title: 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.affiliation: From the Robarts Research Institute and.
authors.forename: Hao
authors.initials: H
authors.lastname: Yin
authors.affiliation: From the Robarts Research Institute and Departments of Biochemistry.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Frontini
authors.affiliation: From the Robarts Research Institute and Medical Biophysics.
authors.forename: John-Michael
authors.initials: JM
authors.lastname: Arpino
authors.affiliation: From the Robarts Research Institute and.
authors.forename: Zengxuan
authors.initials: Z
authors.lastname: Nong
authors.affiliation: From the Robarts Research Institute and.
authors.forename: Caroline
authors.initials: C
authors.lastname: O'Neil
authors.affiliation: From the Robarts Research Institute and Medical Biophysics.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Xu
authors.affiliation: From the Robarts Research Institute and Medical Biophysics.
authors.forename: Brittany
authors.initials: B
authors.lastname: Balint
authors.affiliation: Medical Biophysics.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Ward
authors.affiliation: Pathology.
authors.forename: Subrata
authors.initials: S
authors.lastname: Chakrabarti
authors.affiliation: Medical Biophysics.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Ellis
authors.affiliation: From the Robarts Research Institute and Physiology and Pharmacology, and Medicine, University of Western Ontario.
authors.forename: Robert
authors.initials: R
authors.lastname: Gros
authors.affiliation: From the Robarts Research Institute and Departments of Biochemistry, Medical Biophysics, Medicine, University of Western Ontario, London Health Sciences Centre, London, Ontario N6A 5A5, Canada gpickering@robarts.ca.
authors.forename: J Geoffrey
authors.initials: JG
authors.lastname: Pickering
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007680:Kidney Neoplasms / Q000098:blood supply* / Q000235:genetics* / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C496459:FGF9 protein, human; D051525:Fibroblast Growth Factor 9; D042461:Vascular Endothelial Growth Factor A; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: angiogenesis; fibroblast growth factor (FGF); hypoxia; metastasis; microvascular flow; tumor microenvironment; vascular biology; vasoreactivity