Endosialin (Tem1) Is a Marker of Tumor-Associated Myofibroblasts and Tumor Vessel-Associated Mural Cells

Abstract

Tumor progression and metastasis are critically dependent on the tumor stroma consisting of fibrous connective tissue, newly formed blood vessels, extracellular matrix, and recruited inflammatory cells. Tumor stromal fibroblasts (activated fibroblasts or myofibroblasts) acquire a specific phenotype that differentiates them from normal resting fibroblasts. They express smooth muscle actin (SMA), and isolated myofibroblasts have higher proliferation rates than their normal counterparts.1 The importance of stromal mesenchymal interactions with adjacent epithelial cells during development is well characterized. Proliferation of mesenchymal cells is tightly controlled by soluble paracrine factors. Conversely, differentiated fibroblasts do not proliferate and acquire a quiescent phenotype.2 In contrast, the complex paracrine regulatory mechanisms between the mesenchymal tumor stroma compartment and the tumor compartment are far from being understood. Coinjection of activated fibroblasts and tumor cells has been shown to enhance the invasiveness of colon tumors.3 Tumor-associated fibroblasts affect migration and invasion of tumor cells by secreting extracellular matrix proteins, matrix metalloproteinases, and growth factors.4,5 Paracrine-acting factors affecting tumor and stromal cell interactions include fibroblast growth factors, hepatocyte growth factor, and transforming growth factor-␤. Correspondingly, elevated plasma levels of transforming growth factor-␤ have been shown to predict early metastasis.

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

“…Thus, the presence of CD248 within cells leads to an increase in proliferation, which interestingly was more pronounced at higher cell densities. These data are consistent with the previous in vitro studies which suggested a role for human CD248 in regulating proliferation, migration and adhesion to fibronectin, as well as sensing an increase in cell density [7,18].…”

“…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].…”

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

“…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).…”

Shikonin-loaded antibody-armed nanoparticles for targeted therapy of ovarian cancer

“…Thus, to exploit both passive and active targeting potentials, we engineered SHK-loaded PEGylated PLGA NPs decorated with anti-TEM1 Ab/scFv. TEM1 has been reported to be expressed by the endothelial cells of ovarian tumor vasculature 25,[44][45][46][47] and other malignancies such as brain and abdominal tumors. 48,49 Based on the release profile, less than 20% of drug can be released within 2 hours, during which the engineered NPs can safely pass the blood stream and reach the target site with negligible inadvertent detrimental impacts on blood-circulating immune system cells.…”