Mesenchymal Stromal Cells Promote Tumor Growth through the Enhancement of Neovascularization

Kazuhiro Suzuki,Ruowen Sun,Masahiko Kanehira,Hiroshi Kijima,Akihiro Umezawa,Makoto Origuchi,Shinsaku Fukuda,Yasuo Saijo,Jugoh Itoh,Takenori Takahata

doi:10.2119/molmed.2010.00157

Abstract

Mesenchymal stromal cells (MSCs), also called mesenchymal stem cells, migrate and function as stromal cells in tumor tissues. The effects of MSCs on tumor growth are controversial. In this study, we showed that MSCs increase proliferation of tumor cells in vitro and promote tumor growth in vivo. We also further analyzed the mechanisms that underlie these effects. For use in in vitro and in vivo experiments, we established a bone marrow-derived mesenchymal stromal cell line from cells isolated in C57BL/6 mice. Effects of murine MSCs on tumor cell proliferation in vitro were analyzed in a coculture model with B16-LacZ cells. Both coculture with MSCs and treatment with MSC-conditioned media led to enhanced growth of B16-LacZ cells, although the magnitude of growth stimulation in cocultured cells was greater than that of cells treated with conditioned media. Co-injection of B16-LacZ cells and MSCs into syngeneic mice led to increased tumor size compared with injection of B16-LacZ cells alone. Identical experiments using Lewis lung carcinoma (LLC) cells instead of B16-LacZ cells yielded similar results. Consistent with a role for neovascularization in MSC-mediated tumor growth, tumor vessel area was greater in tumors resulting from co-injection of B16-LacZ cells or LLCs with MSCs than in tumors induced by injection of cancer cells alone. Co-injected MSCs directly supported the tumor vasculature by localizing close to vascular walls and by expressing an endothelial marker. Furthermore, secretion of leukemia inhibitory factor, macrophage colony-stimulating factor, macrophage inflammatory protein-2 and vascular endothelial growth factor was increased in cocultures of MSCs and B16-LacZ cells compared with B16-LacZ cells alone. Together, these results indicate that MSCs promote tumor growth both in vitro and in vivo and suggest that tumor promotion in vivo may be attributable in part to enhanced angiogenesis.

Highlights

Growth of solid tumors requires formation of the tumor stroma, which supplies oxygen and nutrients to tumor cells [1]
Mouse bone marrow–derived Mesenchymal stromal cells (MSCs) cultures were established from bone marrow cells isolated in C57BL/6 mice
Combined administration of MSCs and tumor cells (B16-LacZ cells or Lewis lung carcinoma (LLC)) promoted tumor growth by enhancing angiogenesis in syngeneic tumor models. This enhanced neovascularization can likely be attributed to direct support of neovascularization by MSCs and to secretion of angiogenic factors, including vascular endothelial growth factor (VEGF) and others, by MSCs

Summary

Introduction

Growth of solid tumors requires formation of the tumor stroma, which supplies oxygen and nutrients to tumor cells [1]. The tumor stroma is composed of extracellular matrix and various mesenchymal cell types, including macrophages, endothelial cells, lymphocytes, pericytes, fibroblasts and myofibroblasts [2]. These stromal cells communicate with tumor cells both through direct contact and through paracrine signaling mechanisms, mediated by secretion of soluble factors, including cytokines, chemokines and growth factors [3,4,5,6,7]. Tumor-associated fibroblasts have been shown to be associated with increases in tumor growth and metastatic potential, leading to a poor prognosis [8,9]. Data from human tumors and mouse tumor models suggest that at least a portion of the stromal cells are derived from the bone marrow [11,12,13]

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Results

Conclusion