title: TNFalpha accelerates monocyte to endothelial transdifferentiation in tumors by the induction of integrin alpha5 expression and adhesion to fibronectin.
abstract: Tumor-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).
authors.affiliation: Vanderbilt University School of Medicine, Department of Pathology, 1161 21st Avenue South, C2217A MCN, Nashville, TN 37232, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
authors.forename: Pampee P
authors.initials: PP
authors.lastname: Young
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D004727:Endothelium / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D005353:Fibronectins; D039081:Integrin alpha5beta1; D014409:Tumor Necrosis Factor-alpha; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5