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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

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
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
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
cancer biology the basics
Cancer Biology: The Basics
  • Impact of cancer on human population
  • Causes of human cancer
  • Classification of human cancer
  • Experimental approaches to cancer
change in causes of death

Rate Per 100,000







* 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
Invasive Cancer versus Age

data from National Cancer Institute

cancers by type in u s
Cancers by Type in U.S.

from American Cancer Society

cancer death rates in u s



Cancer Death Rates in U.S.

from American Cancer Society

enough s nuff the sot weed factor
Enough S’nuff – The Sot Weed Factor

1761 – Sir John Hill notes that snuff causes nasal cancer

human migration and cancer
Human Migration and Cancer

from Rubin and Farber, Pathology

same virus different outcomes
Same Virus, Different Outcomes





Burkitt’s Lymphoma

Immune Suppression



Organ Transplants

Dietary Factors

known causes of human cancer
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
Diagnosis of Neoplasia


Weight loss

Rectal bleeding

Persistent cough


Pap smear


Occult blood



> ~1 gm (109 cells)





the vocabulary
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
Colonic Polyps

from Rubin and Farber, Pathology

histology of colonic polyps
Histology of Colonic Polyps

from Kinzler and Vogelstein, Cell 1996

colon cancer
Colon Cancer


classification of neoplasms
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

Basal Lamina

Carcinoma vs Sarcoma






blood vessels

blood cells


adipocytes (fat)



types of epithelia
Types of Epithelia

from Junqueira, et al.,

Basic Histology

epithelial origin of glands
Epithelial Origin of Glands

from Poirier and Dumas,

Review of Medical Histology

the prognosis
The Prognosis

“It’s tough to make predictions, especially about the future.”

benign vs malignant histology tissue
Benign vs Malignant Histology (tissue)


of Uterus


of Uterus

from WebPath

predictors of behavior
Predictors of Behavior
  • Grade – How bad do the cells look?
  • Stage – Where has the cancer spread?
    • Tumor
    • Nodes (Lymph)
    • Metastases
grading cancer
Grading Cancer

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%

Staging Colon Cancer

from Rubin and Farber, Pathology

  • Seeding body cavities
  • Lymphatic drainage to lymph nodes
  • Hematogenous via blood vessels
cancer arises from single cells
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 cells1
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]





Random Inactivation

of X Chromosomes

During Early Development



Polyclonal Tumor

[two G6PD isoenzymes]

Tumor Clonality by X-Inactivation
tumor clonality as a diagnostic
Tumor Clonality as a Diagnostic
  • Immunoglobulin and TCR genes rearrange
  • Rearrangements are unique in each cell
  • Rearrangements display allelic exclusion
cancer selection for single cell survival in a multi cellular organism
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.
growth fraction
Growth Fraction

Growth Fraction Doubling

Fraction (%) Time (days)

what makes the water level rise
What Makes the Water Level Rise?

US Army Corps of Engineers

when you shake hands with me
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
Coal Tar Causes Skin Cancer

1891 -- Katsusabura Yamagiwa shows that coal tar

causes skin cancer when painted on rabbits’ ears.

radiation causes cancer
Radiation Causes Cancer

1908 – Clunet shows that X-rays cause cancer in animals.

carcinogens 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
what about hormones
What About Hormones?

Estrogens and Androgens Score Negatively in Ames Tests

promoter initiator model






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
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
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
Genetic Theory of Cancer

dispermic fertilization in sea urchin

Theodor Boveri, 1914



IF by Bill Brinkley