Slides - MIT

CANCER

Clonal Evolution Theory of Tumor Development

How-to 2 3D

PROBLEMS

SYSTEMS BIOLOGY

FUTURE

LIFE

STEM CELLS, CLONING

1,2, 3

STRUCTURE

NERVOUS

SYSTEMS How-to 1 REC. DNA

FORMATION

SYSTEMS VIRUSES BIOLOGY

1,2 1,2

CELL TYPE

BIOCHEM

START

GENETICS

MOL. BIO

1

1

1 1

GENOMICS

FOUNDATIONS

1,2, 3

1

CELL BIOL

HUMAN DISEASE

1

1,2, 3

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Normal

Cancer-associated mutations affect: -proliferation -cell death -angiogenesis -cell motility -invasion -other

Tumor

Chromosomal Abnormalities are Common in Cancer Cells

chromosomes of a normal cell

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chromosomes of a cancer cell

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Figure 3.7b The Biology of Cancer (© Garland Science 2007)

In Vitro Assay for Cellular Transformation

DNA From Transformed Fibroblasts is Sufficient to Transform Recipient Cells (Donor cells)

(Recipient cells)

Figure 4.2 The Biology of Cancer (© Garland Science 2007)

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Figure 3.7a The Biology of Cancer (© Garland Science 2007)

Clone DNA from Tumor that is Capable of Transforming Recipient Cells

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Cloned Oncogene DNA Transforms but not Cloned Proto-oncogene (Normal Gene)

cloned tumor DNA

Figure 4.9 The Biology of Cancer (© Garland Science 2007)

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Signal Transduction - Slide 6 - 7.013 - 3/21/07

Sequencing Reveals Oncogene is Signaling Factor Ras!

Mutant Ras constitutively active

Purves Figure 15.9

Transcription factor activated by phosphorylation

Figure 4.10 The Biology of Cancer (© Garland Science 2007)

Binds to target gene promoters Slide 9 - 7.013 - 4/30/07

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GROWTH/PROLIFERATION

1 1 2 2 3 GTP

RAS GTP

RAS GDP

1-growth factor 2-growth factor receptor 3-adaptor protein 4-exchange factor 5,6,7-protein kinases 8-a transcription factor 9-RNA polymerase

4

Pi

+ GDP

5 6 7

7 8

8

8

P

9

P

target genes

Table 4.2 The Biology of Cancer (© Garland Science 2007)

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Cell division

Translocation Between Two Chromosomes Fuses myc proto-oncogene to New Highly Active IgH Promoter

Normal allele of myc

Makes growthpromoting transcription factor

Production of excess myc transcription factor

TF

Figure 4.13b The Biology of Cancer (© Garland Science 2007)

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Because we carry two copies of all genes, two mutational events are required to eliminate the function of a tumor suppressor gene.

New approaches to cancer therapy •

chromosome loss

Ras therapies EGF Receptor angiogenesis

X

Rb A

• 1st Rb A

mutation

Rb a

X

Rb a

Therapies to replace lost genes: gene therapy

2nd Rb A

de novo mutation

Targeted therapies against pathways/ genes activated in cancer cells:

Rb X A

X

Rb a

•

Cancer vaccination e.g., HPV vaccines

mitotic recombination Rb X A

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Rb X A

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