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Cancer Biology 241:Molecular, Cellular and Genetic
Basis of Cancer
Lectures: Mon and Wed 9-11 AM, CCSR 4105Discussion Section: Friday 9-11AM, TBA
Course Directors: Laura Attardi and Joe LipsickTA: Gabe Quinones
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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
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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
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http://coursework.stanford.edu
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http://lane.stanford.edu/index.html
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Books
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Cancer Biology: The Basics
• Impact of cancer on human population
• Causes of human cancer
• Classification of human cancer
• Experimental approaches to cancer
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Leading Causes of Death in U.S.Death Rate
0
200
400
600
800
1000
1200
1400
1600
1950 1960 1970 1980 1990 2000
Year
De
ath
s p
er
10
0,0
00
TotalHeartCancerStrokeAccident
from CDC
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Change in Causes of Death
* Age-adjusted to the 2000 US standard population.Source: US Mortality Volume 1950, National Vital Statistics Report, 2002, Vol. 50, No. 15.
586.8
180.5
48.160.923.7
200.9193.7
258.2
0
100
200
300
400
500
600
HeartDiseases
CerebrovascularDiseases
Pneumonia/Influenza
Cancer
1950
2000
Rate Per 100,000
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Invasive Cancer versus Age
0
500
1000
1500
2000
2500
3000
3500
<1
1-4
5-9
10-1
4
15-1
9
20-2
4
25-2
9
30-3
4
35-3
9
40-4
4
45-4
9
50-5
4
55-5
9
60-6
4
65-6
9
70-7
4
75-7
9
80-8
4
85+
Age at Diagnosis (Years)
per
100,
000
data from National Cancer Institutehttp://www.cdc.gov/cancer/npcr/uscs/report/
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Cancers by Type in U.S.
from American Cancer Society
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Cancer Death Rates in U.S.
MALE FEMALE
from American Cancer Society
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From Suffrage to Suffering
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Enough S’nuff – The Sot Weed Factor
1761 – Sir John Hill notes that snuff causes nasal cancer
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Human Migration and Cancer
from Rubin and Farber, Pathology
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Same Virus, Different Outcomes
EBV
Mononucleosis Burkitt’s LymphomaNasopharyngealCancer
Immune Suppression Malaria AIDS Organ Transplants
Dietary Factors
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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
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Diagnosis of NeoplasiaSymptoms Weight loss Rectal bleeding Persistent cough
Screening Pap smear Mammogram Occult blood
Incidental Radiology > ~1 gm (109 cells)
Biopsy
Histopathology
Staging
Autopsy
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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
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Colonic Polyps
from Rubin and Farber, Pathology
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Histology of Colonic Polyps
from Kinzler and Vogelstein, Cell 1996
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Colon Cancer
from WebPath
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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
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Carcinoma vs Sarcoma
EPITHELIUM => CARCINOMA
MESENCHYMAL ORIGIN=> SARCOMA
fibroblasts blood vessels blood cells muscle adipocytes (fat) bone cartilage
Basal Lamina
Collagen
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Types of Epithelia
from Junqueira, et al.,Basic Histology
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Epithelial Origin of Glands
from Poirier and Dumas,Review of Medical Histology
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The Prognosis
“It’s tough to make predictions, especially about the future.”
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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
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Cytology (cells)
from NCI
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Benign vs Malignant Histology (tissue)
Leiomyomaof Uterus
Leiomyosarcomaof Uterus
from WebPath
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Predictors of Behavior
• Grade – How bad do the cells look?
• Stage – Where has the cancer spread?– Tumor– Nodes (Lymph)– Metastases
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Grading Cancer
Grade 1 welldifferentiated
Grade 2 moderatelydifferentiated
Grade 3 poorlydifferentiated
Grade 4 anaplastic
adapted from WebPath
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Staging Colon Cancer
from Rubin and Farber, Pathology
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%
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Metastases
• Seeding body cavities
• Lymphatic drainage to lymph nodes
• Hematogenous via blood vessels
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Cancer Arises from Single Cells
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.
metastatic adenocarcinoma within lymphatic vessel in lung (WebPath)
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Cancer Arises from Single Cells
• Cancers are usually clonal in origin.– X-inactivation studies in human cancer
• Transformation can be observed in cell culture.
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Tumor Clonality by X-Inactivation
Heterozygous Female Zygote
Random Inactivation of X Chromosomes During Early Development Malignancy
Monoclonal Tumor [single G6PD isoenyzme]
Polyclonal Tumor [two G6PD isoenzymes]
AB
AB
X XA B
OR
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Tumor Clonality as a Diagnostic
• Immunoglobulin and TCR genes rearrange
• Rearrangements are unique in each cell
• Rearrangements display allelic exclusion
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Clonality of Lymphoid Proliferation
Cell Type Benign Malignant
B Lymphocyte Ig Light ChainHeterogeneity
Ig Kappa or Lambda Only
Plasma Cells Heterogeneous Ig Electrophoresis
Monoclonal IgSpike
T Lymphocyte Heterogeneous Variable Regions
HomogeneousVariable Regions
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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.
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Decisions Cells Must Make
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Growth Fraction
Experimental tumors
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
Normal Human Bone Marrow
6
35
83
--
Growth Fraction DoublingFraction (%) Time (days)
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What Makes the Water Level Rise?
US Army Corps of Engineers
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Good luck will rub off…
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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
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Coal Tar Causes Skin Cancer
1891 -- Katsusabura Yamagiwa shows that coal tarcauses skin cancer when painted on rabbits’ ears.
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Radiation Causes Cancer
1908 – Clunet shows that X-rays cause cancer in animals.
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X-Rays Are Mutagens
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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
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Modified Ames Test for Carcinogens
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What About Hormones?
Estrogens and Androgens Score Negatively in Ames Tests
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Promoter-Initiator Model
Time
Initiator
Promoter
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.
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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
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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.
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Genetic Theory of Cancer
IF by Bill Brinkley
Theodor Boveri, 1914
dispermic fertilization in sea urchin
normal cancer
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How Many Genetic Changes?
Nordling, 1953
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Which Genetic Changes?