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Flt-1 Signaling in Macrophages Promotes Glioma Growth In vivo

¹ Tumor Angiogenesis Research Group, Department of Neurosurgery, University of Freiburg, Freiburg, Germany; ² Institute of Neurology, Edinger Institute, University of Frankfurt, Frankfurt, Germany; ³ Department of Medical Physics in Radiology, Junior Group Molecular Imaging, German Cancer Research Center, Heidelberg, Germany; ⁴ Department of Experimental Cardiology, Max-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; ⁵ Department of Cardiology and Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands; and ⁶ Department of Genetics, Institute of Medical Science, University of Tokyo, Tokyo, Japan

Requests for reprints: Marcia Machein, Department of Neurosurgery, Neurocenter, University of Freiburg, Breisacher Straβe 64, 79106 Freiburg, Germany. Phone: 49-761-2705147; Fax: 49-761-2705147; E-mail: Marcia.machein{at}uniklinik-freiburg.de.

Key Words: VEGF • VEGF Receptors • angiogenesis • glioma • macrophages

Several lines of evidence indicate that Flt-1, a fms-like tyrosine kinase receptor, which binds to vascular endothelial growth factor (VEGF)-A, VEGF-B, and PlGF, is a positive regulator of angiogenesis in the context of tumor growth and metastasis. However, the molecular basis of its action is still not clear. Besides endothelial cells, Flt-1 is also expressed by other different cell types, including myeloid hematopoeitic cells (monocytes and macrophages). To examine the functions of Flt-1 expressed by bone marrow–derived myeloid cells in supporting tumor growth and angiogenesis, Flt-1 tyrosine kinase–deficient (Flt-1 TK–/–) bone marrow cells were transplanted into lethally irradiated syngeneic recipients. After hematopoietic reconstitution, we orthotopically implanted syngeneic wild-type glioma cells or glioma cells overexpressing either VEGF₁₆₄ or PlGF-2. Loss of Flt-1 signaling in bone marrow–derived myeloid cells led to a significant decrease in tumor volume and vascularization in gliomas. VEGF but not PlGF overexpressed by glioma cells restored the tumor growth rate in Flt-1 TK–/– bone marrow chimera. VEGF and PlGF overexpression by tumor cells induced an accumulation of bone marrow–derived myeloid cells into tumor tissue. This infiltration was decreased in tumors grown in Flt-1 TK–/– bone marrow chimeras. When investigating chemokines and growth factors involved in myeloid cell recruitment, we determined elevated SDF-1/CXCL12 levels in VEGF- and PlGF-overexpressing tumors. Collectively, these results suggest that Flt-1 signaling in myeloid cells is essential to amplify the angiogenic response and to promote glioma growth. [Cancer Res 2008;68(18):7342–51]

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