Endosialin (CD248) is a marker of tumor-associated pericytes in high-grade glioma

Simonavicius, Nicole; Robertson, David; Bax, Dorine A.; Jones, Chris; Huijbers, Ivo J.; Isacke, Clare M.

doi:10.1038/modpathol.3801006

Cited by 105 publications

(115 citation statements)

References 20 publications

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“…According to recent data, endosialin is preferentially associated with pericytes and stromal fibroblasts, but not with endothelial cells, as suggested in earlier studies (MacFadyen et al, 2005;Christian et al, 2008;Simonavicius et al, 2008). Pericytes form an outer sheath around the endothelium and play an important role in maturation of blood microvessels and stabilisation of vascular network, whereas stromal fibroblasts stimulate angiogenesis by trophic effects and extracellular matrix reorganisation (Jain, 2003;Armulik et al, 2005).…”

Section: Discussionmentioning

confidence: 62%

Hypoxia upregulates expression of human endosialin gene via hypoxia-inducible factor 2

et al. 2008

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Endosialin is a transmembrane glycoprotein selectively expressed in blood vessels and stromal fibroblasts of various human tumours. It has been functionally implicated in angiogenesis, but the factors that control its expression have remained unclear. As insufficient delivery of oxygen is a driving force of angiogenesis in growing tumours, we investigated whether hypoxia regulates endosialin expression. Here, we demonstrate that endosialin gene transcription is induced by hypoxia predominantly through a mechanism involving hypoxia-inducible factor-2 (HIF-2) cooperating with the Ets-1 transcription factor. We show that HIF-2 activates the endosialin promoter both directly, through binding to a hypoxia-response element adjacent to an Ets-binding site in the distal part of the upstream regulatory region, and indirectly, through Ets-1 and its two cognate elements in the proximal promoter. Our data also suggest that the SP1 transcription factor mediates responsiveness of the endosialin promoter to high cell density. These findings elucidate important aspects of endosialin gene regulation and provide a rational frame for future investigations towards better understanding of its biological significance.

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Section: Discussionmentioning

confidence: 62%

Hypoxia upregulates expression of human endosialin gene via hypoxia-inducible factor 2

et al. 2008

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“…It is a member of an emerging transmembrane protein family implicated in tissue remodelling and repair, which includes CD141 and CD93 [2,3]. CD248 is expressed on fibroblasts and pericytes during development and in tumour-associated stroma [4][5][6][7]. An important role for CD248 within tumour stroma has been highlighted in CD248-deficient mice; abdominal tumours implanted into mice lacking CD248 demonstrated reduced growth, invasion and metastasis [8].…”

Section: Introductionmentioning

confidence: 99%

The pericyte and stromal cell marker CD248 (endosialin) is required for efficient lymph node expansion

