Normal development is an integral part of tumorigenesis in T cell-specific PTEN-deficient mice.
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 p27(kip1), 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.
Xue
Ling
L
Cancer Research Laboratory and Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200, USA.
Nolla
Hector
H
Suzuki
Akira
A
Mak
Tak W
TW
Winoto
Astar
A
D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D017931:DNA Primers; D005260:Female; D005434:Flow Cytometry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism
D017931:DNA Primers; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse