title: Differential Expression of VEGFA Isoforms Regulates Metastasis and Response to Anti-VEGFA Therapy in Sarcoma.
abstract: Elevated plasma concentrations of soluble VEGFA isoforms are associated with poor prognosis in parallel with improved response to treatment with the anti-VEGFA antibody bevacizumab. To uncover the underlying mechanism to these observations, we administered anti-VEGFA therapy to mice bearing luminescent mouse fibrosarcomas expressing single VEGFA isoforms or their wild-type counterparts expressing all isoforms (fs120, fs164, fs188, or fsWT). Expression of the more soluble isoforms conferred an advantage for lung metastasis from subcutaneous tumors (fs120/164 vs. fs188/WT); fs120 cells also produced more lung colonies than fs188 cells when injected intravenously. Metastasis from subcutaneous fs120 tumors was more sensitive than fs188 to treatment with the anti-VEGFA antibody B20-4.1.1. Despite elevated plasma levels of VEGFA in fs120 tumor-bearing mice and a dependence on VEGF receptor 1 activity for metastasis to the lung, B20-4.1.1 did not affect survival in the lung on intravenous injection. B20-4.1.1 inhibited subcutaneous tumor growth and decreased vascular density in both fs120 and fs188 tumors. However, migration of fs120, but not fs188 cells,in vitrowas inhibited by B20-4.1.1. The greater survival of fs120 cells in the lung was associated with VEGFR1-dependent accumulation of CD11b-positive myeloid cells and higher expression of the VEGFR1 ligand, PlGF2, by the fs120 cellsin vitroand in the plasma and lungs of fs120 tumor-bearing mice. We conclude that soluble VEGFA isoform expression increases fibrosarcoma metastasis through multiple mechanisms that vary in their sensitivity to anti-VEGF/VEGFR inhibition, with VEGFA-targeted therapy suppressing metastasis through effects on the primary tumor rather than the metastatic site.Cancer Res; 77(10); 2633-46. ©2017 AACR.
authors.affiliation: Tumor Microcirculation Group, Department of Oncology and Metabolism, University of Sheffield School of Medicine, Beech Hill Road, Sheffield, United Kingdom. w.english@sheffield.ac.uk.
authors.forename: William R
authors.initials: WR
authors.lastname: English
authors.affiliation: Tumor Microcirculation Group, Department of Oncology and Metabolism, University of Sheffield School of Medicine, Beech Hill Road, Sheffield, United Kingdom.
authors.forename: Sarah Jane
authors.initials: SJ
authors.lastname: Lunt
authors.affiliation: Tumor Microcirculation Group, Department of Oncology and Metabolism, University of Sheffield School of Medicine, Beech Hill Road, Sheffield, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Fisher
authors.affiliation: Tumor Microcirculation Group, Department of Oncology and Metabolism, University of Sheffield School of Medicine, Beech Hill Road, Sheffield, United Kingdom.
authors.forename: Diane V
authors.initials: DV
authors.lastname: Lefley
authors.affiliation: Tumor Microcirculation Group, Department of Oncology and Metabolism, University of Sheffield School of Medicine, Beech Hill Road, Sheffield, United Kingdom.
authors.forename: Mohit
authors.initials: M
authors.lastname: Dhingra
authors.affiliation: Tumor Microcirculation Group, Department of Oncology and Metabolism, University of Sheffield School of Medicine, Beech Hill Road, Sheffield, United Kingdom.
authors.forename: Yu-Chin
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Tumor Microcirculation Group, Department of Oncology and Metabolism, University of Sheffield School of Medicine, Beech Hill Road, Sheffield, United Kingdom.
authors.forename: Karina
authors.initials: K
authors.lastname: Bingham
authors.affiliation: Tumor Microcirculation Group, Department of Oncology and Metabolism, University of Sheffield School of Medicine, Beech Hill Road, Sheffield, United Kingdom.
authors.forename: Jack E
authors.initials: JE
authors.lastname: Hurrell
authors.affiliation: CR-UK Cambridge Institute, The Li Ka Shing Building, Cambridge, United Kingdom.
authors.forename: Scott K
authors.initials: SK
authors.lastname: Lyons
authors.affiliation: Tumor Microcirculation Group, Department of Oncology and Metabolism, University of Sheffield School of Medicine, Beech Hill Road, Sheffield, United Kingdom.
authors.forename: Chryso
authors.initials: C
authors.lastname: Kanthou
authors.affiliation: Tumor Microcirculation Group, Department of Oncology and Metabolism, University of Sheffield School of Medicine, Beech Hill Road, Sheffield, United Kingdom.
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Tozer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012509:Sarcoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015415:Biomarkers; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A