et al. 2010

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CD248 is a cell surface receptor that specifically identifies fibroblasts and pericytes during development and in association with cancer and inflammation. However, its function is poorly defined and its role in lymphoid organs not studied. Here, we used (4-hydroxy-3-nitrophenyl)acetyl chicken c-globulin immunisation and mice lacking CD248 to study whether CD248 modulates popliteal LN (pLN) expansion and subsequent immune responses. We have found that CD248 is required for complete pLN expansion but not for co-ordination of B and T cell compartmentalisation or antibody production following (4-hydroxy-3-nitrophenyl)acetyl chicken c-globulin immunisation. In vitro, we show that CD248 expression in human MG63 stromal cells and mouse embryonic fibroblasts leads to a pro-proliferative and pro-migratory phenotype. This correlates with a proliferating CD248 1 population observed in vivo during pLN expansion. Taken together, these data highlight a role for CD248 in secondary lymphoid organ remodelling during adaptive immune responses.Key words: CD248 . Endosialin . Fibroblast . Lymphoid tissue . Stromal cells IntroductionDuring an immune response, secondary lymphoid organs (SLO) expand significantly. However, mechanisms that regulate this have been relatively understudied with leucocyte accumulation rather than stromal cell expansion being the focus. Logic dictates that there has to be co-ordinated expansion of tissue structure to accommodate the rapidly expanding leucocyte populations. This expansion includes not only an intricate network of fibroblasts that provide an important structural scaffold but also the formation of new blood and lymph vessels to oxygenate and allow transport of lymphocytes into and out of the organ [1].CD248/endosialin is a relatively new marker for a subset of stromal cells in developing tissues. It is a member of an emerging transmembrane protein family implicated in tissue remodelling and repair, which includes CD141 and CD93 [2,3] 1884expressed on fibroblasts and pericytes during development and in tumour-associated stroma [4][5][6][7]. An important role for CD248 within tumour stroma has been highlighted in CD248-deficient mice; abdominal tumours implanted into mice lacking CD248 demonstrated reduced growth, invasion and metastasis [8]. This, coupled with the finding that CD248 expression is regulated by hypoxia inducible factor-2a [9], suggests that CD248 may provide an important link between hypoxia and tissue remodelling allowing synchronisation of these processes.We have previously proposed a role for CD248 in development and infection-dependent activation of SLO stroma [10]. Whether CD248 is required for tissue remodelling was not explored nor was its function. Therefore, to more fully understand the requirements for CD248 during remodelling, we compared the degree of popliteal LN (pLN) expansion in WT and CD248 KO mice following immunisation with (4-hydroxy-3-nitrophenyl)acetyl chicken g-globulin (NP-CGG). The ability of CD248 to regulate cell migration and proliferation in vitro w...

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“…Therefore, in addition to the developmental plasticity inherent to glioma cells as a property that accounts for substantial changes in differentiation, the fusogenicity of glioma cells should also be considered as a significant factor that, in the interactions with other cells, elicits tumor cell phenotypic changes. In advanced stages of malignancy, gliomas display a great deal of supportive tissue throughout the tumor mass, composing a vascular network with endothelial cells, pericytes, and, in a lesser extent, fibroblasts, 14,30 separated by extracellular stroma from the transformed cells. Although many cell lines established from high-grade gliomas, including U87MG, exhibit mesenchymal characteristics, it is significant that the recombination with fibroblasts reinforced the migratory capacity of the cells.…”

Section: Discussionmentioning

confidence: 99%

The intrinsic fusogenicity of glioma cells as a factor of transformation and progression in the tumor microenvironment

Mercapide¹,

Rappa²,

Lorico

2011

Intl Journal of Cancer

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We have previously reported in vitro heterotypic fusion of glioma cells with neural progenitor cells, producing tetraploid cells expressing genetic complements of each partner. Herein, we investigated the fusogenicity of glioma cells. In 1:1 cocultures of single-labeled cells, U87MG cells presented high frequency of homotypic fusogenic events, producing cells that coexpressed both fluorescent proteins. Six percent of the total cells had 8n DNA content, consistent with the finding that the doublelabeled cells were actively proliferating. In coculture with fibroblasts, glioma cell fusogenicity resulted in viable reprogrammed cells, thus emerging as a plausible source of tumor cell heterogeneity. As for heterotypic fusion to happen, glioma cells have to establish direct contact with other cells, the effect of stroma on glioma cells was analyzed. Proliferation assays and array analysis of cancer-related pathways established a promalignant effect of stroma. This effect was mediated by fibronectin and was nearly completely abolished by inhibitors of the epidermal-growth-factor receptor. That stroma elicited transduction signaling through the mitogen-activated-protein kinase/extracellular-signal-regulated kinase pathway, which is linked to increased tumor cell migration through extracellular matrix, suggested that glioma cells may actively approach nontumor cells in stromal niches. According to these results, the fusogenicity of glioma cells emerged as an inherent factor for phenotypic changes leading to glioma progression.

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Endosialin (CD248) is a marker of tumor-associated pericytes in high-grade glioma

Cited by 105 publications

References 20 publications

Hypoxia upregulates expression of human endosialin gene via hypoxia-inducible factor 2

Hypoxia upregulates expression of human endosialin gene via hypoxia-inducible factor 2

The pericyte and stromal cell marker CD248 (endosialin) is required for efficient lymph node expansion

The intrinsic fusogenicity of glioma cells as a factor of transformation and progression in the tumor microenvironment

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