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

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

3. 3 Change in the US Death Rates* by Cause, 1950 & 2004 * 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 Heart Diseases Cerebrovascular Diseases Pneumonia/ Influenza Cancer 1950 2004 Rate Per 100,000

4. 4 US Mortality, 2004 Source: US Mortality Public Use Data Tape 2004, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006. 1.Heart Diseases652,486 27.2 2.Cancer553,888 23.1 3.Cerebrovascular diseases150,074 6.3 4.Chronic lower respiratory diseases121,987 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 9.Nephritis 42,480 1.8 10.Septicemia 33,373 1.4 RankCause of Death No. of deaths % of all deaths

5. 5 2007 Estimated US Cancer Deaths* ONS=Other nervous system. Source: American Cancer Society, 2007. Men 289,550 Women 270,100 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 Lung & bronchus31% Colon & rectum9% Prostate9% Pancreas6% Leukemia4% Liver & intrahepatic4% bile duct Esophagus4% Non-Hodgkin 3% lymphoma Urinary bladder3% Kidney3% All other sites 23%

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

7. 7 2007 Estimated US Cancer Cases* *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2007. Men 766,860 (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 Prostate29% Lung & bronchus15% Colon & rectum10% Urinary bladder7% Melanoma of skin4% Non-Hodgkin 4% lymphoma Kidney4% Oral cavity3% Leukemia3% Pancreas2% All Other Sites19%

8. 8 Cancer Incidence Rates*, All Sites Combined, All Races, 1975-2003 Both Sexes Men Women Rate Per 100,000 *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. 9 Cancer Incidence Rates* for Men, 1975-2003 Prostate Lung & Bronchus Colon and rectum Urinary bladder Non-Hodgkin lymphoma Rate Per 100,000 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. 10 Cancer Incidence Rates* for Women, 1975-2003 *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. Colon and rectum Rate Per 100,000 Breast Lung & bronchus Uterine Corpus Ovary Non-Hodgkin lymphoma

11. 11 Lifetime Probability of Developing Cancer, by Site, Men, 2001-2003* SiteRisk All sites † 1 in 2 Prostate1 in 6 Lung and bronchus1 in 12 Colon and rectum1 in 17 Urinary bladder ‡ 1 in 28 Non-Hodgkin lymphoma1 in 47 Melanoma1 in 49 [1 in 52 (2002)] Kidney1 in 61 [1 in 64 (2002)] Leukemia1 in 67 Oral Cavity1 in 72 Stomach1 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 † All Sites exclude basal and squamous cell skin cancers and in situ cancers except urinary bladder. ‡ Includes invasive and in situ cancer cases

12. 12 Lifetime Probability of Developing Cancer, by Site, Women, US, 2000-2003* SiteRisk 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) 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 * For those free of cancer at beginning of age interval. Based on cancer cases diagnosed during 2000 to 2002. † All Sites exclude basal and squamous cell skin cancers and in situ cancers except urinary bladder. ‡ Includes invasive and in situ cancer cases

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

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

15. 15 Definitions CANCERMeans any malignant tumor TUMORis a nonspecific term meaning lump or swelling. In current usage, however, it is a synonym for neoplasm NEOPLASMmeans a new growth, an aberrent proliferation of cells NEOPLASIAis a disease of cells characterized by alteration of normal growth regulatory mechanisms METAPLASIAis 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. 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 primary tumor, tumor size, number of tumors, and lymph node involvement (spread of cancer into lymph nodes).

17. 17 Tumor grading 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. 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 poorly differentiated. 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. http://www.cancer.gov/cancertopics/factsheet/Detection/staging

18. 18 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. Significance of tumor grading

19. 19 Significance of tumor grading (II) The American Joint Commission on Cancer recommends the following guidelines for grading tumors (1): Grade GX Grade 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. 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. 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. 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. 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 A.I only B.III only C.I and II only D.I and III only E.I, II and III

24. 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. A.I only B.III only C.I and II only D.I and III only E.I, II and III

25. 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 A.I only B.III only C.I and II only D.I and III only E.I, II and III

26. 26 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. Tissues

27. 27 Fibroblasts Adipocytes Bone Cells Astrocytes Epithelial cells

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

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

30. 30 Benign vs. Malignant Tumors Characteristics Benign Malignant DifferentiationStructure often typicalStructure often atypical, of tissue of originI.e., poor differentiation Mode ofPurely expansive;Infiltrative and expansive Growthwith capsuleno capsule Rate ofSlowly progressive orMay be rapid with Growthmay stop and retrogressmany abnormal mitotic figures scanty mitotic figures and normal Metastasis AbsentFrequently present

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

32. 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. 33 Metastasis Cascade

34. 34

35. 35 Basal Cell Carcinoma * * * *

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

37. 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. 38 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 OriginMetastatic Site Breast - Lungs, Bone, Brain Lungs - Brain, Bone, Adrenal Glands, Liver Prostate - Bone Bone - Liver, Lung Colon -Liver Characteristics of Metastasis

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

40. 40 Malignant Melanoma

41. 41 Metastatic Melanoma

42. 42 Types of Malignant Neoplasms 1. CarcinomasArise 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. SarcomasArise 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. UndifferentiatedAt times malignant neoplasms are so poorly differentiated Neoplasmsthat 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. 43 Sample Question An intestinal polyp I. Benign tumor of the intestine II. Has a low growth rate III. Do not metastasize A.I only B.III only C.I and II only D.I and III only E.I, II and III

44. 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. 45 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 What is the Cause of Cancer?

