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A Typical Solid Tumor…. The size of a tumor first detectable by X-ray: 10 8 cells The size of a tumor first palpable: 10 9 cells The size of tumor at death of patient: 10 12 cells. Is Unregulated Cell Division Sufficient To Cause an Increase in Tumor Size??. Growth with

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A Typical Solid Tumor…

The size of a tumor first detectable by X-ray: 108 cells

The size of a tumor first palpable: 109 cells

The size of tumor at death of patient: 1012 cells

Is Unregulated Cell Division Sufficient

To Cause an Increase in Tumor Size??


Growth with

No Cell Division

Cell Division + Growth =

Proliferation!

Cell Division

No Growth

The Difference Between Growth and Cell Division


Growth with

No Cell Division:

A Differentiated Neuron


Cell Division with No Growth: Early Development

OOCYTE GROWS WITHOUT DIVIDING

(MONTHS)

FERTILIZED EGG DIVIDES WITHOUT GROWING

(HOURS)

FERTILIZATION

1 mm

sperm

tadpole feeds, grows

and bcecomes an adult frog


A Typical Solid Tumor…Needs to Grow

The size of a tumor first detectable by X-ray: 108 cells

The size of a tumor first palpable: 109 cells

The size of tumor at death of patient: 1012 cells

Unregulated Proliferation: Cancer!


Budding Yeast Saccharomyces cerevisiae


Cdc Mutants Affect the Cell Cycle, Not Growth

Permissive (low) temperature

Restrictive (high) temperature


Cell Division can be Uncoupled

From Growth in Drosophila

Wild Type:

Cdc2 active

everywhere

Cdc2 inactive in

anterior cells

Cdc2 active in

posterior cells

But the overall tissue size

is the same as wild type.

Weigmann et al., Development 124, 3555-3563 (1997)


Mammalian Cells Growing in Cell Culture

1961Hayflick and Moorhead

Showed that human fibroblasts die after a finite number of divisions in culture.

This is called “The Hayflick Limit”



Growth Factors Induce Cell Cycle Progression

Growth Factors act

at the Restriction Point


pm = post mitotic

ps = pre-synthetic

Zetterberg and Larsson, PNAS 82:5365 (1985)




Growth Factors Induce Cyclin D1 Expression

c-fos is a

subunit of AP1!

Sherr and McCormick, Cancer Cell, Vol 2, 103-112 (2002)



Cyclin D/cdk4 Controls

Growth in Flies

Meyer et al., EMBO19: 4533-4542 (2000)

Datar et al., EMBO 19: 4543-4554 (2000)


p18 (cycD/cdk4 CKI) Mutation Induces Growth in Mice

Franklin et al., Molecular and Cellular Biology, 20: 6147-6158 (2000)



Cyclin D as an Oncogene

Disease: INVOLVED IN B-LYMPHOCYTIC MALIGNANCY (PARTICULARLY MANTLE-CELL LYMPHOMA)

BY A CHROMOSOMAL TRANSLOCATION T(11;14)(Q13;Q32) THAT INVOLVES CCND1 AND IMMUNOGLOBULIN

GENE REGIONS (BCL1 ONCOGENE).

Disease: INVOLVED IN A SUBSET OF PARATHYROID ADENOMAS BY A CHROMOSOMAL TRANSLOCATIONT(11;11)(Q13;P15) THAT INVOLVES CCND1 AND THE PARATHYROID HORMONE (PTH) ENHANCER (PRAD1 ONCOGENE).


Translocations Cause One Gene

to be Controlled by Another


Cancer Cells Display Genetic Instability

Examples of genetic instability:

1) gene amplification

2) anueploidy: chromosome gain and loss

3) chromosome rearragements

4) somatic point mutations


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