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