A Heterogeneous Population of Stem Cells Within Glioblastoma Tumors in the Setting of Disease Relapse
Engh, Johnathan A
One of the more promising recent developments in glioblastoma (GBM) research was the isolation of cancer stem cells (CSCs) from these tumors.1,2 Just like CSCs isolated from other solid tumors, this cell population was found to be capable of self-renewal and differentiation into multiple different cell types. These cells were distinguished from other tumor cells by their expression of a transmembrane glycoprotein known as CD133. Multiple subsequent studies have further characterized this cell population. As a result, it has become clear that CD133 alone does not differentiate GBM CSCs from other cancer cells; for example, selected CD133 negative cells from GBM specimens have been shown to be capable of self-renewal and tumorigenicity upon implantation.3 Nonetheless, CD133 positive cells have been shown in vitro to be resistant to both radiation therapy and chemotherapy relative to other GBM cells.4,5 Finally, there is some evidence that initial CD133 expression correlates with poor prognosis in the setting of GBM.6 Therefore, this cell population may be a critical therapeutic target in the treatment of these cancers.
A growing body of research suggests that stem-like cells from GBM specimens are not uniformly CSCs, or even tumor cells. This other population may represent neural cells that are recruited to the tumor site from elsewhere as part of the body's response to the tumor.7 Successful recruitment of these non-tumoral precursor cells to the tumor site appears to be associated with improved survival.8 However, much remains unknown regarding the CD133 status of this cell population as well as the prognostic significance of CD133 expression in GBM following standard therapy.
In a recent study performed at the Catholic University School of Medicine in Rome, Italy, fluorescence-activated cell sorting analysis was used to evaluate CD133 expression in paired samples from GBM resections performed both at initial presentation and after first relapse, following adjuvant chemotherapy and radiation.9 Specimens were collected from 37 consecutive patients, and assessed for expression of CD133. The percentage of CD133 cells was increased at repeat surgery in 19 cases, unchanged in 12 cases, and decreased in 6 cases.9 Surprisingly, increased CD133 expression at the time of disease relapse was associated with improved overall survival (Figure).
Figure. A, axial con...Image Tools
Further tests demonstrated that this CD133 positive population was heterogeneous. After testing for the hematopoietic markers CD34 and CD45, the authors demonstrated that the CD133 positive population included both tumoral and non-tumoral stem cells.9
This data, as well as the correlation of CD133 positive cell density with improved survival, provides additional evidence that the stem cell population within GBM is both heterogeneous and dynamic. Such findings will be an important stepping stone for further research on the role of CD133 non-tumor stem cells in glioma biology.
Johnathan A. Engh
1. Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63(18):5821-5828.
2. Singh SK, Hawkins C, Clarke ID, et al. Identification of brain tumor initiating cells. Nature. 2004;432(7015):396-401.
3. Wang J, Sakariassen PO, Tsinkalovsky O, et al. CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. Int J Cancer. 2008;122(4):761-768.
4. Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756-760.
5. Liu G, Yuan X, Zeng Z, et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer. 2006;5:67.
6. Pallini R, Ricci-Vitiani L, Banna GL, et al. Cancer stem cell analysis and clinical outcome in patients with glioblastoma multiforme. Clin Cancer Res. 2008;14(24):8205-8212.
7. Aboody KS, Brown A, Rainov NG, et al. Neural stem cells display extensive tropism for pathology in the adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci USA. 2000;97(23):12846-12851.
8. Glass R, Synowitz M, Kronenberg G, et al. Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival. J Neurosci. 2005;25(10):2637-1646.
9. Pallini R, Ricci-Vitiani L, Montano N, et al. Expression of the stem cell marker CD133 in recurrent glioblastoma and its value for prognosis. Cancer. 2011;117(1):162-174.
Copyright © by the Congress of Neurological Surgeons