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

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

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

49. 49 What Type of Genes are Mutated During Tumorigenesis?

50. 50 Genes that Regulate: Cell Growth Cell Death (Apoptosis) DNA Repair Angiogenesis Cellular Cohesion Drug/Xenobiotic Metabolism Drug Resistance What Type of Genes are Mutated During Tumorigenesis ? Cancer is caused by anaccumulation 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

51. 51 Genetic Changes that Alter Cell Proliferation Mutations that result in unrestrained cell proliferation occur in two classes of genes: ONCOGENES:The products of proto-oncogenes act at many points along the pathways that stimulate cell proliferation. Genetic mutations that result in an altered protein that has increased activity or changes that result in increased expression of a proto-oncogene are termed oncogenes. The genetic alterations are typically “Gain of Function” mutations and are dominant in nature (ie - only one allele needs to be altered) TUMOR SUPRESSORTumor supressor genes encode proteins that inhibit GENES:cell proliferation and ensure the stability of the genome. The genetic alterations that occur in this class of genes during tumorigenesis are typically “Loss of Function” mutations and are recessive in nature (ie - requires that both genetic loci are altered)

52. 52 Growth Factor Signal Transduction and Cancer Growth factors in normal cells serve as environmental signals and regulate growth, proliferation, and survival. These are all deregulated in cancer. Growth Factors Gene Transcription Entry into S-phase Phosphorylation Signaling Cascade: Involves multiple proteins to transfer growth signals from the plasma membrane to the nucleus

53. 53 FactorPrincipal Source Primary ActivityComments PDGF platelets, endothelial cells, placenta promotes proliferation of connective tissue, glial and smooth muscle cells two different protein chains form 3 distinct dimer forms; AA, AB and BB EGF submaxillary gland, Brunners gland promotes proliferation of mesenchymal, glial and epithelial cells TGF-  common in transformed cells may be important for normal wound healing/tumor growth related to EGF FGF wide range of cells; protein is associated with the ECM promotes proliferation of many cells; inhibits some stem cells; induces mesoderm to form in early embryos at least 19 family members, 4 distinct receptors NGF promotes neurite outgrowth and neural cell survival several related proteins first identified as proto-oncogenes; trkA (trackA), trkB, trkC Erythropoietin kidneypromotes proliferation and differentiation of erythrocytes TGF-  activated TH 1 cells (T-helper) and natural killer (NK) cells anti-inflammatory (suppresses cytokine production and class II MHC expression), promotes wound healing, inhibits macrophage and lymphocyte proliferation at least 100 different family members IGF-I primarily liverpromotes proliferation of many cell types related to IGF-II and proinsulin, also called Somatomedin C IGF-II variety of cellspromotes proliferation of many cell types primarily of fetal origin related to IGF-I and proinsulin Growth Factors

54. 54 Most growth factors bind Receptor Tyrosine Kinases Adapted from Molecular Biology of the Cell,(2002), 4th edition, Alberts et al.

55. 55 Why is it important to study cancer cell signaling ??? It helps us to better understand the mechanisms of cancer development and progression. We can target deregulated signaling pathways to improve cancer management.

56. 56 Signal Transduction and Cancer A)What are the signal transduction pathways involved? B)What are their cell biological outputs? C)What are the targets of these pathways ? D)How do these targets evoke changes leading to cancer? E)How can we exploit signaling pathways for therapy?

57. 57 Mechanism of signal transduction and gene expression promoting cell growth and proliferation

58. 58 GDP Receptor Tyrosine Kinase Plasma Membrane Nuclear Membrane Grb2 Sos Ras GAP Raf Family Kinases MEK Family KinasesERKs Growth Factors GTP Ras ERKs c-jun c-fos (Other Targets: Elk-1, C/EBP b, c-Myc) Cyclin D

59. 59 GDP Receptor Tyrosine Kinase Plasma Membrane Grb2 Sos Ras GAP Raf Family Kinases MEK Family KinasesERKs Growth Factors GTP Ras ERKs c-jun c-fos Cyclin D HER2 Tyrosine Kinase Receptor is overexpressed in 30% of breast cancers Mutations in k-Ras occur in 19% of small cell lung carcinomas and 60% of all pancreatic carcinomas Genetic amplification of Cyclin D1 occurs in breast, colon and hepatocellular carcinomas as well as gliomas Constituitive expression of transcription factors involved in proliferation occurs in a wide array of human tumors

