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 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 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 http://coursework.stanford.edu http://lane.stanford.edu/index.html Books Cancer Biology: The Basics • Impact of cancer on human population • Causes of human cancer • Classification of human cancer • Experimental approaches to cancer Leading Causes of Death in U.S. from CDC Change in Causes of Death Rate Per 100,000 1950 2000 Heart Cerebrovascular Pneumonia/ Cancer Diseases Diseases Influenza * Age-adjusted to the 2000 US standard population. Source: US Mortality Volume 1950, National Vital Statistics Report, 2002, Vol. 50, No. 15. Invasive Cancer versus Age data from National Cancer Institute http://www.cdc.gov/cancer/npcr/uscs/report/ Cancers by Type in U.S. from American Cancer Society Cancer Death Rates in U.S. MALE FEMALE from American Cancer Society From Suffrage to Suffering Enough S’nuff – The Sot Weed Factor 1761 – Sir John Hill notes that snuff causes nasal cancer Human Migration and Cancer from Rubin and Farber, Pathology Same Virus, Different Outcomes EBV Nasopharyngeal Mononucleosis Burkitt’s Lymphoma Cancer Immune Suppression Malaria Dietary Factors AIDS Organ Transplants 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 Diagnosis of Neoplasia Symptoms Screening Incidental Weight loss Pap smear Radiology Rectal bleeding Mammogram > ~1 gm (109 cells) Persistent cough Occult blood Biopsy Histopathology Autopsy Staging 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 Colonic Polyps from Rubin and Farber, Pathology Histology of Colonic Polyps from Kinzler and Vogelstein, Cell 1996 Colon Cancer from WebPath 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 Carcinoma vs Sarcoma EPITHELIUM => CARCINOMA Basal Lamina Collagen MESENCHYMAL ORIGIN => SARCOMA fibroblasts blood vessels blood cells muscle adipocytes (fat) bone cartilage Types of Epithelia from Junqueira, et al., Basic Histology Epithelial Origin of Glands from Poirier and Dumas, Review of Medical Histology The Prognosis “It’s tough to make predictions, especially about the future.” Neoplasms BENIGN MALIGNANT NON-INVASIVE INVASIVE / METASTATIC ~well-defined borders ~irregular borders ~well differentiated ~poorly differentiated ~regular nuclei ~irregular, larger nuclei ~rare mitoses ~more frequent and/ or abnormal mitoses Cytology (cells) from NCI Benign vs Malignant Histology (tissue) Leiomyoma Leiomyosarcoma of Uterus of Uterus from WebPath Predictors of Behavior • Grade – How bad do the cells look? • Stage – Where has the cancer spread? – Tumor – Nodes (Lymph) – Metastases Grading Cancer Grade 1 well differentiated Grade 2 moderately differentiated Grade 3 poorly differentiated Grade 4 anaplastic adapted from WebPath Staging Colon Cancer 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% from Rubin and Farber, Pathology Metastases • Seeding body cavities • Lymphatic drainage to lymph nodes • Hematogenous via blood vessels 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. Cancer Arises from Single Cells • Cancers are usually clonal in origin. – X-inactivation studies in human cancer • Transformation can be observed in cell culture. Tumor Clonality by X-Inactivation Heterozygous Female Zygote Monoclonal Tumor [single G6PD isoenyzme] X A XB OR AB Random Inactivation of X Chromosomes Malignancy During Early Development AB Polyclonal Tumor [two G6PD isoenzymes] Tumor Clonality as a Diagnostic • Immunoglobulin and TCR genes rearrange • Rearrangements are unique in each cell • Rearrangements display allelic exclusion Clonality of Lymphoid Proliferation Cell Type Benign Malignant B Lymphocyte Ig Light Chain Ig Kappa or Heterogeneity Lambda Only Plasma Cells Heterogeneous Ig Monoclonal Ig Electrophoresis Spike T Lymphocyte Heterogeneous Homogeneous Variable Regions Variable Regions 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. Decisions Cells Must Make Growth Fraction Growth Fraction Doubling Experimental tumors Fraction (%) Time (days) L1210 (mouse) 86 0.5 B16 (mouse) 55 1.9 LL (mouse) 38 2.9 DMBA (rat) 10 7.4 Human tumors Embryonal carcinoma 90 27 Lymphoma (high grade) 90 29 Squamous cell carcinoma 25 58 Adenocarcinoma 6 83 Normal Human Bone Marrow 35 -- What Makes the Water Level Rise? US Army Corps of Engineers Good luck will rub off… 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 Coal Tar Causes Skin Cancer 1891 -- Katsusabura Yamagiwa shows that coal tar causes skin cancer when painted on rabbits’ ears. Radiation Causes Cancer 1908 – Clunet shows that X-rays cause cancer in animals. X-Rays Are Mutagens Carcinogens Are Mutagens • X-rays are carcinogenic • X-rays cause mutations • Therefore, carcinogens are mutagens? • Puzzle: Ames test for mutagens in Salmonella scores some by not all carcinogens Modified Ames Test for Carcinogens What About Hormones? Estrogens and Androgens Score Negatively in Ames Tests Promoter-Initiator Model Initiator Promoter Time Cancer Cancer No Cancer No Cancer 1940s -- Berenblum and Shubik develop model of carcinogenesis by painting polycyclic aromatic hydrocarbons and croton oil on mouse skin. Initiators and Promoters • Tumor Initiators = Mutagens – X rays – Ultraviolet Light – DNA alkylating agents • Tumor Promoters = Proliferation Inducers – Phorbol Esters (croton oil) – Inflammation (hepatitis) – Estrogens and Androgens – Epstein-Barr Virus Cancer is a Genetic Disease • Somatic mutations occur in most cancers. • Inherited germline mutations occur in rare familial cancer syndromes. • Increases in mutation rate or genomic instability increase frequency of cancer. • Aneuploidy is a hallmark of cancer cells. • Genetic selection at the level of single cells. Genetic Theory of Cancer dispermic fertilization in sea urchin Theodor Boveri, 1914 normal cancer IF by Bill Brinkley How Many Genetic Changes? Nordling, 1953 Which Genetic Changes?
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