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Cancer Biology 243Molecular_ Cellular and Genetic Basis of Cancer

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Cancer Biology 243Molecular_ Cellular and Genetic Basis of Cancer Powered By Docstoc
					     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.
                                       Death Rate

                       1600
                       1400
  Deaths per 100,000




                       1200                                   Total
                       1000                                   Heart
                                                              Cancer
                        800
                                                              Stroke
                        600
                                                              Accident
                        400
                        200
                          0
                              1950 1960 1970 1980 1990 2000
                                          Year
                                                              from CDC
         Change in Causes of Death
       Rate Per 100,000
600         586.8
                                                                                         1950
500
                                                                                         2000
400

300                   258.2

                                      180.5                                                  193.7 200.9
200

100                                               60.9            48.1
                                                                            23.7
   0
               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
                       Invasive Cancer Incidence in U.S.

              3500

              3000

              2500
per 100,000




              2000

              1500

              1000

               500

                0




                                                                                                                                                              85+
                     <1




                                      10-14
                                              15-19
                                                      20-24
                                                              25-29
                                                                      30-34
                                                                              35-39
                                                                                      40-44
                                                                                              45-49
                                                                                                      50-54
                                                                                                              55-59
                                                                                                                      60-64
                                                                                                                              65-69
                                                                                                                                      70-74
                                                                                                                                              75-79
                                                                                                                                                      80-84
                          1-4
                                5-9




                                                          Age at Diagnosis (Years)

                                                                               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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