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

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

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
Invasive Cancer versus Age

data from National Cancer Institute

http://www.cdc.gov/cancer/npcr/uscs/report/


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

from American Cancer Society


Cancer death rates in u s

MALE

FEMALE

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

EBV

Nasopharyngeal

Cancer

Mononucleosis

Burkitt’s Lymphoma

Immune Suppression

Malaria

AIDS

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

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
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

fromWebPath


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

EPITHELIUM => CARCINOMA

Collagen

MESENCHYMAL ORIGIN

=> SARCOMA

fibroblasts

blood vessels

blood cells

muscle

adipocytes (fat)

bone

cartilage


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)

Leiomyosarcoma

of Uterus

Leiomyoma

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


Metastases
Metastases

  • 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]

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
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.


Decisions cells must make
Decisions Cells Must Make Multi-Cellular Organism


Growth fraction
Growth Fraction Multi-Cellular Organism

Growth Fraction Doubling

Fraction (%) Time (days)


What makes the water level rise
What Makes the Water Level Rise? Multi-Cellular Organism

US Army Corps of Engineers


Good luck will rub off
Good luck will rub off… Multi-Cellular Organism


When you shake hands with me
when you shake hands with me! Multi-Cellular Organism

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 Multi-Cellular Organism

1891 -- Katsusabura Yamagiwa shows that coal tar

causes skin cancer when painted on rabbits’ ears.


Radiation causes cancer
Radiation Causes Cancer Multi-Cellular Organism

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


X rays are mutagens
X-Rays Are Mutagens Multi-Cellular Organism


Carcinogens are mutagens
Carcinogens Are Mutagens Multi-Cellular Organism

  • 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
Modified Ames Test for Carcinogens Multi-Cellular Organism


What about hormones
What About Hormones? Multi-Cellular Organism

Estrogens and Androgens Score Negatively in Ames Tests


Promoter initiator model

Initiator Multi-Cellular Organism

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
Initiators and Promoters Multi-Cellular Organism

  • 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 Multi-Cellular Organism

  • 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 Multi-Cellular Organism

dispermic fertilization in sea urchin

Theodor Boveri, 1914

normal

cancer

IF by Bill Brinkley


How many genetic changes
How Many Genetic Changes? Multi-Cellular Organism

Nordling, 1953


Which genetic changes
Which Genetic Changes? Multi-Cellular Organism


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