TNFalpha accelerates monocyte to endothelial transdifferentiation in tumors by the induction of integrin alpha5 expression and adhesion to fibronectin.
TNFalpha accelerates monocyte to endothelial transdifferentiation in tumors by the induction of integrin alpha5 expression and adhesion to fibronectin.
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DOI：
10.1158/1541-7786.mcr-10-0484
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发表时间：
2011-06
期刊：
影响因子：
--
通讯作者：
Young PP
中科院分区：
文献类型：
--
作者：
Li B;Pozzi A;Young PP
Tumor associated myeloid cells are believed to promote tumor development by stimulating tumor growth, angiogenesis, invasion and metastasis. Tumor associated myeloid cells that co-express endothelial and myeloid markers represent a pro-angiogenic subpopulation known as vascular leukocytes. Recently, we and others have demonstrated that tumor-derived TNFα promotes local tumor growth and vascularity. Our data suggest that tumor growth is in part due to TNFα-mediated increased numbers of tumor-associated vascular leukocytes (ie 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 α5β1 integrin, a major fibronectin receptor enriched on endothelial cells, leading to a consequent 4-fold increase in fibronectin adhesion. Furthermore, TNFα treated monocytes upregulated expression of endothelial markers, flk-1(VEGFR2/KDR) and VE-cadherin. Integrin α5 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 α5β1 integrin after binding fibronectin. Finally, treatment of mouse tumors with anti-α5 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 towards a proangiogenic/provasculogenic myeloid-endothelial phenotype via upregulation of the fibronectin receptor α5β1.