60. 60 Signal Transduction intermediates can be targets for anti-cancer drugs Kinases: Raf

61. 61 Sample Question Chemically induced skin cancer progression is a multi-stage process that invloves I. Initiation stage by mutation of the H-Ras gene II. Activation of the Ras-Raf-MAPK pathway III. Promotion and progression stage to invasive carcinoma A.I only B.III only C.I and II only D.I and III only E.I, II and III

62. 62 Cyclin D/Cdk4,6 Cyclin E/Cdk2 Cyclin A/Cdk2 Cyclin A/Cdc2 Cyclin B1/Cdc2 G2 Mitosis (M) G1 DNA Synthesis (S) Mammalian Cell Cycle

63. 63 Cyclin D Cyclin A Cyclin E Cyclin B G1 S-phase G2 Mitosis Cyclin Concentration cdk Inactive Kinase -A catalytically active protein that acts to phosphorylate a substrate, usually another protein. cyclin cdk Active Cyclin - acts as a regulatory subunit

64. 64 Mammalian Cell cycle- cell growth and division

65. 65 E2F cyclin cdk E2F pRb PP P Repressed Transcription Factor Active Transcription Factor Expression of S-phase genes Including: Cyclin A Cyclin B Cdc2 E2F Retinoblastoma Protein Mutations that affect the pRb-signaling Pathway have been documented in nearly Every type of adult tumor and include (I) Deletion of or point mutations in the pRb gene

66. 66 Stress Stress Cell Cycle arrest Repair Normal Cell Apoptosis Normal Cell p53 Permanent Genetic Alterations Cell

67. 67 Ac P p53 Oncogene Activation Hypoxia Heat Shock DNA Damage (UV, IR, Drugs) Metabolic Changes pH Changes Stabilization / Activation

68. 68 p53 role in cancer

69. 69 Ac Apoptosis Active p53 p53 P Growth Arrest p53 is the most commonly mutated gene in all human tumors (60%) and mutations that occur in p53 mediated signaling pathways are present in over 90% of all human tumors. p53 is a transcription factor - it binds with DNA in a sequence specific manner and has been shown to activate or repress the expression of downstream target genes involved in growth arrest, apoptosis, DNA repair, and angiogenesis. DNA Repair Angiogenesis

70. 70 Regulation of gene expression by p53

71. 71 Ac p53 P Ac p53 P Ac p53 P Cell Stress p21 Growth Arrest and Maintenance of Genomic Integrity p53 Mediated Growth Arrest Cyclin-dependent kinase inhibitor

72. 72 E2F cyclin cdk E2F pRb Expression of S-phase genes Including: Cyclin A Cyclin B Cdc2 pRb PP P Repressed Transcription Factor Active Transcription Factor E2F Retinoblastoma Protein p21 X

73. 73 Cyclin D/cdk4,6 Cyclin E/cdk2 Cyclin A/cdk2 Cyclin A/cdc2 Cyclin B1/cdc2 G2 Mitosis (M) G1 DNA Synthesis (S) p21

74. 74 Mutations that affect the pRb-signaling pathway have been documented in nearly every type of adult tumor and include: (I) Deletion of or point mutations in the pRb gene (II)The constituitive activation or overexpression of tyrosine kinase receptors, Ras family members, growth stimulatory transcription factors, cyclin D1, and cdk4 (III)The loss of other tumor suppressors, including p53,PTEN. All of these events allow the unscheduled activation of E2F transcription factors and entry in S-phase Summary of Genetic Mutations that Effect Cell Proliferation

75. 75 Sample Question In mammalian cell-cycle progression Cyclin D acts as a Regulatory subunit that I. is phosphorylated by CDK2 II. Participates in the G1 phase of the cell cycle III. Facilitates RB hyperproliferation A.I only B.III only C.I and II only D.II and III only E.I, II and III

76. 76 Sample Question Tumor suppressor p53 is the gate keeper molecule which I. is mutated in most human cancer II. Activated by various external stimuli like UV, hypoxia, and heat shock III. Induces growth arrest, repair DNA and facilitates programmed cell death A.I only B.III only C.I and II only D.II and III only E.I, II and III

77. 77 Sample Question Alterations of the RB signalling pathway in human cancer includes I. Mutation of the RB gene II. Activation of the cyclin D1/Cdk4 III.Enhanced expression of S-phase E2F target genes. A.I only B.III only C.I and II only D.II and III only E.I, II and III

78. 78 What happens when DNA mutations occur ?

79. 79 DNA Repair When DNA is damaged a large number of proteins are called into action to repair the DNA Most DNA mutations are repaired!! But over a lifetime – some mutations slip by…

80. 80 How Important is DNA Repair? DNA is: The repository of hereditary information The blueprint for operation of individual cells The importance of DNA Repair is exemplified by the facts that: DNA is the only biomolecule that is specifically repaired. All others are replaced > 100 genes participate in various aspects of DNA repair,even in organisms with very small genomes In most cases, “genetic instability” (elevation of mutation rate) is required to permit accumulation of sufficient mutations to generate cancer during a human lifetime. DNA repair mechanisms promote genetic stability and prevent cancer. Many cancers are in part, attributable to defects in repair genes.

