Editorial: glioma subpopulations

It has been more than 25 years since investigators first discussed the existence of glioma “stem” cells,7,8 but only in the last 5 years or so have scientists been able to identify such cells in tumors based on expression of specific markers or defined phenotypes and behaviors.1,3,6,9,10 This type of identification has led to the hypothesis that therapies aimed at such cells within tumors would eliminate the glioma’s ability to self-renew and thus be more efficacious than current treatments that target all of the neoplasm, but to which glioma stem cells are resistant. Therefore, the effort to seek new therapies that target such cells has become a hotbed of research. In this issue of the Journal of Neurosurgery, Ma et al.5 report that cyclooxygenase-2 (COX-2) is overexpressed in glioma cells that express the CD133 marker, previously shown to be one of the markers of “stemness.”9 Based on this discovery of COX-2 overexpression, they were able to demonstrate antiproliferative and proapoptotic effects against CD133+ glioma cells using the COX-2 inhibitor celecoxib in combination with radiation. They were able to demonstrate this effect both in vitro and in animal models (in vivo). Therefore, celecoxib may become a useful therapeutic agent against CD133+ glioma cells when used in combination with radiation. There are some limitations in the study. First, clinical trials of celecoxib in human patients with gliomas do not seem to show a therapeutic effect.4 Although these trials are not being conducted in combination with radiotherapy, such a finding still dampens enthusiasm for future use of this particular drug. Second, the data in Fig. 5A show that COX-2 expression was only partially inhibited by celecoxib, even at the highest dose tested. This raises the concern that the observed anticancer biological effect of celecoxib may result from a yet-undiscovered “off-target” effect. Third, their procedure to obtain CD133+ “stem” cells starts off with a population of CD133− cells from resected specimens that are then radiated to obtain radioresistant CD133+ cells. All subsequent comparisons are then made between the original parental CD133− cells and the derived radioresistant CD133+ cells. This is not the usual methodology for isolation of glioma “stem” cells, raising concern that the comparison is not between glioma non– stem cells and stem cells but rather between radiosensitive glioma cells and radioresistant cells. In fact, a recent report linked CD133 expression not to “stemness,” but rather to a marker for “bioenergetic stress.”2 In spite of these limitations, the study does raise awareness that drugs targeting a particular glioma subpopulation (the CD133+ subpopulation) can be discovered, raising the possibility that the future therapeutic armamentarium against these tumors will become stratified and “personalized” based on the molecular profile of the particular tumor.