Tumor-derived mesenchymal stem cells in human gliomas: Isolation and biological properties

Lang, Frederick F.; Gumin, Joy; Amano, Toshiyuki; Hata, Nobuhiro; Heimberger, Amy B.; Marini, Frank C.; Andreeff, Michael; Aldape, K. D.; Sulman, Erik P.; Colman, Howard

doi:10.1200/jco.2008.26.15_suppl.2001

Cited by 9 publications

(7 citation statements)

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“…Furthermore, tumor-derived MSCs were recently isolated and characterized as CD133 À cells, indicating that they are distinct from classic CD133 þ glioma cancer stem cells. These CD133 À MSCs were more commonly isolated from high-grade tumors than from low-grade gliomas, supporting the hypothesis that tumor-derived MSCs are involved in glioma progression from low to high grade [48]. Accordingly, extremely low CD133 À glioblastomas were found to show a mesenchymal subclass-like gene expression profile, which has the worst clinical outcome [49].…”

Section: Discussionmentioning

confidence: 59%

Evidence for Transcriptional Regulation of the Glucose-6-Phosphate Transporter by HIF-1α: Targeting G6PT with Mumbaistatin Analogs in Hypoxic Mesenchymal Stromal Cells

et al. 2009

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Mesenchymal stromal cell (MSC) markers are expressed on brain tumor-initiating cells involved in the development of hypoxic glioblastoma. Given that MSCs can survive hypoxia and that the glucose-6-phosphate transporter (G6PT) provides metabolic control that contributes to MSC mobilization and survival, we investigated the effects of low oxygen (1.2% O 2 ) exposure on G6PT gene expression. We found that MSCs significantly expressed G6PT and the glucose-6-phosphatase catalytic subunit b, whereas expression of the glucose-6-phosphatase catalytic subunit a and the islet-specific glucose-6-phosphatase catalytic subunit-related protein was low to undetectable. Analysis of the G6PT promoter sequence revealed potential binding sites for hypoxia inducible factor (HIF)-1a and for the aryl hydrocarbon receptor (AhR) and its dimerization partner, the AhR nuclear translocator (ARNT), AhR:ARNT. In agreement with this, hypoxia and the hypoxia mimetic cobalt chloride induced the expression of G6PT, vascular endothelial growth factor (VEGF), and HIF-1a. Gene silencing of HIF-1a prevented G6PT and VEGF induction in hypoxic MSCs whereas generation of cells stably expressing HIF-1a resulted in increased endogenous G6PT gene expression. A semisynthetic analog of the polyketide mumbaistatin, a potent G6PT inhibitor, specifically reduced MSC-HIF-1a cell survival. Collectively, our data suggest that G6PT may account for the metabolic flexibility that enables MSCs to survive under conditions characterized by hypoxia and could be specifically targeted within developing tumors.

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Section: Discussionmentioning

confidence: 59%

Evidence for Transcriptional Regulation of the Glucose-6-Phosphate Transporter by HIF-1α: Targeting G6PT with Mumbaistatin Analogs in Hypoxic Mesenchymal Stromal Cells

et al. 2009

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“…51–53 Most important and consistent with other studies, 53,54 we have shown that cells similar to BM-MSCs can be isolated and cultured from fresh glioma specimens obtained at surgery. 26,27 Evidence suggests that these tumor-derived MSCs may contribute to the stroma of human gliomas, potentially by modifying the vascular niche. Although it has been presumed that tumor-derived MSCs arise from a circulating pool of BM-MSCs, the finding that there are local MSCs intrinsic to the brain suggests that the source of MSCs in gliomas may be Br-MSCs rather than circulating BM-MSCs.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, cells resembling MSCs can be isolated from fresh glioma specimens obtained at surgery. 26,27 Like BM-MSCs, these tumor derived-MSCs grow as adherent cells in culture; differentiate into adipocytes, chondrocytes, and osteocytes; and express the requisite MSC surface markers. 26,27 These tumor-derived MSCs are thought to contribute to the stroma of human gliomas.…”

