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 SufficientTo Cause an Increase in Tumor Size??

A Typical Solid Tumor…

The Difference Between Growth and Cell Division

Cell DivisionNo Growth

Cell Division + Growth =Proliferation!

Growth with

No Cell Division

Growth withNo Cell Division:

A Differentiated Neuron

Cell Division with No Growth: Early Development

1 mm

spermtadpole feeds, grows

and bcecomes an adult frog

OOCYTE GROWS WITHOUT DIVIDING(MONTHS) FERTILIZATION

FERTILIZED EGG DIVIDES WITHOUT GROWING(HOURS)

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!

A Typical Solid Tumor…Needs to Grow

Budding Yeast Saccharomyces cerevisiae

Permissive (low) temperature Restrictive (high) temperature

Cdc Mutants Affect the Cell Cycle, Not Growth

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

Cell Division can be UncoupledFrom Growth in Drosophila

Wild Type:Cdc2 active everywhere

Cdc2 inactive inanterior cells

Cdc2 active inposterior cells

But the overall tissue sizeis the same as wild type.

Mammalian Cells Growing in Cell Culture

Amino Acids Vitamins Salts Miscellaneous

Arginine

Cystine

Glutamine

Histidine

Isoleucine

Leucine

Lysine

Methionine

Phenylalanine

Threonine

Tryptophan

Tyrosine

Valine

Biotin

Choline

Folate

Nicotinamide

Pantothenate

Pyridoxal

Thiamine

Riboflavin

NaCl

KCl

NaH2PO4

NaHCO3

CaCl2

MgCl2

Glucose

Penicillin

Streptomycin

Phenol red

Whole serum

Specific growth factors

1961Hayflick and Moorhead Showed that human fibroblasts die after a finite number of divisions in culture.This is called “The Hayflick Limit”

Some Commonly Used Cell Lines

Cell Line* Cell Type and Origin

3T 3 fibroblast (mouse)

BHK 21 fibroblast (Syrian hamster)

MDCK epithelial cell (dog)

HeLa epithelial cell (human)

PtK 1 epithelial cell (rat kangaroo)

L 6 myoblast (rat)

PC 12 chromaffin cell (rat)

SP 2 plasma cell (mouse)

*Many of these cell lines were derived from tumors. All of them are capable of indefinite replication in culture and express at least some of the differentiated properties of their cell of origin. BHK 21 cells, HeLa cells, and SP 2 cells are capable of growth in suspension; the other cell lines require a solid culture substratum in order to multiply.

Growth Factors actat the Restriction Point

Growth Factors Induce Cell Cycle Progression

Zetterberg and Larsson, PNAS 82:5365 (1985)

pm = post mitoticps = pre-synthetic

Growth Factors Induce Gene Expression

Growth Factors Oncogene Expression

Growth Factors Induce Cyclin D1 Expression

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

c-fos is asubunit of AP1!

Cyclin D Expression is Required for S Phase

Cyclin D/cdk4 ControlsGrowth in Flies

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

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

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

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

Mitogen Induced Cell Cycle Progression in Cell Culture

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 Geneto be Controlled by Another

Examples of genetic instability:

1) gene amplification2) anueploidy: chromosome gain and loss3) chromosome rearragements4) somatic point mutations

Cancer Cells Display Genetic Instability