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How-to 2How-to 2

SYSTEMSSYSTEMSPR

OB

LE

MS

PR

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LE

MS

BIOCHEM GENETICS GENOMICSMOL. BIO

STEM

CELLS,

CLONING

REC. DNA

CELL TYPE

3DSTRUCTURE

CELL BIOL

VIRUSES

CANCER

HUMAN

DISEASE

LIFELIFE

NERVOUS

SYSTEMS

BIOLOGY FUTUREFUTURE

SYSTEMS

BIOLOGY

Lung cancer detection

Lung masses evident on chest X-ray Lung masses evident by computedtomography (CT)

Slide 2 - 7.013 - 4/27/07

Leukemia is a overabundance of abnormal

cells in the blood

Leukemic cells in a blood smearNormal blood smear

Slide 3 - 7.013 - 4/27/07

Colon Cancer Progression

Normal colon(endoscopy)

Colon polyp Colon carcinoma

Section of colonwith carcinoma

(circled)

Slide 4 - 7.013 - 4/27/07

Hyperplasia

Benign Tumor

(e.g., an adenoma)

In Situ Cancer

(e.g. an adenocarcinoma

bloodvessels

Advanced Primary Cancer

(locally invasive)

basementmembrane

stem/precursor cells

Normal Tissue

Cancer develops in stages

MetastaticSpread

Steps in Tumor Progression

*Scale bar equals 50µM

Atypical Adenomatous Hyperplasia (AAH) Adenoma Adenocarcinoma

high magnification high magnification

chromosomes of a

normal cellchromosomes of a

cancer cell

Chromosomal Abnormalities are Common in Cancer Cells

Slide 7 - 7.013 - 4/27/07

Causes of cancer: compounds that are morecarcinogenic are also more mutagenic

Inference: cancer cells are likely to carry mutant genes

More potent mutagen

More

Potent

carcinogen

Slide 8

7.013

4/27/07

Conversion of benzo(a)pyrene to mutagenic epoxides

O B(a)P 7,8 epoxide

OH

OH

OH

OH

O

Cytochrome P450

(metabolic enzyme

in liver)

Epoxide hydrolase

P450

B(a)P 7,8 dihydrodiol(+(anti))B(a)P

7,8 dihydrodiol 9,10 epoxide

Benzo(a)pyrene (B(a)P)

Slide 9 - 7.013 - 4/27/07

Tobacco Use in the US, 1900-1999

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

1900

1905

1910

1915

1920

1925

1930

1935

1940

1945

1950

1955

1960

1965

1970

1975

1980

1985

1990

1995

2000

Year

Pe

r C

ap

ita

Cig

are

tte

Co

ns

um

pti

on

0

10

20

30

40

50

60

70

80

90

100

Ag

e-A

dju

ste

d L

un

g C

an

ce

r D

ea

th

Ra

tes

*

*Age-adjusted to 2000 US standard population.

Source: Death rates: US Mortality Public Use Tapes, 1960-1999, US Mortality Volumes,

1930-1959, National Center for Health Statistics, Centers for Disease Control and

Prevention, 2001. Cigarette consumption: Us Department of Agriculture, 1900-1999.

Per capita cigarette consumption

Male lung cancer death rate

Female lung cancer death rate

Slide 10

7.013

4/27/07

chromosomes of a

normal cellchromosomes of a

cancer cell

Chromosomal Abnormalities are Common in Cancer Cells

Slide 11

7.013

4/27/07

Clonal Evolution Theory of Tumor Development

1

1,2

1,2

1

1

1

1,2,

3

1,2,

3

1

1

1,2,

3

Numbers represent sequential mutations to cellular genes

Slide 12 - 7.013 - 4/27/07

Clonal Evolution Theory of Tumor Development

Cancer-associated mutations

affect:

-proliferation

-cell death

-angiogenesis

-cell motility

-invasion

-other

1

1,2

1,2

1

1

1

1,2,

3

1,2,

3

1

1

1,2,

3

Slide 13 - 7.013 - 4/27/07

Tumors and Angiogenesis

Carmeliet and Jain. Nature (2000) 407:249.

Somatic mutation

Proangiogenicfactors secreted

by tumor andstroma

Tumor growth andmetastasis

Smallavascular

tumor

= Angiogenic inhibitor

= Proangiogenic factor, VEGF

Slide 14 - 7.013 - 4/27/07

Hyperplasia

Benign Tumor

(e.g., an adenoma)

In Situ Cancer

(e.g. an adenocarcinoma

bloodvessels

Advanced Primary Cancer

(locally invasive)

basementmembrane

stem/precursor cells

Normal Tissue

Cancer develops in stages

MetastaticSpread