No abstract

The human population is increasingly facing various diseases, including types of cancer, that cannot be cured with conventional drugs. Advanced drug targeting of tumor cells is also often impossible when treating highly invasive and infiltrative tumors such as glioblastoma or pulmonary cancer, because of tumor cells' high migration and invasiveness. Pluripotent human mesenchymal stem cells (hMSCs) have been extensively studied, and strategies are being proposed for treating ''incurable'' cancers and injury/disease-affected organs. Because of their own intrinsic properties, involving homing and immunomodulatory potency, hMSCs could be used as an excellent cell/drug delivery vehicle in those cell-based therapies. Their unprecedented use has been shadowed, however, by their spontaneous transformation, which links them to cancer-initiating cells during tumor development. How malignant initiation proceeds in vivo, and what are the exact characteristics of the cancer-initiating cells, still remain to be investigated. In the present review, the authors summed up the most recent knowledge about hMSC characteristics, their malignant transformation, and outlined the possibilities of their safe use in novel cell-based therapies. Cancer 2010;116:2519-30.

The cancer stem cell model suggests that glioblastomas contain a subpopulation of stem-like tumor cells that reproduce themselves to sustain tumor growth. Targeting these cells thus represents a novel treatment strategy and therefore more specific markers that characterize glioblastoma stem cells need to be identified. In the present study, we performed transcriptomic analysis of glioblastoma tissues compared to normal brain tissues revealing sensible up-regulation of CD9 gene. CD9 encodes the transmembrane protein tetraspanin which is involved in tumor cell invasion, apoptosis and resistance to chemotherapy. Using the public REMBRANDT database for brain tumors, we confirmed the prognostic value of CD9, whereby a more than two fold up-regulation correlates with shorter patient survival. We validated CD9 gene and protein expression showing selective up-regulation in glioblastoma stem cells isolated from primary biopsies and in primary organotypic glioblastoma spheroids as well as in U87-MG and U373 glioblastoma cell lines. In contrast, no or low CD9 gene expression was observed in normal human astrocytes, normal brain tissue and neural stem cells. CD9 silencing in three CD133+ glioblastoma cell lines (NCH644, NCH421k and NCH660h) led to decreased cell proliferation, survival, invasion, and self-renewal ability, and altered expression of the stem-cell markers CD133, nestin and SOX2. Moreover, CD9-silenced glioblastoma stem cells showed altered activation patterns of the Akt, MapK and Stat3 signaling transducers. Orthotopic xenotransplantation of CD9-silenced glioblastoma stem cells into nude rats promoted prolonged survival. Therefore, CD9 should be further evaluated as a target for glioblastoma treatment.