Cancer Biology

1. Cancer Biology Pharmacy 754 Spring 2007 Arup INDRA Office: Pharmacy 325 Tel;737-5775 Email: arup@oregonstate.edu

2. Hubble Telescope Ultra Deep Field Infrared View of countless "ENTIRE" Galaxies Billions of Light-Years Away.

3. Change in the US Death Rates* by Cause, 1950 & 2004 Rate Per 100,000 1950 2004 HeartDiseases CerebrovascularDiseases Pneumonia/Influenza Cancer * Age-adjusted to 2000 US standard population. Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised. 2004 Mortality Data: US Mortality Public Use Data Tape, 2004, NCHS, Centers for Disease Control and Prevention, 2006

4. US Mortality, 2004 No. of deaths % of all deaths Rank Cause of Death 1. Heart Diseases 652,486 27.2 2. Cancer 553,888 23.1 3. Cerebrovascular diseases 150,074 6.3 4. Chronic lower respiratory diseases 121,987 5.1 5. Accidents (Unintentional injuries) 112,012 4.7 6. Diabetes mellitus 73,138 3.1 7. Alzheimer disease 65,965 2.8 8. Influenza & pneumonia 59,664 2.5 • Nephritis 42,480 1.8 10. Septicemia 33,373 1.4 Source: US Mortality Public Use Data Tape 2004, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006.

5. 2007 Estimated US Cancer Deaths* Men289,550 Women270,100 Lung & bronchus 31% Colon & rectum 9% Prostate 9% Pancreas 6% Leukemia 4% Liver & intrahepatic 4%bile duct Esophagus 4% Non-Hodgkin 3% lymphoma Urinary bladder 3% Kidney 3% All other sites 23% • 26% Lung & bronchus • 15% Breast • 10% Colon & rectum • 6% Pancreas • 6% Ovary • 4% Leukemia • 3% Non-Hodgkin lymphoma • 3% Uterine corpus • 2% Liver & intrahepatic bile duct • 2% Brain/ONS • 23% All other sites ONS=Other nervous system. Source: American Cancer Society, 2007.

6. Trends in the Number of Cancer Deaths Among Men and Women, US, 1930-2004 Men Men Women Women Number of Cancer Deaths Source: US Mortality Public Use Data Tape, 2004, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006.

7. 2007 Estimated US Cancer Cases* Men766,860 (720,280 in 2006) Women 678,060 (679,510 in 2006) 26% Breast 15% Lung & bronchus 11% Colon & rectum 6% Uterine corpus 4% Non-Hodgkin lymphoma 4% Melanoma of skin 4% Thyroid 3% Ovary 2% kidney 3% Leukemia 21% All Other Sites Prostate 29% Lung & bronchus 15% Colon & rectum 10% Urinary bladder 7% Melanoma of skin 4% Non-Hodgkin 4% lymphoma Kidney 4% Oral cavity 3% Leukemia 3% Pancreas 2% All Other Sites 19% *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2007.

8. Cancer Incidence Rates*, All Sites Combined, All Races, 1975-2003 Rate Per 100,000 Men Both Sexes Women *Age-adjusted to the 2000 US standard population and adjusted for delay in reporting. Source: Surveillance, Epidemiology, and End Results Program, 1973-2003, Division of Cancer Control and Population Sciences, National Cancer Institute, 2006.

9. Cancer Incidence Rates* for Men, 1975-2003 Rate Per 100,000 Prostate Lung & Bronchus Colon and rectum Urinary bladder Non-Hodgkin lymphoma Melanoma of the skin *Age-adjusted to the 2000 US standard population and adjusted for delays in reporting. Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control and Population Sciences, National Cancer Institute, 2006.

10. Cancer Incidence Rates* for Women, 1975-2003 Rate Per 100,000 Breast Colon and rectum Lung & bronchus Uterine Corpus Ovary Non-Hodgkin lymphoma *Age-adjusted to the 2000 US standard population and adjusted for delays in reporting. Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control and Population Sciences, National Cancer Institute, 2006.

