Modeling Variation in Tumors in vivo

Transgenic mice that allow mutant cells to be visualized in situ were used to study variation in tumors. These mice carry the G11 placental alkaline phosphatase (PLAP) transgene, a mutant allele rendered incapable of producing its enzyme product by a frameshift caused by insertion of a tract of G:C...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 7; pp. 2408 - 2413
Main Authors Stringer, James R., Larson, Jon S., Fischer, Jared M., Medvedovic, Mario, Hersh, Megan N., Boivin, Gregory P., Stringer, Saundra L., Vogt, Peter K.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 15.02.2005
National Acad Sciences
Subjects
3T3 cells
Alkaline Phosphatase - genetics
Animals
Biological Sciences
Cell growth
Cell Proliferation
Cells
Cellular biology
Computer Simulation
Female
Frameshift Mutation
Genes, Reporter
Genetic mutation
Genetic Variation
Genetics
GPI-Linked Proteins
Human genetics
Isoenzymes - genetics
Male
Mammary Neoplasms, Experimental - enzymology
Mammary Neoplasms, Experimental - genetics
Mammary Neoplasms, Experimental - pathology
Mice
Mice, Transgenic
Models, Genetic
Mutation
Phenotypes
Placenta - enzymology
Pregnancy
Rodents
Somatic cells
Transgenes
Tumors
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Summary:Transgenic mice that allow mutant cells to be visualized in situ were used to study variation in tumors. These mice carry the G11 placental alkaline phosphatase (PLAP) transgene, a mutant allele rendered incapable of producing its enzyme product by a frameshift caused by insertion of a tract of G:C base pairs in a coding region. Spontaneous deletion of one G:C base pair from this tract restores gene function, and cells with PLAP activity can be detected histochemically. To study tumors, the G11 PLAP transgene was introduced into the polyoma virus middle T antigen mammary tumor model. Tumors in these mice exhibited up to 300 times more PLAP+cells than normal tissues. PLAP+cells were located throughout each tumor. Many of the PLAP+cells were singlets, but clusters also were common, with one cluster containing >30,000 cells. Comparison of these data to simulations produced by computer models suggested that multiple factors were involved in generating mutant cells in tumors. Although genetic instability appeared to have occurred in most tumors, large clusters were much more common than expected based on instability alone.
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Present address: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, S-809, Mailstop 225, Houston, TX 77030-3411.
Abbreviation: PLAP, placental alkaline phosphatase.
Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA
This paper was submitted directly (Track II) to the PNAS office.
Author contributions: J.R.S., S.L.S., and M.N.H. designed research; S.L.S., J.S.L., J.M.F., and M.N.H. performed research; J.M.F., M.M., and G.P.B. contributed new reagents/analytic tools; J.R.S., S.L.S., M.M., J.S.L., J.M.F., and G.P.B. analyzed data; and J.R.S. wrote the paper.
To whom correspondence should be addressed. E-mail: stringjr@ucmail.uc.edu.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0401340102