Fibroblast Growth Factor 9 Imparts Hierarchy and Vasoreactivity to the Microcirculation of Renal Tumors and Suppresses Metastases.

Abstract

Tumor vessel normalization has been proposed as a therapeutic paradigm. However, normal microvessels are hierarchical and vasoreactive with single file transit of red blood cells through capillaries. Such a network has not been identified in malignant tumors. We tested whether the chaotic tumor microcirculation could be reconfigured by the mesenchyme-selective growth factor, FGF9. Delivery of FGF9 to renal tumors in mice yielded microvessels that were covered by pericytes, smooth muscle cells, and a collagen-fortified basement membrane. This was associated with reduced pulmonary metastases. Intravital microvascular imaging revealed a haphazard web of channels in control tumors but a network of arterioles, bona fide capillaries, and venules in FGF9-expressing tumors. Moreover, whereas vasoreactivity was absent in control tumors, arterioles in FGF9-expressing tumors could constrict and dilate in response to adrenergic and nitric oxide releasing agents, respectively. These changes were accompanied by reduced hypoxia in the tumor core and reduced expression of the angiogenic factor VEGF-A. FGF9 was found to selectively amplify a population of PDGFRβ-positive stromal cells in the tumor and blocking PDGFRβ prevented microvascular differentiation by FGF9 and also worsened metastases. We conclude that harnessing local mesenchymal stromal cells with FGF9 can differentiate the tumor microvasculature to an extent not observed previously.

• Authors: Hao Yin, Matthew J Frontini, John-Michael Arpino, Zengxuan Nong, Caroline O'Neil, Yiwen Xu, Brittany Balint, Aaron D Ward, Subrata Chakrabarti, Christopher G Ellis, Robert Gros, J Geoffrey Pickering
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 36 Pg. 22127-42 (Sep 04 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26183774 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• FGF9 protein, human
• Fibroblast Growth Factor 9
• Vascular Endothelial Growth Factor A
• Receptor, Platelet-Derived Growth Factor beta

Topics

• Animals
• Cell Line
• Cell Line, Tumor
• Cells, Cultured
• Female
• Fibroblast Growth Factor 9 (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Immunoblotting
• Kidney Neoplasms (blood supply, genetics, pathology)
• Lung Neoplasms (genetics, metabolism, secondary)
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Microcirculation
• Receptor, Platelet-Derived Growth Factor beta (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Transgenes (genetics)
• Vascular Endothelial Growth Factor A (genetics, metabolism)