11. Lifetime Probability of Developing Cancer, by Site, Men, 2001-2003* Site Risk All sites† 1 in 2 Prostate 1 in 6 Lung and bronchus 1 in 12 Colon and rectum 1 in 17 Urinary bladder‡ 1 in 28 Non-Hodgkin lymphoma 1 in 47 Melanoma 1 in 49 [1 in 52 (2002)] Kidney 1 in 61 [1 in 64 (2002)] Leukemia 1 in 67 Oral Cavity 1 in 72 Stomach 1 in 89 [1 in 82 (2002)] * For those free of cancer at beginning of age interval. Based on cancer cases diagnosed during 2001 to 2003. Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 6.1.1 Statistical Research and Applications Branch, NCI, 2006. http://srab.cancer.gov/devcan

12. Lifetime Probability of Developing Cancer, by Site, Women, US, 2000-2003* Site Risk All sites† 1 in 3 Breast 1 in 8 Lung & bronchus 1 in 16 (17) Colon & rectum 1 in 19 (18) Uterine corpus 1 in 40 (38) Non-Hodgkin lymphoma 1 in 55 Ovary 1 in 68 Melanoma 1 in 73 (77) Pancreas 1 in 79 Urinary bladder‡ 1 in 87 (88) Uterine cervix 1 in 138 (135) * For those free of cancer at beginning of age interval. Based on cancer cases diagnosed during 2000 to 2002. Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 6.0 Statistical Research and Applications Branch, NCI, 2005. http://srab.cancer.gov/devcan

13. Sample Question The highest estimated cancer cases in men in US Colon Cancer Prostate Cancer Melanoma Pancreatic cancer

14. Sample Question The highest estimated cancer cases in women in US Lung Cancer Ovarian Cancer Uterine Cancer Breast cancer

15. Definitions CANCER Means any malignant tumor TUMOR is a nonspecific term meaning lump or swelling. In current usage, however, it is a synonym for neoplasm NEOPLASM means a new growth, an aberrent proliferation of cells NEOPLASIA is a disease of cells characterized by alteration of normal growth regulatory mechanisms METAPLASIA is an adaptive substitution of one type of adult tissue to another type of adult tissue. Under stress a more vulnerable type of tissue is replaced by another type more capable of meeting stress. An example is metaplasia of the respiratory tract - ciliated columnar epithelium is replaced by flattened squamous cells. METASTASIS The discontinuous spread of a neoplasm to distant sites by seeding directly through body cavities, lymphatic channels, blood vessels, veins, and arteries, or by direct transplantation during surgery

16. Biological and Clinical Behavior of Cancers Tumor grade: It is a system used to classify cancer cells in terms of how abnormal they look under a microscope and how quickly the tumor is likely to grow and spread. Many factors are considered, including the structure and growth pattern of the cells. The specific factors used to determine tumor grade vary with each type of cancer. Cancer Stage : Cancer stage refers to the extent or severity of the cancer, based on factors such as the location of the primarytumor, tumor size, number of tumors, and lymph node involvement (spread of cancer into lymph nodes).

17. Tumor grading Histologic grade:Also called differentiation, refers to how much the tumor cells resemble normal cells of the same tissue type. The more closely tumor cells resemble normal tissue, the less malignant the behavior. Tumors are generally graded as well, moderately, and poorlydifferentiated. Differentiated (well and moderately) tumor cells resemble normal cells and tend to grow and spread at a slower rate than undifferentiated or poorly differentiated tumor cells, which lack the structure and function of normal cells and grow uncontrollably. Undifferentiated tumors have no histological clues to tissue of origin and are highly malignant. Nuclear grade:An evaluation of the size and shape of the nucleus in tumor cells and the percentage of tumor cells that are in the process of dividing or growing. Cancers with low nuclear grade grow and spread less quickly than cancers with high nuclear grade. http://www.cancer.gov/cancertopics/factsheet/Detection/staging

18. Significance of tumor grading Based on the microscopic appearance of cancer cells, pathologists commonly describe tumor grade by four degrees of severity: Grades 1, 2, 3, and 4. The cells of Grade 1(also 2) tumors resemble normal cells, and tend to grow and multiply slowly. Grade 1 tumors are generally considered the least aggressive in behavior. Conversely, the cells of Grade 3 or Grade 4 tumors do not look like normal cells of the same type. Grade 3 and 4 tumors tend to grow rapidly and spread faster than tumors with a lower grade.

19. Significance of tumor grading (II) The American Joint Commission on Cancer recommends the following guidelines for grading tumors (1): Grade GXGrade cannot be assessed (Undetermined grade) G1 Well-differentiated (Low grade) G2 Moderately differentiated (Intermediate grade) G3 Poorly differentiated (High grade) G4 Undifferentiated (High grade) 1. American Joint Committee on Cancer. AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002.

