1. Is Unregulated Cell Division Sufficient
A Typical Solid Tumor…
The size of a tumor first detectable by X-ray: 108 cells
The size of a tumor first palpable: cells
The size of tumor at death of patient: cells
Is Unregulated Cell Division Sufficient
To Cause an Increase in Tumor Size??

2. Cell Division + Growth =
The Difference Between Growth and Cell Division
Growth with
No Cell Division
Cell Division
No Growth
Cell Division + Growth =
Proliferation!

3. A Differentiated Neuron
Growth with
No Cell Division:
A Differentiated Neuron

4. 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

5. Unregulated Proliferation: Cancer!
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: cells
The size of tumor at death of patient: cells
Unregulated Proliferation: Cancer!

6. Budding Yeast Saccharomyces cerevisiae

7. Cdc Mutants Affect the Cell Cycle, Not Growth
Permissive (low) temperature
Restrictive (high) temperature

8. 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”

9. Some Commonly Used Cell Lines
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.

10. Growth Factors Induce Cell Cycle Progression
act Prior to
the Restriction Point
Modified from The Biology of Cancer (© Garland Science 2007)

11. Restriction Point pm = post mitotic ps = pre-synthetic
Zetterberg and Larsson, PNAS 82:5365 (1985)

12. Growth Factors Induce Gene Expression

13. Growth Factors Induce Oncogene Expression As Early Response Genes

14. Growth Factors Induce Cyclin D1 Expression
c-fos is a
subunit of AP1!
Sherr and McCormick, Cancer Cell, Vol 2, (2002)

15. Cyclin D/cdk4 Controls Growth in Flies
Meyer et al., EMBO19: (2000)
Datar et al., EMBO 19: (2000)

16. Figure 8.2a The Biology of Cancer (© Garland Science 2007)

17. p18 (cdk4 CKI) Mutation Induces Growth in Mice
Franklin et al., Molecular and Cellular Biology, 12: (1998)

18. Mitogen Induced Cell Cycle Progression in Cell Culture

19. 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).

20. Translocations Cause One Gene to be Controlled by Another