Cancer biology 241 molecular cellular and genetic basis of cancer
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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

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Cancer Biology 241: Molecular, Cellular and Genetic Basis of Cancer

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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


Rate Per 100,000

1950

2000

Cancer

HeartDiseases

Pneumonia/Influenza

CerebrovascularDiseases

* Age-adjusted to the 2000 US standard population.

Source: US Mortality Volume 1950, National Vital Statistics Report, 2002, Vol. 50, No. 15.

Change in Causes of Death


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


MALE

FEMALE

Cancer Death Rates in U.S.

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

Cancer

Mononucleosis

Burkitt’s Lymphoma

Immune Suppression

Malaria

AIDS

Organ Transplants

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

  • 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

fromWebPath


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


Basal Lamina

Carcinoma vs Sarcoma

EPITHELIUM => CARCINOMA

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


Cytology (cells)

from NCI


Benign vs Malignant Histology (tissue)

Leiomyosarcoma

of Uterus

Leiomyoma

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

adapted from WebPath


Duke’s A5 yr survival> 90%

Duke’s B5 yr survival 55% to 85%

Duke’s C5 yr survival20% to 55%

Duke’s D5 yr survival< 5%

Staging Colon Cancer

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.


Heterozygous Female Zygote

Monoclonal Tumor

[single G6PD isoenyzme]

X X

A B

OR

AB

Random Inactivation

of X Chromosomes

During Early Development

Malignancy

AB

Polyclonal Tumor

[two G6PD isoenzymes]

Tumor Clonality by X-Inactivation


Tumor Clonality as a Diagnostic

  • Immunoglobulin and TCR genes rearrange

  • Rearrangements are unique in each cell

  • Rearrangements display allelic exclusion


Clonality of Lymphoid Proliferation


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

Fraction (%) Time (days)


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


Initiator

Promoter

Cancer

Time

Cancer

No Cancer

No Cancer

Promoter-Initiator Model

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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