Embryonic stem cell markers distinguishing cancer stem cells from normal human neuronal stem cell populations in malignant glioma patients.

Abstract

G lioblastoma multiforme (GBM) is the most common and the most aggressive type of brain tumor, responsible for 18.5% of all primary central nervous system tumors. Treatment of these tumors remains a difficult clinical challenge and requires a multimodal approach. Despite obvious benefits, surgery alone or in combination with radiation therapy does not provide prolonged remissions, yielding median survivals of 20 and 36 weeks, respectively, for GBM patients. Median survival times may be increased to up to nearly 15 months if .98% of the tumor is removed or if chemotherapy is integrated with surgery and radiation. Standard chemotherapy plus fractionated radiation therapy and surgery yields a median survival between 50 and 60 weeks. Unfortunately, there has been little improvement in survival relative to the original average span of 44 to 52 weeks documented .80 years ago. The presence of a blood-brain barrier and the remarkable degree of molecular heterogeneity within malignant glial cells limit the therapeutic effect of chemotherapy and make patient prognosis poor and recurrence rates reach close to 100%. Tumor stem (TS) cells are believed to be a major component of resistance to the existing therapies for GBM. The heterogeneity of human glioma tumors, and particularly the existence of a subpopulation of TS cells, is believed to be critical to the tumorigenic process. Previous studies have suggested that these TS cells, identified as being positive for the surface marker CD133, within GBM tumors are able to give rise to new tumors after transplantation into nude mice. Interestingly, transplantation of CD133-negative cancer cells does not appear to form tumors on transplantation. CD133-positive cancer stem cells have been compared with human neural stem cells on both growth properties and gene expression. However, many of these comparative studies have been carried out using fetal neural stem cells rather than endogenous adult neural stem cells. All studies that cite CD133 positivity to be an adult neural stem cell marker refer to research on fetal or embryonic stem cell-derived neural stem cells. This distinction may be important because nonfetal adult neural stem cells, at least in the subventricular zone, do not express CD133 and have not been as well characterized. Previous comparative studies of malignant glioma tumor cell heterogeneity have failed to provide valuable information as to the similarity of cancer stem cells to adult neural stem cells. Many studies have cited CD133 positivity to be a TS cell marker even though CD133 positivity has also been established as a marker for normal neuronal stem (NS) cells. Thus, the use of CD133 as a surrogate marker to identify TS cells within a GBM may not be clinically useful because glioblastomas contain both differentiated cancer cells and cancer stem cells in addition to normal adult neural stem cells that migrate into the tumor. Both NS cells and glial progenitor cells have been found throughout the healthy normal adult brain. NS cells travel with tumor cells migrating through the parenchyma of the central nervous system. In fact, NS cells appear in the area adjacent to glioma implants 5 days after injection in mice. This migratory phenomenon, which is also observed in brain injury, has been proposed as a means of anticancer gene delivery. If stem cells are to be a viable vehicle for tumor therapies, then more detailed identification is needed to prevent the accidental implantation of cancer stem cells. Thus, identifying a specific TS cell marker to distinguish neoplastic stem cells from NS cells is crucial for not only understanding the biology of TS cells but also developing effective therapy for GBM. The ability of TS cells to undergo tumorigenesis, combined with their resistance to chemotherapy and radiation therapy, is of particular clinical importance given the propensity of gliomas to reemerge after surgery and therapy. As a result, TS cells may represent a primary therapeutic target to achieve complete eradication of the tumor. Although CD133-positive TS cells have been compared with human NS cells on both growth properties and gene expression, definitive TS cell-specific markers that relate to TS biology have not been found. To help address this problem, this study aimed to characterize different cell populations on the basis of growth properties and to show a distinct population of cells with cancer stem cell properties based on specific cell marker expression patterns. Copyright 2010 by The Congress of Neurological Surgeons 0148-396X