half of all human cancers: most common in colorectal, lung, and breast cancer.

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

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

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

16. 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. 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.

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

18. 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. 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.

19. 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. 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.

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

21. 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: Reversible damage to the proliferation mechanism of the cell; the effects of the promoting factors may be inhibited: Cancer-reversing agent. Cancer-reversing agent. Host Characteristics Host Characteristics Time and dose limits. Time and dose limits.

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

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

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

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

26. Carcinoma in Situ Mild dysplasia Carcinoma in situ (severe dysplasia) Cancer (invasive) NormalHyperplasia

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

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

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

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

31. Naming Cancers PrefixMeaning 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 Cancer Prefixes Point to Location

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

33. Tumor Grading General Relationship Between Tumor Grade and Prognosis Patient Survival Rate Years High grade Low grade 100% 12345

34. Tumor Staging Five-Year Survival Rates for Patients with Melanoma (by stage) Stage at Time of Initial Diagnosis 100% 50% IIIIII

35. What Causes Cancer? Some viruses or bacteria Heredity Diet Hormones RadiationSome chemicals

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

37. Heredity? Behaviors? Other Factors? 100 50 5 0 Stomach Cancer (Number of new cases per 100,000 people) U.S.JapanJapanese families in U.S. 100 70 7 0 Colon Cancer (Number of new cases per 100,000 people) U.S.JapanJapanese families in U.S.

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

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

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

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

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

43. Viruses Virus inserts and changes genes for cell growth Cancer-linked virus

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

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

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

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

48. Mutations and Cancer Genes Implicated in Cancer

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

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

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

52. Protect Yourself From Excessive Sunlight

53. Skin cancers most common with UVR Melanoma Melanoma Basal cell carcinoma Basal cell carcinoma Squamous cell carcinoma Squamous cell carcinoma

54. Avoid Cancer Viruses Noninfected women HPV Infection Increases Risk for Cervical Cancer Cervical Cancer Risk Low High Women infected with HPV

55. Chemical Carcinogens Chemical substances that alter DNA Chemical substances that alter DNA

56. Avoid Carcinogens at Work Some Carcinogens in the Workplace

57. Examples of ionizing radiation Most exposure is natural and unavoidable. Most exposure is natural and unavoidable. Diagnostic radiographs, radiation therapy, radioisotopes used in imaging. Diagnostic radiographs, radiation therapy, radioisotopes used in imaging. Cosmic rays. Cosmic rays. Radioactive ground minerals and gases-radon, radium, uranium. Radioactive ground minerals and gases-radon, radium, uranium. Cancers linked to ionizing radiation. Cancers linked to ionizing radiation.

58. Compromised Immune System Immune surveillance against cancer Immune surveillance against cancer Surveillance occurs via recognition of tumor- associated antigens Surveillance occurs via recognition of tumor- associated antigens Immune response may fail. Immune response may fail. Age Age Tumor burden Tumor burden Shed substances Shed substances Outside factors Outside factors

59. Microscopic Appearance of Cancer Cells

60. Staging of Cancer TNM TNM T-extent or size of the tumor T-extent or size of the tumor N-absence or presence and extent of regional lymph node metastasis N-absence or presence and extent of regional lymph node metastasis M-absence or presence of distant metastases. M-absence or presence of distant metastases.