Normal development is an integral part of tumorigenesis in T cell-specific PTEN-deficient mice

Abstract

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.lymphomas ͉ senescence ͉ double positive thymocytes ͉ p27 ͉ cyclin A H ow premalignancy arises, how the cells respond to it, and what the molecular steps leading to tumors are remain crucial questions in understanding cancer and designing possible future therapies. It has been widely accepted that cancer can be initiated by a combination of gain-of-function mutations of oncogenes and/or loss-of-function mutations of tumor suppressor genes. Whether cells become transformed immediately or other ''tumorinitiating'' events are still needed for tumor development is not completely known. Recent evidence has demonstrated that leukemia and some solid tumors might contain ''cancer stem cells'' within the tumors (1, 2). This population is distinct from the cancer cells, exhibit the ability to self-renew, and undergo differentiation to produce cancer cells. However, a more recent study strongly argued against the stem cell model for cancer at least for myc-induced B cell lymphomas and ras-induced T cell lymphomas (3). As the development of B and T cells is a sequential process occurring in different organs, one possible explanation in these cases is that the tumorinitiating cells might be located in other organs rather than the tumor-arising sites.PTEN is a negative regulator of PI3 kinase pathway (4, 5) and a tumor suppressor gene commonly lost or inactivated in many human cancers. In addition, germ-line PTEN mutations result in the Cowden syndrome, in which patients develop hyperplastic lesions in multiple organs with increased risks of malignant transformation (6, 7). Thus, understanding PTEN biology and how it regulates cell death and cell proliferation during tumor development should yield significant insights into how cancer cells arise. The importance of PTEN in controlling tumor formation was also shown by the phenoty...

Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes

“…Here, it is important to note that in young PTENnull mice (4-6 wk), before tumor development, mature T lymphocytes are found in the spleen and lymph nodes (Xue et al, 2008). However, it is difficult to judge from this type of analysis whether PTEN-null T cells traffic normally in the periphery because T cell numbers in secondary lymphoid organs are determined by a balance of the following factors: the efficiency of transendothelial migration from the blood into secondary lymphoid tissue; the homeostatic proliferation of peripheral T cells in the lymphopenic environment found in neonates (Min et al, 2002); and the rate at which cells egress secondary lymphoid tissue (Schwab and Cyster, 2007).…”

“…The present results showing that PTEN-null T cells can proliferate in vivo without PDK1/PKB signaling argue that this idea needs further evaluation. In this context, multiple genetic events contribute to transformation in PTEN-null hematopoietic cells (Xue et al, 2008) and one recurring event is the acquisition of chromosomal translocations that cause overexpression of c-myc (Guo et al, 2008). It is known that c-myc target genes include those with essential functions for cell metabolism and cell growth (DeBerardinis et al, 2008).…”

“…However, PTEN deletion alone does not result in cancer (Xue et al, 2008). PTEN-null tumors thus have secondary genetic alterations that are necessary for malignancy (Guo et al, 2008;Hagenbeek and Spits, 2008;Xue et al, 2008). Accordingly, the abnormal cell growth and proliferation of PTEN-null cells may not be a direct consequence of PI(3,4,5)P 3 signaling, but mediated by other pathways.…”

“…In the absence of PDK1 or PKB, thymocytes cannot increase metabolism to match the energy demands of proliferation and hence they atrophy, go through cell cycle arrest, and ultimately die (Juntilla et al, 2007;Kelly et al, 2007;Mao et al, 2007). In this context, Xue and colleagues (Xue et al, 2008) have suggested that normal thymocyte development is integral to lymphomagenesis in PTEN-null thymocytes (Xue et al, 2008). The PDK1 requirement for transformation of PTEN-null thymocytes could therefore reflect that PDK1 activation of PKB is necessary for nutrient receptor expression, cell growth and proliferation and thymic development of PTEN-deleted cells.…”

“…On this basis, the PDK1-PKB signaling axis has been proposed to be a suitable target for anticancer drug therapy (Garcia-Echeverria and Sellers, 2008;Peifer and Alessi, 2009). However, PTEN deletion alone does not result in cancer (Xue et al, 2008). PTEN-null tumors thus have secondary genetic alterations that are necessary for malignancy (Guo et al, 2008;Hagenbeek and Spits, 2008;Xue et al, 2008).…”