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confidence: 99%

Isolation and Perivascular Localization of Mesenchymal Stem Cells From Mouse Brain

et al. 2010

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BACKGROUND Although originally isolated from the bone marrow, mesenchymal stem cells (MSCs) have recently been detected in other tissues. However, little is known about MSCs in the brain. OBJECTIVE To determine the extent to which cells with the features of MSCs exist in normal brain tissue and to determine the location of these cells in the brain. METHODS Single-cell suspensions from mouse brains were cultured according to the same methods used for culturing bone marrow–derived MSCs (BM-MSCs). These brain-derived cells were analyzed by fluorescence-activated cell sorting for surface markers associated with BM-MSCs (stem cell antigen 1 [Sca-1+], CD9+, CD45−, CD11b−, and CD31−). Brain-derived cells were exposed to mesenchymal differentiation conditions. To determine the locations of these cells within the brain, sections of normal brains were analyzed by immunostaining for Sca-1, CD31, and nerve/glial antigen 2. RESULTS Cells morphologically similar to mouse BM-MSCs were identified and called brain-derived MSCs (Br-MSCs). Fluorescence-activated cell sorting indicated that the isolated cells had a surface marker profile similar to BM-MSCs, ie, Sca-1+, CD9+, CD45−, and CD11b−. Like BM-MSCs, Br-MSCs were capable of differentiation into adipocytes, osteocytes, and chondrocytes. Immunostaining indicated that Sca-1+ Br-MSCs are located around blood vessels and may represent progenitor cells that serve as a source of mesenchymal elements (eg, pericytes) within the brain. CONCLUSION Our results indicate that cells similar to BM-MSCs exist in the brain. These Br-MSCs appear to be located within the vascular niche and may provide the mesenchymal elements of this niche. Because MSCs may be part of the cellular response to tissue injury, Br-MSCs may represent targets in the therapy of pathological processes such as stroke, trauma, and tumorigenesis.

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“…The authors conclude that the benign MSCs likely represent “tumor stroma”. Another abstract reports isolation of MSCs from glioma(43). To our knowledge, these are the only studies reporting isolation of MSCs from human tumors of any histology.…”

Section: Discussionmentioning

confidence: 99%

Benign Mesenchymal Stromal Cells in Human Sarcomas

Morozov

Downey

Healey

et al. 2010

Clinical Cancer Research

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Purpose Recent evidence suggests that at least some sarcomas arise through aberrant differentiation of mesenchymal stromal cells (MSCs), but MSCs have never been isolated directly from human sarcoma specimens. Experimental Design We examined human sarcoma cell lines and primary adherent cultures derived from human sarcoma surgical samples for features of MSCs. We further characterized primary cultures as either benign or malignant by the presence of tumor-defining genetic lesions and tumor formation in immunocompromised mice. Results We show that a dedifferentiated liposarcoma cell line DDLS8817 demonstrates fat, bone and cartilage trilineage differentiation potential characteristic of MSCs. Primary sarcoma cultures have the morphology, surface immunophenotype and differentiation potential characteristic of MSCs. Surprisingly, many of these cultures are benign as they do not form tumors in mice and lack sarcoma-defining genetic lesions. Consistent with the recently proposed pericyte origin of MSCs in normal human tissues, sarcoma-derived benign MSCs express markers of pericytes and cooperate with endothelial cells in tube formation assays. In human sarcoma specimens, a subset of CD146-positive microvascular pericytes express CD105, an MSC marker, while malignant cells largely do not. In an in vitro co-culture model, sarcoma-derived benign MSCs as well as normal human pericytes markedly stimulate the growth of sarcoma cell lines. Conclusions Sarcoma-derived benign MSCs/pericytes represent a previously undescribed stromal cell type in sarcoma which may contribute to tumor formation.

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Tumor-derived mesenchymal stem cells in human gliomas: Isolation and biological properties

Cited by 9 publications

References 0 publications

Evidence for Transcriptional Regulation of the Glucose-6-Phosphate Transporter by HIF-1α: Targeting G6PT with Mumbaistatin Analogs in Hypoxic Mesenchymal Stromal Cells

Evidence for Transcriptional Regulation of the Glucose-6-Phosphate Transporter by HIF-1α: Targeting G6PT with Mumbaistatin Analogs in Hypoxic Mesenchymal Stromal Cells

Isolation and Perivascular Localization of Mesenchymal Stem Cells From Mouse Brain

Benign Mesenchymal Stromal Cells in Human Sarcomas

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