Abstract C250: The pericyte as a novel stromal element and therapeutic target in sarcoma

Abstract

Abstract Background: Mesenchymal Stem Cells (MSCs) have been proposed as the cell of origin of sarcoma. In soft tissues, the microvascular pericyte has been recently shown to have MSC properties (Crisan et al, Cell Stem Cell 3:301). We have previously reported the isolation of benign mesenchymal cultures from sarcoma surgical samples. These cells have the immunophenotype (CD45-CD31- CD73+CD105+CD90+) and in vitro differentiation potential characteristic of MSCs. We hypothesized that these sarcoma-associated MSCs (SA-MSCs) are derived from pericytes associated with the sarcoma vasculature. Methods: We examined whether benign SA-MSCs have surface markers characteristic of pericytes and cooperate with endothelial cells in tube formation assays. We also examined expression of CD146, a pericyte marker, and CD105, an MSC marker, in sarcoma archived tissue by IHC. Results: Benign SA-MSCs indeed demonstrated properties of pericytes, such as characteristic cytoplasmic projections at low density, surface expression of pericyte markers (CD146, PDGFR-beta, NG2 and endosialin) and cooperation with endothelial cells in tube formation assays in matrigel. To demonstrate the existence of pericytes in sarcoma archived tissue, we used CD146 that has been shown to be restricted to the vasculature in sarcoma, but thought to be an endothelial marker (Shih et al, CCR 2:569). We demonstrate for the first time the existence of CD146+ pericytes in diverse sarcoma subtypes. In addition, we examined sarcoma archived material for expression of CD105 (endoglin), an MSC marker and a known tumor-specific endothelial marker in carcinoma. We found that CD105 was expressed in sarcoma endothelium similarly to its expression on carcinoma endothelium. In addition, by three-color immunofluorescence, CD105 was expressed in a subset of sarcoma pericytes. It was not expressed in normal surrounding tissues. Conclusion: We show that SA-MSC cultures have properties of pericytes. Using a novel combination of markers we demonstrate that pericytes are abundant in sarcoma. Being in contact with both the endothelial cells and the malignant sarcoma cells, pericytes represent a novel stromal element in sarcoma and a potential therapeutic target. Based on these findings we are evaluating endosialin (CD248) and CD105 antibodies, both of which are in clinical development, for effectiveness in preclinical models of sarcoma. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C250.