81. 81 Xeroderma Pigmentosum (XP) Autosomal recessive disorder caused by mutations in any of 7 DNA repair genes (XPA-XPG). Patients suffering from XP have: Severe light sensitivity Severe pigmentation irregularities Early onset of skin cancer at high incidence They cannot repair damage caused by Ultraviolet radiation!! Patients have a 1000-fold increased risk for the development of Several types of skin cancers, including melanoma Onset of tumors can occur as early as age 4, as compared with age 60 in the general population. Most patients (<40%) suffering from XP do not live past the age of 20

82. 82 What Type of Mutations Occur During Tumorigenesis?

83. 83 1. Genetic Lesions that usually affect only one gene: Point Mutations Frame Shift Mutations Insertions/Deletions Amplification 2.Major Chromosome Abnormalities Translocations Chromosomal Loss

84. 84 Genetic alteration in cancer

85. 85 Found in Most Cases of CML (Chronic Myelogenous Leukemia)

86. 86 GDP Receptor Tyrosine Kinase Plasma Membrane Nuclear Membrane Grb2 Sos Ras GAP Raf Family Kinases MEK Family KinasesERKs Growth Factors GTP Ras ERKs c-jun c-fos (Other Targets: Elk-1, C/EBP b, c-Myc) Cyclin D Bcr-Abl Fusion

87. 87 Kinases: Bcr-Abl Signal Transduction intermediates can be targets for anti-cancer drugs

88. 88 Proto-oncogene Myc European Journal of Cancer European Journal of Cancer Volume 41: 2485-2501 (2005)

89. 89 Myc and cancer

90. 90 Turn off myc, tumors differentiate Myc onMyc off Osteogenic sarcomas Science 297: 102 (2002)

91. 91 Turn Myc back on, cells die Science 297: 102 (2002) H &E TUNEL DAPI Myc onMyc off Myc on again 5 days Myc on again 14 days

92. 92 1.Dynamic changes (activation and silencing) of genes - Association of DNA with Histones - DNA methylation Example: p21 A.Re-expression of such silenced genes can lead to suppression of tumor growth or sensitization to anticancer therapies. B.Agents that can reverse DNA methylation include nucleoside and non-nucleoside inhibitors of DNA methyltransferase. C.Such agents are now undergoing preclinical evaluation and clinical trials in cancer patients. Epigenetic Factors that Cause Tumorigenesis

93. 93

94. 94 Sample Question Patients suffering from XP disease I. have mutation(s) in the DNA repair genes II. Are susceptible to UV induced DNA damage and chromosomal instability III. have increased risk to develop melanoma A.I only B.III only C.I and II only D.II and III only E.I, II and III

95. 95 Sample Question “Philadelphia chromosome”--- I. found in patients with Acute Myelogenous Leukemia II. Contain the fused abl-bcr gene III. Acitvates aberrant signalling through the Ras-Raf pathway A.I only B.III only C.I and II only D.II and III only E.I, II and III

96. 96 Cancer Angiogenesis

97. 97 Regulation of Angiogenesis

98. 98 Role of VEGF in Cancer Angiogenesis

99. 99 What qualifications do you need to be a cancer cell? Hanahan and Weinberg, (2000) Hallmarks of Cancer, Cell (100) 57

100. 100 1) Self-sufficiency in growth signals All normal cells require extrinsic factors produced by other cells “Social control” model for cell growth GROWTH FACTORS

101. 101 2) Overcome growth-inhibitory signals Most cells in your body are sitting there happily in G0 Are growth inhibitory proteins in the extracellular space Terminal differentiation inhibits further cell growth Oncogene expression can produce cell cycle arrest

102. 102 3) Evade apoptosis Fas/TNFa extrinsic pathway for apoptosis Mitochondrial intrinsic pathway Both pathways have caspases in common Ironically, oncogenes can also induce apoptosis

103. 103 4) Limitless replicative potential Avoid replicative senescence: a non- dividing state from which cells do not recover (mutate p53/Rb) Avoid crisis: massive cell death and karyotypic disarray (activate telomerase)

104. 104 5)Tumors require angiogenesis Greater than 1-2 mm sphere needs a blood supply Tumors often have a necrotic center—angiogenesis does not keep up VHL/Hif/VEGF axis Angiogenesis inhibitors in clinical trials

105. 105 6) Invasive potential Metastases kill you, not the primary tumor Metastatic cells must be able to enter and leave bloodstream and to survive in an ectopic location Part of explanation of the role for Rho/Rac, integrins, and matrix metalloproteases in cancer

106. 106 Cancer Paradigm Tumors as Complex Tissues in which mutant cancer cells have conscripted and subverted normal cell types to serve as active collaborators in their neoplastic agenda (right panel). The interactions between the genetically altered malignant cells and these supporting coconspirators will prove critical to understanding cancer pathogenesis and to the development of novel, effective therapies. Hanahan and Weineberg, Cell, 2000

107. 107 Nature Reviews Cancer 4; 839-849 (2004); FRIENDS OR FOES — BIPOLAR EFFECTS OF THE TUMOUR STROMA IN CANCER | Tumour stage depends on stromal activation.

