Download Proliferation

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??
The Difference Between Growth and Cell Division
Growth with
No Cell Division
Cell Division
No Growth
Cell Division + Growth =
Proliferation!
Growth with
No Cell Division:
A Differentiated Neuron
Cell Division with No Growth: Early Development
OOCYTE GROWS WITHOUT DIVIDING
(MONTHS)
FERTILIZATION
FERTILIZED EGG DIVIDES WITHOUT GROWING
(HOURS)
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
Mammalian Cells Growing in Cell Culture
Amino
Acids
Arginine
Cystine
Glutamine
Histidine
Isoleucine
Leucine
Lysine
Methionine
Phenylalanine
Threonine
Tryptophan
Tyrosine
Valine
Vitamins
Salts
Miscellaneous
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)
L6
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 Induce Cell Cycle Progression
Growth Factors
act Prior to
the Restriction Point
Modified from The Biology of Cancer (© Garland Science 2007)
Restriction Point
pm = post mitotic
ps = pre-synthetic
Zetterberg and Larsson, PNAS 82:5365 (1985)
Growth Factors Induce Gene Expression
Growth Factors Induce Oncogene Expression
As Early Response Genes
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)
Figure 8.2a The Biology of Cancer (© Garland Science 2007)
p18 (cdk4 CKI) Mutation Induces Growth in Mice
Franklin et al., Molecular and Cellular Biology, 12: 2899-2911 (1998)
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 TRANSLOCATION
T(11;11)(Q13;P15) THAT INVOLVES CCND1 AND THE PARATHYROID HORMONE (PTH) ENHANCER (PRAD1 ONCOGENE).
Translocations Cause One Gene
to be Controlled by Another