20. Components of Cancer Stage 1. Size, extent of invasion and penetration of anatomic boundaries by the primary tumor. 2. Presence and number of lymph nodes involved with metastatic spread. 3. Presence of distant metastasis. 4. Generalized examples: A.Stage 0 carcinoma, carcinoma in situ, is a malignant neoplasm that has not yet invaded through the basement membrane into the underlying connective tissue or stroma. B.Stage III malignancy has spread widely through the body. C.Stage I and II are in between and vary somewhat in specific definition depending on the tumor type and location under consideration.

21. Histogenesis Neoplasms are classified by their tissue origin. This forms the basis for tumor nomenclature. 1. Benign tumors -are designated by attaching the suffix “oma” to the prefix designating the cell type from which the tumor arises. (e.g. Fibroblasts -Fibroma). Adenoma- (adeno = gland or related to glands) A benign epithelial neoplasm which (1) produces a gland-like pattern, or (2) is derived from glands but not necessarily producing glandular patterns. Papilloma- Benign tumor of surface epithelium in which neoplastic cells growing outward from surface cover finger-like processes of stroma. Polyp - Pedunculated projection arising from mucosal or skin surface -may or may not be neoplastic

22. Histogenesis Malignant Tumors are classified essentially the same as benign tumors with Certain additions: Carcinoma - Malignant neoplasm of epithelial cell origin (usually Squamaous) Sarcoma - Malignant neoplasm, origin in mesenchymal tissues or its derivatives (usually Fibrous) Further classification is based on the cell component, i.e. Squamous cell carcinoma Adenocarcinoma Fibrosarcoma If the tumor cells are undifferentiated (ie. Lack histologic criteria for definate classification) they cannot be further classified and are usually highly metastatic.

23. Sample Question A stage III squamous cell carcinoma is I. Malignant neoplasm of the epithelial origin II. Invades through the basement membrane III. Spreads all throughout the body I only III only I and II only I and III only I, II and III

24. Sample Question A grade 2 (G2) adenoma I. Is an epithelial neoplasm derived from gland. II. resemble normal cells and tend to grow and spread at a slower rate. III. Is a poorly differentiated tumor. I only III only I and II only I and III only I, II and III

25. Sample Question An undifferentiated fibrosarcoma is I. Highly metastatic II. Malignant neoplasm of the epithelial origin III. Does not spread at distant sites through blood vessels I only III only I and II only I and III only I, II and III

26. Tissues EPITHELIUM is a thin layer of cells forming a tissue that covers surfaces of the body and lines holloworgans. It is compactly arranged with little intercellular substance, can regenerate itself very quickly, and performs protective, secretive, and other functions. CONNECTIVE Connect and anchor parts and provide support, strength, TISSUES insulation, padding and form to other tissues and organs of the body. Cell types include: Fibroblasts, Adipose cells, Macrophage, and Mesenchymal cells. BLOOD AND Hematopoiesis, blood cell development occurs primarily in the LYMPH bone marrow in adults, and the lymphoid cells originate from the bone marrow and thymus. Blood cells include erythrocytes, neutrophils, eosinophils, basophils, lymphocytes, monocytes and macrophages.

27. Bone Cells Adipocytes Astrocytes Epithelial cells Fibroblasts

28. Skin (Epidermal tumors, Squamous carcinoma) Keratinocytes (Melanoma) Endothelial cells Fibroblast (Fibrosarcoma) (pilomatricoma) adipocytes

29. Self-maintained replication Longer survival Genetic instability Capable of inducing neoangiogenesis Capable of invasion and metastasis Hallmarks of Cancer Cells

30. Benign vs. Malignant Tumors Characteristics Benign Malignant Differentiation Structure often typical Structure often atypical, of tissue of origin I.e., poor differentiation Mode of Purely expansive; Infiltrative and expansive Growth with capsule no capsule Rate of Slowly progressive or May be rapid with Growth may stop and retrogress many abnormal mitotic figures scanty mitotic figures and normal Metastasis Absent Frequently present

31. Benign tumors arise with great frequency but pose little risk because they are localized and small

32. Malignant tumors generally invade surrounding tissue and spread throughout the body Alterations in cell-cell interactions and the formation of new blood vessels are associated with malignancy

33. Metastasis Cascade

35. Basal Cell Carcinoma * * * *

36. Biology of Invasion and Metastasis • Infiltration/degradation of the basement membrane(BM) • Binding through receptors for fibronectin and laminin • Extra cellular matrix (ECM) enzymatic digestion • Movement through ECM • Autocrine motility factor(AMF) • Chemoattractant: SF/cMet, cytokines • Chemokines (CCR4/CXCL12)

