title: Fibroblast Growth Factor Receptor-Dependent and -Independent Paracrine Signaling by Sunitinib-Resistant Renal Cell Carcinoma.
abstract: Antiangiogenic therapies, such as sunitinib, have revolutionized renal cell carcinoma (RCC) treatment. However, a precarious understanding of how resistance emerges and a lack of tractable experimental systems hinder progress. We evaluated the potential of primary RCC cultures (derived from tumors and tumor grafts) to signal to endothelial cells (EC) and fibroblasts in vitro and to stimulate angiogenesis ex vivo in chorioallantoic membrane (CAM) assays. From 65 patients, 27 primary cultures, including several from patients with sunitinib-resistant RCC, were established. RCC cells supported EC survival in coculture assays and induced angiogenesis in CAM assays. RCC-induced EC survival was sensitive to sunitinib in half of the tumors and was refractory in tumors from resistant patients. Sunitinib sensitivity correlated with vascular endothelial growth factor (VEGF) production. RCC induced paracrine extracellular signal-regulated kinase (ERK) activation in EC which was inhibited by sunitinib in sensitive but not in resistant tumors. As determined by fibroblast growth factor receptor substrate 2 (FRS2) phosphorylation in fibroblasts, RCC broadly induced low-level fibroblast growth factor receptor (FGFR) signaling. Whereas ERK activation in EC was uniformly inhibited by combined VEGF/platelet-derived growth factor (PDGF)/FGF receptor inhibitors, paracrine ERK activation in fibroblasts was blocked in only a fraction of tumors. Our data show that RCC activates EC through VEGF-dependent and -independent pathways, that sunitinib sensitivity correlates with VEGF-mediated ERK activation, and that combined inhibition of VEGF/PDGF/FGF receptors is sufficient to inhibit mitogenic signaling in EC but not in fibroblasts.
authors.affiliation: Kidney Cancer Program, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA Department of Internal Medicine, Oncology Division, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Tram Anh
authors.initials: TA
authors.lastname: Tran
authors.affiliation: Translational Prostate Cancer Research Group, London Regional Cancer Program, Cancer Research Laboratory Program, Western University, London, ON, Canada.
authors.forename: Hon Sing
authors.initials: HS
authors.lastname: Leong
authors.affiliation: Kidney Cancer Program, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA Department of Internal Medicine, Oncology Division, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pavia-Jimenez
authors.affiliation: Translational Prostate Cancer Research Group, London Regional Cancer Program, Cancer Research Laboratory Program, Western University, London, ON, Canada.
authors.forename: Slavic
authors.initials: S
authors.lastname: Fedyshyn
authors.affiliation: Kidney Cancer Program, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA Department of Internal Medicine, Oncology Division, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Yang
authors.affiliation: Kidney Cancer Program, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA Department of Internal Medicine, Oncology Division, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Blanka
authors.initials: B
authors.lastname: Kucejova
authors.affiliation: Kidney Cancer Program, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA Department of Internal Medicine, Oncology Division, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Sharanya
authors.initials: S
authors.lastname: Sivanand
authors.affiliation: Kidney Cancer Program, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA Department of Internal Medicine, Oncology Division, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Spence
authors.affiliation: Kidney Cancer Program, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Xian-Jin
authors.initials: XJ
authors.lastname: Xie
authors.affiliation: Kidney Cancer Program, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA Department of Internal Medicine, Oncology Division, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Peña-Llopis
authors.affiliation: Department of Surgery, Division of Urology, Western University, London, ON, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Power
authors.affiliation: Kidney Cancer Program, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA Department of Internal Medicine, Oncology Division, University of Texas Southwestern Medical Center, Dallas, Texas, USA James.Brugarolas@utsouthwestern.edu.
authors.forename: James
authors.initials: J
authors.lastname: Brugarolas
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D019899:Paracrine Communication / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D000077210:Sunitinib; D014407:Tumor Cells, Cultured
chemical_list: D007211:Indoles; D011758:Pyrroles; D017468:Receptors, Fibroblast Growth Factor; D000077210:Sunitinib