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BIOLOGICAL SCIENCES / IMMUNOLOGY
Normal development is an integral part of tumorigenesis in T cell-specific PTEN-deficient mice
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*Cancer Research Laboratory and Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200; Division of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan; and The Campbell Family Institute for Breast Cancer Research and Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 2C1
Contributed by Tak W. Mak, December 21, 2007 (received for review December 3, 2007)
PTEN is a tumor suppressor gene but whether cancer can develop in all PTEN-deficient cells is not known. In T cell-specific PTEN-deficient (tPTEN–/–) mice, which suffer from mature T cell lymphomas, we found that premalignancy, as defined by elevated AKT and senescence pathways, starts in immature T cell precursors and surprisingly not in mature T cells. Premalignancy only starts in 6-week-old mice and becomes much stronger in 9-week-old mice although PTEN is lost since birth. tPTEN–/– immature T cells do not become tumors, and senescence has no role in this model because these cells exist in a novel cell cycle state, expressing proliferating proteins but not proliferating to any significant degree. Instead, the levels of p27kip1, which is lower in tPTEN–/– immature T cells and almost nonexistent in tPTEN–/– mature T cells, correlate with the proliferation capability of these cells. Interestingly, transient reduction of these cancer precursor cells in adult tPTEN–/– mice within a crucial time window significantly delayed lymphomas and mouse lethality. Thus, loss of PTEN alone is not sufficient for cells to become cancerous, therefore other developmental events are necessary for tumor formation.
lymphomas | senescence | double positive thymocytes | p27 | cyclin A
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0712059105/DC1.
To whom correspondence may be addressed. E-mail: tmak{at}uhnres.utoronto.ca or winoto{at}berkeley.edu
© 2008 by The National Academy of Sciences of the USA
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