108. 108 Crosstalk between tumour cells and their activated stromal surroundings Nature Reviews Cancer 4; 839-849 (2004); FRIENDS OR FOES — BIPOLAR EFFECTS OF THE TUMOUR STROMA IN CANCER

109. 109 How is the knowledge of genetic defects in the development of cancer affecting cancer treatment? 1. It is providing new therapeutic targets for the development of new chemotherapeutic agents that have more directed therapies. Example: farnesyl transferase inhibitors that block the localization of Ras family proteins to the plasma membrane 2. It is increasing our ability to more accurately predict a patient’s prognosis and design better treatment strategies based on the types of mutations present within a tumor.

110. 110 Sample Question “Angiogenesis” is I. mediated by paracrine -autocrine signalling between endothelial cells and tumor cells. II. critical in cancer progression and metastasis III. Involves signalling mediated by VEGF A.I only B.III only C.I and II only D.II and III only E.I, II and III

111. 111 Overview of the major types of Cancer

112. 112 Leukemias and Lymphomas 1.Cancers of blood and lymph systems 2. Most common cancers in children, representing about half of all childhood malignancies. 3. Derived from a common precursor cells, pluripotent stem cells in the bone marrow. 4. Leukemias can result from abnormal proliferation of any of the different kinds of cells within either the myeloid or lymphoid lineages. 5. Lymphomas develop from lymphocytes or macrophages in lymphatic tissues.

113. 113 Development of Blood Cells Blood coagulation O2 transport Inflammatory reaction Ab secretion Cell mediated Immunity

114. 114 Lymphocyte Granulocyte Monocyte Red Blood Cells

115. 115

116. 116 Lymph Node The Lymphatic System

117. 117 Leukemia There are 2 types of leukemia: Lymphoid and Myeloid 1. Lymphoid Leukemia has two subtypes a. Acute Lymphoblastic Leukemia (ALL) b. Chronic Lymphoblastic Leukemia (CLL) 2. Myeloid Leukemia has two subtypes a. Acute Myelogenous Leukemia (AML) b. Chronic Myelogenous Leukemia (CML) Treatments include: Chemotherapy Radiotherapy Bone Marrow Transplant

118. 118 Lymphoblastic Leukemias Acute Lymphoblastic Leukemia (ALL): 1. Usually occurs in childhood (80-90% of all childhood cases) 2. Most common type is pre-B-cell (85%) rather than T-cell (15%). The prognosis of T-cell ALL is worse. 3. The pre-B cell does not bear surface immunoglobulin that mature B-cells carry, although they do have early B-cell markers and rearrangement of immunoglobulin. 4. Cures of ALL have been achieved in the majority of patients with combination chemotherapy and prophylactic chemotherapy of the CNS, a frequent site of relapse. Chronic Lymphoblastic Leukemia (CLL) 1. Occurs predominantly in elderly (~30% of adult patients) 2. Generally has a slow course with survivals of untreated disease of 10yrs 3. Low stage is confined to bone marrow and peripheral blood, whereas higher stage includes spreading to lymph nodes, spleen, liver, etc. 4. A sign of poor prognosis is anemia and low platelet count, as it indicates replacement of most of the bone marrow with tumor cells. 5.Treatment not undertaken until splenomegaly, or cytopenias present and survivals are often long, even with disease.

119. 119 Myelogenous Leukemias Acute Myelogenous Leukemia (AML): 1.Primarily affects young and middle-aged adults, and has an abrupt, stormy onset. 2. Most often the bone marrow almost completely replaced by blast cells, leading to severe pancytopenia. 3. About 80% of patients achieve remission with intensive chemotherapy, although relapse after 12-18 months is common. Bone marrow transplant offers only hope of cure and is a risky procedure. Chronic Myelogenous Leukemia (CML) 1. Primarily affects adults 2. Is associated with a distinctive chromosomal abnormality, the Philadelphia chromosome, a translocation between chromosomes 9 and 22 that results in the fusion of two proteins ( the bcr or break-point cluster region fused to an oncogene, abl) 3. Progression is slow, over a course of 3-5 years. About 50% of patients then enter an accelerated phase or blast crisis, in which they develop acute leukemia and die within a period of months.

