Abstract
BackgroundPTEN (phosphatase and tensin homologue deleted on chromosome ten) is a tumor suppressor gene implicated in a wide variety of human cancers, including glioblastoma. PTEN is a major negative regulator of the PI3K/Akt signaling pathway. Most human gliomas show high levels of activated Akt, whereas less than half of these tumors carry PTEN mutations or homozygous deletions. The unique ability of mesenchymal stem cells to track down tumor cells makes them as potential therapeutic agents. Based on this capability, new therapeutic approaches have been developed using mesenchymal stem cells to cure glioblastoma. However, molecular mechanisms of interactions between glioma cells and stem cells are still unknown.Methodology/Principal FindingsIn order to study the mechanisms by which migration of glioma cells can be inhibited by the upregulation of the PTEN gene, we studied two glioma cell lines (SNB19 and U251) and two glioma xenograft cell lines (4910 and 5310) alone and in co-culture with human umbilical cord blood-derived mesenchymal stem cells (hUCBSC). Co-cultures of glioma cells showed increased expression of PTEN as evaluated by immunofluorescence and immunoblotting assays. Upregulation of PTEN gene is correlated with the downregulation of many genes including Akt, JUN, MAPK14, PDK2, PI3K, PTK2, RAS and RAF1 as revealed by cDNA microarray analysis. These results have been confirmed by reverse-transcription based PCR analysis of PTEN and Akt genes. Upregulation of PTEN resulted in the inhibition of migration capability of glioma cells under in vitro conditions. Also, wound healing capability of glioma cells was significantly inhibited in co-culture with hUCBSC. Under in vivo conditions, intracranial tumor growth was inhibited by hUCBSC in nude mice. Further, hUCBSC upregulated PTEN and decreased the levels of XIAP and Akt, which are responsible for the inhibition of tumor growth in the mouse brain.Conclusions/SignificanceOur studies indicated that upregulation of PTEN by hUCBSC in glioma cells and in the nude mice tumors downregulated Akt and PI3K signaling pathway molecules. This resulted in the inhibition of migration as well as wound healing property of the glioma cells. Taken together, our results suggest hUCBSC as a therapeutic agent in treating malignant gliomas.
Highlights
Despite many advances in the treatment of malignant glioblastoma via surgery, radiotherapy and chemotherapy, patients afflicted with this disease continue to have a very poor prognosis [1,2,3]
We found that PTEN is upregulated many times over in the four tested cell lines
To evaluate whether human umbilical cord blood-derived mesenchymal stem cells (hUCBSC) undergo any changes after co-culturing with glioma cells, hUCBSC were grown in conditioned media of glioma cells and observed for changes in PTEN expression at both transcriptional and translational levels
Summary
Despite many advances in the treatment of malignant glioblastoma via surgery, radiotherapy and chemotherapy, patients afflicted with this disease continue to have a very poor prognosis [1,2,3]. Davidson’s recent data provides a novel tool to address the significance of PTEN’s separable lipid and protein phosphatase activities and suggests that both activities suppress proliferation and both activities are required in concert to achieve efficient inhibition of invasion [13]. It is not clear whether PTEN genuinely regulates cell migration, tumor invasiveness and metastasis in vivo using the mechanisms and pathways defined by in vitro systems [14]. PTEN (phosphatase and tensin homologue deleted on chromosome ten) is a tumor suppressor gene implicated in a wide variety of human cancers, including glioblastoma. Molecular mechanisms of interactions between glioma cells and stem cells are still unknown
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