Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacity

Neuro-Oncology, Oct 2010

Glioblastoma (GBM) is the most aggressive primary brain tumor and is resistant to all therapeutic regimens. Relapse occurs regularly and might be caused by a poorly characterized tumor stem cell (TSC) subpopulation escaping therapy. We suggest aldehyde dehydrogenase 1 (ALDH1) as a novel stem cell marker in human GBM. Using the neurosphere formation assay as a functional method to identify brain TSCs, we show that high protein levels of ALDH1 facilitate neurosphere formation in established GBM cell lines. Even single ALDH1 positive cells give rise to colonies and neurospheres. Consequently, the inhibition of ALDH1 in vitro decreases both the number of neurospheres and their size. Cell lines without expression of ALDH1 do not form tumor spheroids under the same culturing conditions. High levels of ALDH1 seem to keep tumor cells in an undifferentiated, stem cell-like state indicated by the low expression of beta-III-tubulin. In contrast, ALDH1 inhibition induces premature cellular differentiation and reduces clonogenic capacity. Primary cell cultures obtained from fresh tumor samples approve the established GBM cell line results.

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Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacity

Michael Rasper 0 1 2 3 4 Andrea Scha fer 0 1 2 3 4 Guido Piontek 0 1 2 3 4 Julian Teufel 0 1 2 3 4 Gero Brockhoff 0 1 2 3 4 Florian Ringel 0 1 2 3 4 Stefan Heindl 0 1 2 3 4 Claus Zimmer 0 1 2 3 4 Ju rgen Schlegel () 0 1 2 3 4 0 Obstetrics, Caritas Hospital St Josef, University of Regensburg , Regensburg, Germany (G.B.); Department 1 Center for Environmental Health (GmbH) , Neuherberg, Germany (J.S.); Department of Gynaecology 2 Division of Neuropathology, Institute of Pathology, Technische Universita t Mu nchen , Mu nchen, Germany 3 Department of Neuroradiology , Klinikum rechts der Isar, Technische Universita t Mu nchen , Mu nchen 4 of Neurosurgery , Klinikum rechts der Isar, Technische Universita t Mu nchen , Mu nchen, Germany (F.R.) - Glioblastoma (GBM) is the most aggressive primary brain tumor and is resistant to all therapeutic regimens. Relapse occurs regularly and might be caused by a poorly characterized tumor stem cell (TSC) subpopulation escaping therapy. We suggest aldehyde dehydrogenase 1 (ALDH1) as a novel stem cell marker in human GBM. Using the neurosphere formation assay as a functional method to identify brain TSCs, we show that high protein levels of ALDH1 facilitate neurosphere formation in established GBM cell lines. Even single ALDH1 positive cells give rise to colonies and neurospheres. Consequently, the inhibition of ALDH1 in vitro decreases both the number of neurospheres and their size. Cell lines without expression of ALDH1 do not form tumor spheroids under the same culturing conditions. High levels of ALDH1 seem to keep tumor cells in an undifferentiated, stem cell-like state indicated by the low expression of beta-III-tubulin. In contrast, ALDH1 inhibition induces premature cellular differentiation and reduces clonogenic capacity. Primary cell cultures obtained from fresh tumor samples approve the established GBM cell line results. Glioblastoma (GBM) is the most common primary brain tumor in adults with a medium survival of approximately 15 months.1 Despite various efforts to improve the postoperative therapeutic regimen within the last years, the prognosis of this highly aggressive tumor has remained poor. Relapse occurs regularly after resection, irradiation, and chemotherapy. This could in part be due to the existence of so-called tumor stem cells (TSCs), a cellular subfraction within GBM contributing to recurrent tumor growth and resistance to drugs and irradiation. Within the last decade, TSCs have been identified and isolated in a variety of hematologic and solid neoplasms. The characterization of these cells seems to be crucial for a better understanding of tumor biology and for the development of more efficient antitumor therapies. Owing to the TSC paradigm, hematologic and solid tumors consist of hierarchically ordered cellular subdivisions. TSCs are believed to harbor the ability to keep a tumor alive and growing: pluripotency, self-renewal, and resistance to chemo- and irradiation therapy. This concept arose from the notion that a subpopulation of cancer cells shows similarity to normal stem cells.2 Leukemias were the first malignancies from which cells could be isolated that showed the potential to self-renew and to drive tumor formation and growth.3 A stem cell subfraction has been described in brain tumors and especially in high-grade astrocytomas. Singh et al.4 were the first to identify and purify, a population with stem cell properties in pediatric solid brain tumors. Those cells were identified by their ability to form spheroids (neurospheres) when grown under serum-free cell culture conditions and by the expression of CD133 and nestin. CD133 (also known as prominin-1), a 120-kDa pentaspan transmembrane glycoprotein, has been found to be a marker of stemness in hematopoietic5 and neural cells.6 Together with nestin, an intermediate filament protein expressed by undifferentiated neuroepithelial cells7 and tumors of the CNS,8 CD133 has long remained the most important TSC marker in malignant glioma. Aldehyde dehydrogenase 1 (ALDH1) is a cytoplasmatic stem cell marker in a variety of malignant tumors. As a member of the ALDH enzyme family, ALDH1 catalyzes the oxidation of intracellular aldehydes including the transformation of retinol to retinoic acid (RA). RA is a modulator of cell proliferation and differentiation that possibly contributes to the maintenance of an undifferentiated stem cell phenotype. Jones et al.9 presented a method to isolate human cells via flow cytometry depending on the amount of cytosolic ALDH. They were able to enrich human hematopoietic precursor cells capable of reconstituting bone marrow in irradiated animals. Recently, Ginestier et al.10 found ALDH1 to be a stem cell marker in breast carcinoma associated with poor clinical outcome. Since then ALDH1 has been described as a marker of stemness in other solid malignancies including lung cancer11 and colorectal cancer.12 Here, we show that ALDH1 overexpression correlates with stem c (...truncated)


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Michael Rasper, Andrea Schäfer, Guido Piontek, Julian Teufel, Gero Brockhoff, Florian Ringel, Stefan Heindl, Claus Zimmer, Jürgen Schlegel. Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacity, Neuro-Oncology, 2010, pp. 1024-1033, 12/10, DOI: 10.1093/neuonc/noq070