Cancer Biology 241: Molecular, Cellular and Genetic Basis of Cancer

1. Cancer Biology 241:Molecular, Cellular and Genetic Basis of Cancer Lectures: Mon and Wed 9-11 AM, CCSR 4105 Discussion Section: Friday 9-11AM, TBA Course Directors: Laura Attardi and Joe Lipsick TA: Gabe Quinones

2. Focus of This Course • Cancer research • HOW we know what we know • Key observations and experiments • Historical context • Generalization of key experiments as a basis for further discoveries • Learning to read the primary literature • Learning about experimental methods

3. Responsibilities and Grading • Read papers PRIOR to discussion section • Participate actively in discussion sections • Submit original grant proposal on time • Peer review (anonymous) of two grants • Grading • 50% discussion section participation • 30% grant proposal • 20% grant review • Honor Code

4. http://coursework.stanford.edu

7. http://lane.stanford.edu/index.html

8. Books

11. Cancer Biology: The Basics • Impact of cancer on human population • Causes of human cancer • Classification of human cancer • Experimental approaches to cancer

12. Leading Causes of Death in U.S. from CDC

13. Rate Per 100,000 1950 2000 Cancer HeartDiseases Pneumonia/Influenza CerebrovascularDiseases * Age-adjusted to the 2000 US standard population. Source: US Mortality Volume 1950, National Vital Statistics Report, 2002, Vol. 50, No. 15. Change in Causes of Death

14. Invasive Cancer versus Age data from National Cancer Institute http://www.cdc.gov/cancer/npcr/uscs/report/

15. Cancers by Type in U.S. from American Cancer Society

16. MALE FEMALE Cancer Death Rates in U.S. from American Cancer Society

17. From Suffrage to Suffering

19. Enough S’nuff – The Sot Weed Factor 1761 – Sir John Hill notes that snuff causes nasal cancer

20. Human Migration and Cancer from Rubin and Farber, Pathology

21. Same Virus, Different Outcomes EBV Nasopharyngeal Cancer Mononucleosis Burkitt’s Lymphoma Immune Suppression Malaria AIDS Organ Transplants Dietary Factors

22. Known Causes of Human Cancer • Chemical Exposure • Tobacco smoke • Environmental (PCBs) • Occupational (coal tar, asbestos, aniline dye) • Diet (aflatoxin) • Radiation (UV, ionizing) • Infection • Viruses (EBV, hepatitis B, papilloma) • Bacteria (Helicobacter) • Inherited familial cancer syndromes

23. Diagnosis of Neoplasia Symptoms Weight loss Rectal bleeding Persistent cough Screening Pap smear Mammogram Occult blood Incidental Radiology > ~1 gm (109 cells) Biopsy Histopathology Autopsy Staging

24. The Vocabulary • Hyperplasia – increased number of cells • Hypertrophy – increased size of cells • Dysplasia – disorderly proliferation • Neoplasia – abnormal new growth • Anaplasia – lack of differentiation • Tumor – originally meant any swelling, but now equated with neoplasia • Metastasis –growth at a distant site

25. Colonic Polyps from Rubin and Farber, Pathology

26. Histology of Colonic Polyps from Kinzler and Vogelstein, Cell 1996

27. Colon Cancer fromWebPath

28. Classification of Neoplasms • Benign Tumor (-oma) • Adenoma (“adeno-” means gland-like) • Fibroma • Lipoma (“lipo-” means fat) • Malignant Cancer (carcinoma or sarcoma) • Adenocarcinoma • Fibrosarcoma (“sar-” means fleshy) • Liposarcoma • Leukemia and Lymphoma

29. Basal Lamina Carcinoma vs Sarcoma EPITHELIUM => CARCINOMA Collagen MESENCHYMAL ORIGIN => SARCOMA fibroblasts blood vessels blood cells muscle adipocytes (fat) bone cartilage

30. Types of Epithelia from Junqueira, et al., Basic Histology

31. Epithelial Origin of Glands from Poirier and Dumas, Review of Medical Histology

32. The Prognosis “It’s tough to make predictions, especially about the future.”

33. Neoplasms

34. Cytology (cells) from NCI

35. Benign vs Malignant Histology (tissue) Leiomyosarcoma of Uterus Leiomyoma of Uterus from WebPath

36. Predictors of Behavior • Grade – How bad do the cells look? • Stage – Where has the cancer spread? • Tumor • Nodes (Lymph) • Metastases

37. Grading Cancer adapted from WebPath

38. Duke’s A 5 yr survival > 90% Duke’s B 5 yr survival 55% to 85% Duke’s C 5 yr survival 20% to 55% Duke’s D 5 yr survival < 5% Staging Colon Cancer from Rubin and Farber, Pathology

39. Metastases • Seeding body cavities • Lymphatic drainage to lymph nodes • Hematogenous via blood vessels

40. Cancer Arises from Single Cells metastatic adenocarcinoma within lymphatic vessel in lung (WebPath) • 1858 – Rudolf Virchow proposes that “omnis cellula e cellula”. • All cells come from cells. • Metastatic cancer cells resemble the primary. • All cells of a cancer come from a single cell.

41. Cancer Arises from Single Cells • Cancers are usually clonal in origin. • X-inactivation studies in human cancer • Transformation can be observed in cell culture.

42. Heterozygous Female Zygote Monoclonal Tumor [single G6PD isoenyzme] X X A B OR AB Random Inactivation of X Chromosomes During Early Development Malignancy AB Polyclonal Tumor [two G6PD isoenzymes] Tumor Clonality by X-Inactivation

43. Tumor Clonality as a Diagnostic • Immunoglobulin and TCR genes rearrange • Rearrangements are unique in each cell • Rearrangements display allelic exclusion

44. Clonality of Lymphoid Proliferation

45. Cancer: Selection for Single-Cell Survival in a Multi-Cellular Organism • Cells must make critical decisions. • Stem cell renewal • Differentiation • Growth / quiescence • Death • Things can go wrong at all of these levels.

46. Decisions Cells Must Make

47. Growth Fraction Growth Fraction Doubling Fraction (%) Time (days)

48. What Makes the Water Level Rise? US Army Corps of Engineers

49. Good luck will rub off…

50. when you shake hands with me! 1775 – Percival Pott discovers “occupational cancer” of scrotum in chimney sweeps and in hands of gardeners who spread coal tar