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: 109 cells The size of tumor at death of patient: 1012 cells Is Unregulated Cell Division Sufficient To Cause an Increase in Tumor Size??

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

A Differentiated Neuron 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

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: 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 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 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 Induce Cell Cycle Progression 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