37. Characteristics of Metastasis • How Often? • - 30% of cancers have overt metastasis: cancer spreads to other organs on a • finite time line • -30-40% of cancers appear clinically free of metastasis but occult (hidden) • metastasis will appear as new cancers later in life • -30% of cancers do not appear to metastasis at all, and can be cured by • therapy directed only towards the primary site • How Soon? • Metastasis can occur before the cancer has grown to a detectable size. • (small cell lung cancer and undifferentiated tumors of the thyroid) • Metastasis can occur on the basis of size: Large tumors have a higher • chance for metastasis. (breast cancer, squamous carcinoma of the lung, and • colon cancer) • Metastasis may be very infrequent/does not happen at all (basal cell carcinoma)

38. Characteristics of Metastasis Where? - Metastatic tumors display organ specificity based on their tissue of origin Paget’s theory: Cells are dispersed randomly but only grow in organs that provide the correct factors necessary for growth Ewing’s theory: The first site to which a cancer metastasizes is the closest one in which there are small blood vessels. Examples: Tumor Origin Metastatic Site Breast - Lungs, Bone, Brain Lungs - Brain, Bone, Adrenal Glands, Liver Prostate - Bone Bone - Liver, Lung Colon - Liver

39. Model of Chemokine Regulation of Breast-Cancer Metastasis Murphy, P. M. N Engl J Med 2001;345:833-835

40. Malignant Melanoma

41. Metastatic Melanoma

42. Types of Malignant Neoplasms 1. Carcinomas Arise from epithelial precursor cells. These neoplasms generally spread via the lymphatics to regional and then distant lymph nodes and via the bloodstream to other organs. 2. Sarcomas Arise from stromal or mesenchymal components of organs (Connective and supporting tissues, and muscle). Bone (osteocytes), muscle,fibroblasts, and fat cells. Frequently metastasize via the bloodstream to distant sites. 3. Undifferentiated At times malignant neoplasms are so poorly differentiated Neoplasms that it is not possible to decide whether they are of epithelial or mesenchymal origin. 4.Carcinosarcomas and These neoplasms show mixtures of cells having mixed malignant teratomas epithelial and mesenchymal cell origin.

43. Sample Question An intestinal polyp I. Benign tumor of the intestine II. Has a low growth rate III. Do not metastasize I only III only I and II only I and III only I, II and III

44. Cancer Warning Signs 1. Change in bowel or bladder habits 2. A sore that does not heal 3. Unusual bleeding or discharge 4. Thickening or lump in breast or elsewhere 5. Indigestion or difficulty swallowing 6. Obvious change in a mole or wart 7. Nagging cough or hoarseness 8. Unexplained symptoms lasting longer than 2 weeks

45. What is the Cause of Cancer? Cancer is caused by an accumulation of genetic mutations…It is typical to identify tumors containing 5 or more genetic alterations. Over 300 different genes have been shown to be altered in human tumors and many still remain undetermined. Thus Cancer termed as a disease is a misnomer. Cancer is really a term that encompasses many different genetic diseases that result in inappropriate cellular growth

46. Tumor Fomation is a Multistage Process The mutations don’t happen all together…. they take a long time to accumulate!!

47. Multistage Genetic Model for the Development of Colon Cancer Chrom. Alter. Gene: 12p K-Ras 5q APC Clonal Expansion Normal Epithelium Hyperproliferation of Epithelium Early Adenoma Intermediate Adenoma 18q DCC 17p p53 Other Genetic Alterations Metastasis to distant sites via blood and lymph Late Adenoma Carcinoma

48. H-Ras mutation Ras activation PKC /MAPK pathway activation Multistage processes of skin-cancer formation

49. What Type of Genes are Mutated During Tumorigenesis?

50. What Type of Genes are Mutated During Tumorigenesis ? Genes that Regulate: Cell Growth Cell Death ( Apoptosis ) DNA Repair Angiogenesis Cellular Cohesion Drug/ Xenobiotic Metabolism Drug Resistance Cancer is caused by an accumulation of genetic mutations .Cancer does not arise from only one genetic alteration. It is typical to identify tumors Containing 5 or more genetic alterations. http://www. infobiogen . fr /services/ chromcancer /Genes/ Geneliste .html