120. 120 Sample Question B-cell acute Lymphoblastic Leukemia is I. Most common type of childhood leukemias. II. Derived from the pluripotent stem cells of the bone marrow. III. Lacking the surface immunoglobulin on the mature B-cells. A.I only B.III only C.I and II only D.II and III only E.I, II and III

121. 121 Childhood Solid Tumors Leukemia and Lymphomas Brain Tumor Neuroblastoma Wilm’s Tumor Bone Tumor Soft Tissue Sarcomas Retinoblastoma

122. 122 Brain Tumor a. Most common childhood solid tumors b. Several different types- astrocytomas, medulloblastomas, ependymomas and gliomas c. Symptoms-headache, dizziness, blurred Vision, and problems with coordination. d. Diagnosis-Variety of imaging techniques, Particulary CT scan and MRI, recording brains Electrical activity by electroencephalography (EEG) e. The aggressive astrocytoma-anaplastic astrocytomas and Glioblastomas- are malignant tumors with average survival times of 2-3 yrs And about one year, respectively.

123. 123 Neuroblastoma a. Next most common childhood solid tumors b. It is neoplasm of the embryonic neural cells that usually occurs by 2yrs. of age. c. Progression of neuroblastomas to more aggressively growing stages of the disease is associated with high levels of expression of N-myc oncogene. d. Originate most frequently in the abdomen, and are usually detected as a swelling or abdonimal tissue mass. e. The overall survival rate is 50% Arrowhead points towards a tumor behind the liver and is pushing the liver forward and may have possibly spread into the liver tissue.

124. 124 Retinoblastoma a.It is an eye tumor arising from embryonic retinal cells. b. Usually occurs by age 3. c. Both inherited and and noninherited retinoblastomas involve mutations of the RB tumor suppressor gene. d. About 40% of the retinoblastoma cases are hereditary and arise following inheritance of a defective RB gene from one of the parent e. Early diagnosis helps in cure by surgery or radiotherapy without the loss of Vision.

125. 125 Wilm’s Tumor a.Is a tumor of embryonic kidney cells which accounts for about 5 percent of childhood cancer incidence. b. Develops as a result of mutations in a tumor suppressor called WT1. c. In some cases they are inherited and also frequently associated with other congenital abnormalities, including aniridia(absence of the iris), genitourinary defects, and mental Retardation (the WAGR syndrome). d. Usually detected as a swelling or mass in the abdomen and diagnosed by X-rays and other imaging techniques.

126. 126 Bone Tumors This X-ray shows a malignant bone tumor (osteogenic sarcoma) of the knee. This type of tumor is usually seen in adolescents (around 15 yrs.) a.Two types of bone cancer, osteosarcoma and Ewing’s sarcoma, together constitute about 5 % of childhood malignancies. b. Osteosarcoma involves mutations of the RB tumor suppressor gene. c. The p53 tumor suppressor is also frequently mutated in osteosarcoma. d. The primary symptoms of both types are pain and swelling in the area of the tumor. e. Diagnosis is made by x-rays and biopsy.

127. 127 Soft-Tissue sarcoma a. Rhabdomyosarcoma, a cancer of the Skeletal muscle cells is the most common accounting for approx. 4% of the childhood cancers. b. In some cases like in Li-Fraumeni cancer Family syndrome the genetic aleration is inherited. c. Mutation of the RB and p53 tumor suppressor genes occur in these tumors. d. The primary symptoms is a painless lump or mass which is diagnosed by biopsy.

128. 128 Common Solid Tumors of the adults Lung Cancer Colon/Rectal cancer Breast Cancer Prostrate Cancer Urinary Cancer Uterine Cancer a. Cervical cancer b. Endometrial cancer Oral and Esopahgeal cancer Pancreatic cancer Melanoma and non-melanoma skin cancer Ovarian cancer Liver cancer Laryngeal cancer Thyroid cancer Brain Tumors Stomach cancer Testicular cancer

129. 129 Why is skin cancer important?  It’s the most common type of cancer in the United States;  about 40 to 50 percent of Americans who live to age 65 will be diagnosed with it, at least once;  it’s found in more than 1 million Americans each year;  it will kill nearly 8,000 people;  …. and it is largely preventable. skin cancer

130. 130 Primary types Pre-cancerous -Actinic keratosis Cancerous -Basal cell carcinoma -Squamous cell carcinoma -Melanoma -Others (of the specialized structures of the skin)

131. 131 Actinic keratosis  A pre-cancerous condition of thick, scaly patches of sun-damaged skin. Also referred to as solar or senile keratosis.

132. 132 Basal Cell Carcinoma  A type of skin cancer that arises from the basal cells, small round cells found in the lower part (or base) of the epidermis, the outer layer of the skin.

133. 133 Basal Cell Carcinoma  Basal cell carcinoma accounts for more than 90 percent of all skin cancers in the United States.  It is a slow-growing cancer that seldom spreads to other parts of the body, and generally is readily treatable.  May erode into surrounding structures if not treated.

134. 134 Basal Cell Carcinoma Three common presentations: Small, smooth, pale, or waxy shiny lump Firm, red lumpA lump that bleeds or develops a crust

135. 135 Squamous Cell Carcinoma  Cancer that begins in squamous cells, which are thin, flat cells that look like fish scales.  Squamous cells are found in the tissue that forms the surface of the skin.  Also found on other internal and external body surfaces.

