Send to

Choose Destination
See comment in PubMed Commons below
Mol Cancer Res. 2011 Jun;9(6):702-11. doi: 10.1158/1541-7786.MCR-10-0484. Epub 2011 May 2.

TNFalpha accelerates monocyte to endothelial transdifferentiation in tumors by the induction of integrin alpha5 expression and adhesion to fibronectin.

Author information

  • 1Vanderbilt University School of Medicine, Department of Pathology, 1161 21st Avenue South, C2217A MCN, Nashville, TN 37232, USA.


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).

[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk