Identification of endosialin, a cell surface glycoprotein of vascular endothelial cells in human cancer.

Abstract

Cell surface antigens of transformed cells are the traditional targets for antibody-guided detection and therapy of solid neoplasms. Alternative targets may be found in the tumor stroma, which contains newly formed blood vessels, reactive fibroblasts, and extracellular matrix proteins. The F19 cell surface glycoprotein of reactive fibroblasts is a prototypic stromal antigen since it is found in the stroma of >90% of common epithelial cancers but is absent or expressed at low levels in normal tissues and benign epithelial tumors. In the present study, we define an additional tumor stromal antigen, FB5, that is selectively expressed in vascular endothelial cells of malignant tumors. Immunohistochemical analysis of 128 tumors identified FB5 in endothelial cells in 67% of the samples (including 41 of 61 sarcomas, 26 of 37 carcinomas, and 18 of 25 neuroectodermal tumors) whereas normal blood vessels and other adult tissues tested lacked FB5 expression. In vitro studies showed that FB5 is a Mr 165,000 cell surface glycoprotein, comprised of a Mr 95,000 core polypeptide and highly sialylated 0-linked oligosaccharides but few if any N-linked sugars, and that the FB5 gene is located on chromosome llql3-qter. The restricted tissue distribution of the FB5 protein, which we refer to as endosialin, suggests strategies for tumor imaging and therapy that are aimed primarily at the tumor vasculature.

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

“…7 In cultured cells, expression of endosialin has only been reported on fibroblasts and some neuroblastoma cell lines. [6][7][8][9] This pattern is reflected in normal adult tissue, where endosialin expression is predominantly restricted to stromal fibroblasts, and in agreement with the SAGE analysis of St Croix et al 5 little or no endosialin is detected in the mature, normal vasculature. [9][10][11][12][13] In contrast, there is a marked upregulation of endosialin expression in the angiogenic vasculature of a wide variety of different tumor types including those of the brain, colon, breast and in tumor xenografts.…”

“…Endosialin was first identified as the epitope for monoclonal antibody FB5 6 and staining with this antibody revealed an upregulation of endosialin expression in the vasculature of a variety of human tumors. Despite reporting that this represented expression on the endothelial cells, the cell type distribution was not validated by double labeling with endothelial markers.…”

“…5 Endosialin is a type 1 transmembrane glycoprotein originally identified as the target of the FB5 monoclonal antibody. 6 The domain structure of endosialin, with a C-type lectin-like domain, a sushi domain, three epidermal growth factor repeats and a serine/threonine rich mucin-like stalk has placed it in a family of proteins together with CD93 (the complement receptor C1qRp) and CD141 (thrombomodulin). 7 In cultured cells, expression of endosialin has only been reported on fibroblasts and some neuroblastoma cell lines.…”

“…[9][10][11][12][13] In contrast, there is a marked upregulation of endosialin expression in the angiogenic vasculature of a wide variety of different tumor types including those of the brain, colon, breast and in tumor xenografts. 6,9,11,12,14,15 However, there is controversy between these reports as to whether this upregulation is due to expression by the endothelial cells and/or the perivascular cells. Two major difficulties have arisen in resolving this controversy.…”

Characteristics of human Ewing/PNET sarcoma models

“…Endosialin/CD248/TEM-1 was first identified in 1992 as the antigen of an antibody designated FB5 that was raised in mice inoculated with human fetal fibroblasts 495051. In tissues, FB5 reacted strongly with vascular cells in 67% of malignant tumor specimens and more weakly with stromal fibroblasts in a subset of specimens.…”