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      Glioblastoma stem cell differentiation into endothelial cells evidenced through live-cell imaging

      1 , 1 , 1 , 1 , 1
      Neuro-Oncology
      Oxford University Press (OUP)

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          Abstract

          <div class="section"> <a class="named-anchor" id="d6740936e175"> <!-- named anchor --> </a> <h5 class="section-title" id="d6740936e176">Background.</h5> <p id="d6740936e178">Glioblastoma cell-initiated vascularization is an alternative angiogenesis called vasculogenic mimicry. However, current knowledge on the mechanism of de novo vessel formation from glioblastoma stem cells (GSCs) is limited. </p> </div><div class="section"> <a class="named-anchor" id="d6740936e180"> <!-- named anchor --> </a> <h5 class="section-title" id="d6740936e181">Methods.</h5> <p id="d6740936e183">Sixty-four glioblastoma samples from patients and 10 fluorescent glioma xenograft samples were examined by immunofluorescence staining for endothelial marker (CD34 and CD31) and glial cell marker (glial fibrillary acidic protein [GFAP]) expression. GSCs were then isolated from human glioblastoma tissue and CD133+/Sox2+ red fluorescent protein-containing (RFP)–GSC-1 cells were established. The ability of these cells to form vascular structures was examined by live-cell imaging of 3D cultures. </p> </div><div class="section"> <a class="named-anchor" id="d6740936e185"> <!-- named anchor --> </a> <h5 class="section-title" id="d6740936e186">Results.</h5> <p id="d6740936e188">CD34-GFAP or CD31-GFAP coexpressing glioblastoma-derived endothelial cells (GDEC) were found in 30 of 64 (46.9%) of clinical glioblastoma samples. In those 30 samples, GDEC were found to form vessel structures in 21 (70%) samples. Among 21 samples with GDEC vessels, the CD34+ GDEC vessels and CD31+ GDEC vessels accounted for about 14.16% and 18.08% of total vessels, respectively. In the xenograft samples, CD34+ GDEC were found in 7 out of 10 mice, and 4 out of 7 mice had CD34+ GDEC vessels. CD31+ GDEC were also found in 7 mice, and 4 mice had CD31+ GDEC vessels (10 mice in total). Through live-cell imaging, we observed gradual CD34 expression when cultured with vascular endothelial growth factor in some glioma cells, and a dynamic increase in endothelial marker expression in RFP–GSC-1 in vitro was recorded. Cells expressed CD34 (9.46%) after 6 hours in culture. </p> </div><div class="section"> <a class="named-anchor" id="d6740936e190"> <!-- named anchor --> </a> <h5 class="section-title" id="d6740936e191">Conclusions.</h5> <p id="d6740936e193">The results demonstrated that GSCs may differentiate into endothelial cells and promote angiogenesis in glioblastomas. </p> </div>

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          Most cited references21

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          Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry.

          Tissue sections from aggressive human intraocular (uveal) and metastatic cutaneous melanomas generally lack evidence of significant necrosis and contain patterned networks of interconnected loops of extracellular matrix. The matrix that forms these loops or networks may be solid or hollow. Red blood cells have been detected within the hollow channel components of this patterned matrix histologically, and these vascular channel networks have been detected in human tumors angiographically. Endothelial cells were not identified within these matrix-embedded channels by light microscopy, by transmission electron microscopy, or by using an immunohistochemical panel of endothelial cell markers (Factor VIII-related antigen, Ulex, CD31, CD34, and KDR[Flk-1]). Highly invasive primary and metastatic human melanoma cells formed patterned solid and hollow matrix channels (seen in tissue sections of aggressive primary and metastatic human melanomas) in three-dimensional cultures containing Matrigel or dilute Type I collagen, without endothelial cells or fibroblasts. These tumor cell-generated patterned channels conducted dye, highlighting looping patterns visualized angiographically in human tumors. Neither normal melanocytes nor poorly invasive melanoma cells generated these patterned channels in vitro under identical culture conditions, even after the addition of conditioned medium from metastatic pattern-forming melanoma cells, soluble growth factors, or regimes of hypoxia. Highly invasive and metastatic human melanoma cells, but not poorly invasive melanoma cells, contracted and remodeled floating hydrated gels, providing a biomechanical explanation for the generation of microvessels in vitro. cDNA microarray analysis of highly invasive versus poorly invasive melanoma tumor cells confirmed a genetic reversion to a pluripotent embryonic-like genotype in the highly aggressive melanoma cells. These observations strongly suggest that aggressive melanoma cells may generate vascular channels that facilitate tumor perfusion independent of tumor angiogenesis.
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            Intestinal crypt homeostasis revealed at single stem cell level by in vivo live-imaging

            Summary The rapid turnover of the mammalian intestinal epithelium is supported by stem cells located around the base of the crypt 1 . Alongside Lgr5, intestinal stem cells have been associated with various markers, which are expressed heterogeneously within the crypt base region 1-6 . Previous quantitative clonal fate analyses have proposed that homeostasis occurs as the consequence of neutral competition between dividing stem cells 7-9 . However, the short-term behaviour of individual Lgr5+ cells positioned at different locations within the crypt base compartment has not been resolved. Here, we established the short-term dynamics of intestinal stem cells using a novel approach of continuous intravital imaging of Lgr5-Confetti mice. We find that Lgr5+ cells in the upper part of the niche (termed ‘border cells’) can be passively displaced into the transit-amplifying (TA) domain, following division of proximate cells, implying that determination of stem cell fate can be uncoupled from division. Through the quantitative analysis of individual clonal lineages, we show that stem cells at the crypt base, termed ‘central cells’, experience a survival advantage over border stem cells. However, through the transfer of stem cells between the border and central regions, all Lgr5+ cells are endowed with long-term self-renewal potential. These findings establish a novel paradigm for stem cell maintenance in which a dynamically heterogeneous cell population is able to function long-term as a single stem cell pool.
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              A new alternative mechanism in glioblastoma vascularization: tubular vasculogenic mimicry.

              Glioblastoma is one of the most angiogenic human tumours and endothelial proliferation is a hallmark of the disease. A better understanding of glioblastoma vasculature is needed to optimize anti-angiogenic therapy that has shown a high but transient efficacy. We analysed human glioblastoma tissues and found non-endothelial cell-lined blood vessels that were formed by tumour cells (vasculogenic mimicry of the tubular type). We hypothesized that CD133+ glioblastoma cells presenting stem-cell properties may express pro-vascular molecules allowing them to form blood vessels de novo. We demonstrated in vitro that glioblastoma stem-like cells were capable of vasculogenesis and endothelium-associated genes expression. Moreover, a fraction of these glioblastoma stem-like cells could transdifferentiate into vascular smooth muscle-like cells. We describe here a new mechanism of alternative glioblastoma vascularization and open a new perspective for the antivascular treatment strategy.
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                Author and article information

                Journal
                Neuro-Oncology
                Oxford University Press (OUP)
                1522-8517
                1523-5866
                August 2017
                August 01 2017
                March 08 2017
                August 2017
                August 01 2017
                March 08 2017
                : 19
                : 8
                : 1109-1118
                Affiliations
                [1 ] Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China (X.M., Y.S.C., F.R.C., S.Y.X., Z.P.C.)
                Article
                10.1093/neuonc/nox016
                5570159
                28340100
                d54efe80-4aef-41e9-a7cf-2e7efb328ae7
                © 2017
                History

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