136. 136 Squamous Cell Carcinoma  More than 250,000 new cases of squamous cell carcinoma diagnosed each year.  Often develop from sun damaged areas called solar or actinic keratosis.  Look similar to basal cell carcinoma, and even actinic keratosis.

137. 137 Squamous Cell Carcinoma  Similar in appearance to actinic keratosis and basal cell carcinoma.

138. 138 Melanoma  A form of skin cancer that arises in melanocytes, the cells that produce pigment and also are found in the epidermis.  Melanomas usually begin in a mole, which is a benign cluster of melanocytes and other tissue. Normal moles:

139. 139 Melanoma  Melanoma is the deadliest form of skin cancer, causing more than 75% of all skin cancer deaths.  The incidence of melanoma skin cancer is increasing rapidly all over the world.

140. 140 Melanoma (the A-B-C and Ds) A symmetry -- The shape of one half does not match the other.

141. 141 B order -- The edges are often ragged, notched, blurred, or irregular in outline; the pigment may spread into the surrounding skin. Melanoma (the A-B-C and Ds)

142. 142 C olor -- The color is uneven. Shades of black, brown, and tan may be present. Areas of white, grey, red, pink, or blue also may be seen. Melanoma (the A-B-C and Ds)

143. 143 D iameter -- There is a change in size, usually an increase. Melanomas are usually larger than the eraser of a pencil (5 mm or 1/4 inch). Melanoma (the A-B-C and Ds)

144. 144 Melanoma May be found when a pre-existing mole changes: Early changes - forming a new black area - newly formed fine scales - itching in a mole More advanced changes - texture changes (becomes hard or lumpy) - itch, ooze, or bleed - usually do not cause pain

145. 145 Who is at risk for skin cancer?  Light skin color, hair color, eye color.  Family history of skin cancer.  Personal history of skin cancer.  Certain types and a large number of moles.  Freckles, which indicate sun sensitivity and sun damage.  Chronic exposure to the sun.  History of sunburns early in life.

146. 146 Sunburns are common The Behavior Risk Factor Surveillance System provided data showing nearly 32% of all adults in the US report having had a sunburn. More than 57% of adults age 18 to 29 reported having had a sunburn. Over 40% of children are reported to have had sunburns over the preceding year.

147. 147 How is it found?  Mostly by self examination of the skin  By observations by family members  By skin examination during visits to the doctor To catch it early, you have to LOOK for it!… and then you have to DO something about it!

148. 148 How is skin cancer treated? The physician will:  Determine what type it is (medical history, examination, biopsy)  Determine how localized or extensive it is  Then treat it….  surgery (e.g., Moh’s, cryo, laser, curettage, grafts)  chemotherapy  radiation

149. 149 Lung Cancer a.Cancer of the lung is responsible for about 14% of cancer cases, and approx.30% of cancer deaths in the US. b. 80-90 % of the lung cancer is caused by cigarette smoking and therefore could be prevented by avoidance of the single carcinogenic agent. c. Classified as small-cell(SCLC) and non-small cell carcinomas (NSCLC). d. The most common non-small cell types are adeno- carcinomas, squamous cell carcinoma and large-cell carcinomas. e. All types of lung cancer are associated with Mutations of the p53 tumor suppressor gene, and Small cell carcinomas also have RB mutation. Besides, NSCLC frequently involve ras oncogenes.

150. 150 Lung Cancer Healthy lung Lung cancer Lung Cancer shows itself as a shadow caused by the tumor marked as a “Ca”. However, the development of shadowing on the lung cancer on the X ray lags behind formation of the cancer and a lesion has to be over a Centimetre in diameter before it can be recognised. *MRI needed for a definitive diagnosis.

151. 151 Breast Cancer Invasive lobular carcinoma (ducts) (lobules) (dialated duct (nipple) (Fat) (muscle) (rib cage) (normal lobular cells) (lobular cancer cells) (basement membrane) Range of ductal carcinoma

152. 152 Breast Cancer a. Breast Cancer accounts for 31% of the cancer incidence and 15% of the cancer mortality, in the US. b. Most common cancer among women and 1 in every 9 women will develop breast cancer at some point in life. c. 90% percent of the breast cancer arise in the ducts and 10% in the lobules. d.Breast cancers frequently involve RB and p53 tumor suppressor genes, as well as c-Myc and erb2 oncogenes. e.Mutation in the genes Breast Cancer-1 (BRCA-1) located on chromosome #17, and BRCA-2 located on chromosome #13 is associated with hereditary cancer. f. Early detection is of major importance in reducing breast cancer motality. g. Annual screening by mammography for women over age 40 reduces reduces cancer motality by about 30%.

153. 153 Screening Guidelines for the Early Detection of Breast Cancer, American Cancer Society  Yearly mammograms are recommended starting at age 40.  A clinical breast exam should be part of a periodic health exam, about every three years for women in their 20s and 30s, and every year for women 40 and older.  Women should know how their breasts normally feel and report any breast changes promptly to their health care providers. Breast self-exam is an option for women starting in their 20s.  Women at increased risk (e.g., family history, genetic tendency, past breast cancer) should talk with their doctors about the benefits and limitations of starting mammography screening earlier, having additional tests (i.e., breast ultrasound and MRI), or having more frequent exams.

