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: Bin Li, Ambra Pozzi, Pampee P Young
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 9 Issue 6 Pg. 702-11 (Jun 2011) ISSN: 1557-3125 [Electronic] United States
• PMID: 21536688 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antigens, CD
• Cadherins
• Fibronectins
• Integrin alpha5beta1
• Tumor Necrosis Factor-alpha
• cadherin 5
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Animals
• Antigens, CD (genetics, metabolism)
• Cadherins (genetics, metabolism)
• Cell Adhesion
• Cell Transdifferentiation
• Cells, Cultured
• Endothelium (pathology)
• Fibronectins (metabolism)
• Gene Expression Profiling
• Humans
• Integrin alpha5beta1 (metabolism)
• Leukocytes, Mononuclear (metabolism)
• Mice
• Mice, Inbred C57BL
• Monocytes (metabolism)
• Myeloid Cells (metabolism)
• Neoplasms (blood supply, metabolism, pathology)
• Neovascularization, Pathologic (metabolism)
• Tumor Necrosis Factor-alpha (genetics, metabolism)
• Up-Regulation
• Vascular Endothelial Growth Factor Receptor-2 (genetics, metabolism)