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Cancer Biology 243_ Molecular_ Cellular and Genetic Basis

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					     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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