Identification of CD105 (endoglin)-positive stem-like cells in rhabdoid meningioma

Purpose Endoglin (ENG, CD105) is a membranous protein overexpressed in tumor-associated endothelial cells, chemoresistant populations of ovarian cancer cells, and potentially stem cells. Our objective was to evaluate the effects and mechanisms of targeting endoglin in ovarian cancer. Experimental Design Global and membranous endoglin expression was evaluated in multiple ovarian cancer lines. In vitro, the effects of siRNA-mediated endoglin knockdown with and without chemotherapy were evaluated by MTT assay, cell-cycle analysis, alkaline comet assay, γ-H2AX foci formation, and qPCR. In an orthotopic mouse model, endoglin was targeted with chitosan-encapsulated siRNA with and without carboplatin. Results Endoglin expression was surprisingly predominantly cytoplasmic, with a small population of surface-positive cells. Endoglin inhibition decreased cell viability, increased apoptosis, induced double-stranded DNA damage, and increased cisplatin sensitivity. Targeting endoglin downregulates expression of numerous DNA repair genes, including BARD1, H2AFX, NBN, NTHL1, and SIRT1. BARD1 was also associated with platinum resistance, and was induced by platinum exposure. In vivo, anti-endoglin treatment decreased tumor weight in both ES2 and HeyA8MDR models when compared to control (35-41% reduction, p<0.05). Endoglin inhibition with carboplatin was associated with even greater inhibitory effect when compared to control (58-62% reduction, p<0.001). Conclusions Endoglin downregulation promotes apoptosis, induces significant DNA damage through modulation of numerous DNA repair genes, and improves platinum sensitivity both in vivo and in vitro. Anti-endoglin therapy would allow dual treatment of both tumor angiogenesis and a subset of aggressive tumor cells expressing endoglin and is being actively pursued as therapy in ovarian cancer.

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“…Endoglin-positive meningioma cells have similar increased tumorigenicity and capacity to differentiate into adipocytes and osteocytes. 28 …”

Section: Discussionmentioning

confidence: 99%

Endoglin (CD105) Contributes to Platinum Resistance and Is A Target for Tumor-Specific Therapy in Epithelial Ovarian Cancer

Ziebarth

Nowsheen

Steg

et al. 2013

Clinical Cancer Research

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“…Recent studies demonstrated the isolation and characterization of meningioma stem-like cells (21,23). The relationship between these so-called meningioma CSCs (mCSCs) and the MS-MSLCs isolated from meningiomas and described in the present study is not clear.…”

Section: Pathologymentioning

confidence: 69%

“…Although meningioma is one among the most common brain tumors also in Korea (20), little is known about meningioma cell biology. The recent successful isolation and characterization of CSCs from meningioma has provided a better understanding of meningioma biology (21)(22)(23). Components of the meningioma stroma are also likely important, as supported by previous studies (24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 72%

Isolation of mesenchymal stem-like cells in meningioma specimens

Lim

Kim

et al. 2013

International Journal of Oncology

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Cells resembling bone marrow mesenchymal stem cells (BM-MSCs) have been isolated from glioma specimens; however, little is known about the existence of mesenchymal stem-like cells (MSLCs) in meningioma. Here, we hypothesized that cells similar to BM-MSCs exist in meningioma specimens and sought to investigate whether these putative meningioma stroma MSLCs (MS-MSLCs) could be isolated. To this end, we cultured fresh meningioma specimens using the same protocols as used previously to isolate BM-MSC. Cultured cells were analyzed for surface markers associated with BM-MSCs by fluorescence-activated cell sorting (FACS) and candidate cells were exposed to mesenchymal differentiation conditions. Possible locations of MS-MSLCs were determined by immunohistochemical analysis of sections of meningioma specimens. Spindle-shaped and, adherent cells similar to BM-MSCs were isolated in 2 of 20 meningioma specimens. FACS analysis showed that the surface markers of MS-MSLCs were similar to those of BM-MSCs and the chosen cells demonstrated an ability to differentiate into osteogenic, adipogenic and chondrogenic cells. The tumorigenicity of MS-MSLCs was tested by injection of these cells into the brain of athymic nude mice; no tumors were subsequently discovered. Immunohistochemical analyses indicated that CD105+ cells were closely associated with endothelial cells and pericytes in meningioma specimens. Our results established for the first time that cells similar to BM-MSCs exist in meningioma specimens. These cells, termed MS-MSLCs, could be one component of the meningioma cellular microenvironment.

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“…Therefore, we presume that meningioma tumor stem cells may be responsible for these events. According to recent reports, CSC-like cells may be present in meningiomas (13,17,30). Traditionally, Nestin, CD133 and Sox2 are regarded as CSC markers, but they could also be considered specific markers for BTSCs (28).…”

Section: █ Discussionmentioning

confidence: 99%