154. 154 Growth Factor Receptors can be drug targets

155. 155 Prostate Cancer a. Prostate Cancer accounts for 33% of the cancer incidence and 9% of the cancer mortality, in the US. b. Most common cancer among men and 1 in every 6 men will develop prostate cancer. c. Over 80% percent of the prostate cancer occur in men past age 65. d. Benign prostatic hyperplasia(BPH) is a non-cancerous enlargement of the prostate gland, common in men over the age 50. e. Prostate cancers frequently involve RB and PTEN tumor suppressor genes mutation. f. Prostate-specific antigen (PSA) is a glycoprotein in the cytoplasm of prostate epithelial cells detected in the blood of all adult males, and its level is increased in prostate cancer.

156. 156 Screening Guidelines for the Early Detection of Prostate Cancer, American Cancer Society The prostate-specific antigen (PSA) test and the digital rectal examination (DRE) should be offered annually, beginning at age 50, to men who have a life expectancy of at least 10 years. Men at high risk (African-American men and men with a strong family history of one or more first-degree relatives diagnosed with prostate cancer at an early age) should begin testing at age 45. For men at average risk and high risk, information should be provided about what is known and what is uncertain about the benefits and limitations of early detection and treatment of prostate cancer so that they can make an informed decision about testing.

157. 157 Cervical Cancer a. Cervical Cancer usually squamous cell carcinoma-is responsible for about 30% of uterine cancer cases and about 60% of deaths. b. Most cases of cervical cancer are associated with human papilloma viruses, which are sexually transmitted. c. Early detection by Pap smear has been extremely effective against cervical cancer. d. Endometrial cancer, usually adeno- carcinoma, accounts for about 70% of the uterine cancers, excluding cervical carcinomas in situ.

158. 158 Screening Guidelines for the Early Detection of Cervical Cancer, American Cancer Society  Screening should begin approximately three years after a women begins having vaginal intercourse, but no later than 21 years of age.  Screening should be done every year with regular Pap tests or every two years using liquid-based tests.  At or after age 30, women who have had three normal test results in a row may get screened every 2-3 years. However, doctors may suggest a woman get screened more frequently if she has certain risk factors, such as HIV infection or a weakened immune system.  Women 70 and older who have had three or more consecutive Pap tests in the last ten years may choose to stop cervical cancer screening.  Screening after a total hysterectomy (with removal of the cervix) is not necessary unless the surgery was done as a treatment for cervical cancer.

159. 159 Colon Cancer a. Together, colon and rectum cancers account for approx. 33% of the cancer incidence and 9% of mortality, in the US. b. Cancers of these sites are adeno- carcinomas. c. Rare form of colon cancer are inherited, for example, familial adenomatous polyposis. d. The ras oncogene and the APC and MCC tumor suppressor genes appear to be involved in the early stages of the disease process, contributing to the development of pre-malignant adenomas (polyps). e. Progression to malignant carcinomas then involves loss or inactivation of the p53 and DCC tumor suppressor genes. f. Due to the gradual progression of colon cancer, early detection is a feasible approach to reduce mortality from these cancers.

160. 160 Screening Guidelines for the Early Detection of Colorectal Cancer, American Cancer Society Beginning at age 50, men and women should follow one of the following examination schedules:  A fecal occult blood test (FOBT) every year  A flexible sigmoidoscopy (FSIG) every five years  Annual fecal occult blood test and flexible sigmoidoscopy every five years*  A double-contrast barium enema every five years  A colonoscopy every ten years *Combined testing is preferred over either annual FOBT or FSIG every 5 years alone. People who are at moderate or high risk for colorectal cancer should talk with a doctor about a different testing schedule

161. 161 Cancer Hanahan and Weineberg, Cell, 2000 Activate H-Ras oncogene Lose Rb suppressor Inactivate E-cadherin Turn on telomerase Produce VEGF Produce IGF survival factors

162. 162 Sample Question Non small cell lung cancer (NSCLC) is I. one of the most aggressive form of lung cancer II. generally caused by cigarette smoking. III. Associated with oncogenic mutation of ras and tumor suppressor p53. A.I only B.III only C.I and II only D.II and III only E.I, II and III

163. 163 Sample Question Ductal breast cancer I. is the most common cancer among women in the US. II. Constitute about 90% of the breast cancer incidence. III. Frequently involve mutation in tumor suppressor PTEN and activation of c-Myc oncogene. A.I only B.III only C.I and II only D.II and III only E.I, II and III

164. 164 Sample Question Prostate cancer I. is the most common cancer among men in the US. II. Can be detected by analyzing the PSA level in the patients blood. III. Frequently involve mutation in tumor suppressor BRCA1 and RB. A.I only B.III only C.I and II only D.II and III only E.I, II and III

165. 165 Thank you