TNFα Accelerates Monocyte to Endothelial Transdifferentiation in Tumors by the Induction of Integrin α5 Expression and Adhesion to Fibronectin
AbstractTumor-associated myeloid cells are believed to promote tumor development by stimulating tumor growth, angiogenesis, invasion, and metastasis. Tumor-associated myeloid cells that coexpress endothelial and myeloid markers represent a proangiogenic subpopulation known as vascular leukocytes. Recently, we and others had shown that tumor-derived TNFα promotes local tumor growth and vascularity. Our data suggested that tumor growth is in part due to TNFα-mediated increased numbers of tumor-associated vascular leukocytes (i.e., myeloid–endothelial biphenotypic cells). The work detailed herein explored the mechanism by which TNFα mediates endothelial differentiation of myeloid cells. Our studies showed that fibronectin is a robust facilitator of endothelial differentiation of blood mononuclear cells in vitro . We have found that TNFα treatment of monocytes significantly increased expression of α 5 β 1 integrin, a major fibronectin receptor enriched on endothelial cells, leading to a consequent fourfold increase in fibronectin adhesion. Furthermore, TNFα-treated monocytes upregulated expression of endothelial markers, flk-1(VEGFR2/KDR) and VE-cadherin. Integrin α 5 subunit inhibitory antibodies blocked adhesion to fibronectin as well as consequent upregulation of flk-1 and VE-cadherin transcripts, implying a role for outside-in signaling by the α 5 β 1 integrin after binding fibronectin. Finally, treatment of mouse tumors with anti-α 5 antibodies reduced accumulation of tumor vascular leukocytes in vivo . Our studies suggest that tumor cell–derived TNFα constitutes a tumor microenvironment signal that promotes differentiation of tumor-associated monocytes toward a proangiogenic/provasculogenic myeloid–endothelial phenotype via upregulation of the fibronectin receptor α 5 β 1 . Mol Cancer Res; 9(6); 702–11. ©2011 AACR . This article is featured in Highlights of This Issue, p. 671 Received November 1, 2010. Revision received March 31, 2011. Accepted April 26, 2011. ©2011 American Association for Cancer Research.