Transcript Cancer Biology 243: Molecular, Cellular and Genetic Basis of Cancer

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
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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
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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
Deaths per 100,000
1600
1400
Total
Heart
Cancer
Stroke
Accident
1200
1000
800
600
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
200
100
0
193.7 200.9
180.5
60.9
Heart
Diseases
48.1
23.7
Cerebrovascular Pneumonia/
Influenza
Diseases
* Age-adjusted to the 2000 US standard population.
Source: US Mortality Volume 1950, National Vital Statistics Report, 2002, Vol. 50, No. 15.
Cancer
Invasive
Cancer Incidence
in U.S.
Invasive
Cancer
versus
Age
3500
2500
2000
1500
1000
500
85+
80-84
75-79
70-74
65-69
60-64
55-59
50-54
45-49
40-44
35-39
30-34
25-29
20-24
15-19
10-14
5-9
1-4
0
<1
per 100,000
3000
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
Mononucleosis
Burkitt’s Lymphoma
Immune Suppression
Malaria
AIDS
Organ Transplants
Nasopharyngeal
Cancer
Dietary Factors
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
Weight loss
Rectal bleeding
Persistent cough
Screening
Pap smear
Mammogram
Occult blood
Incidental
Radiology
> ~1 gm (109 cells)
Biopsy
Histopathology
Autopsy
Staging
The Vocabulary
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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)
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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
NON-INVASIVE
MALIGNANT
~well-defined borders
INVASIVE /
METASTATIC
~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
of Uterus
Leiomyosarcoma
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
During Early Development
AB
Malignancy
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
Heterogeneity
Ig Kappa or
Lambda Only
Plasma Cells
Heterogeneous Ig
Electrophoresis
Monoclonal Ig
Spike
T Lymphocyte
Heterogeneous
Variable Regions
Homogeneous
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
Experimental tumors
Growth Fraction Doubling
Fraction (%)
Time (days)
L1210 (mouse)
86
0.5
B16 (mouse)
55
1.9
LL (mouse)
38
2.9
DMBA (rat)
10
7.4
Embryonal carcinoma
90
27
Lymphoma (high grade)
90
29
Squamous cell carcinoma
25
58
Adenocarcinoma
6
83
35
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Human tumors
Normal Human Bone Marrow
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
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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?