Journal article
Fibroblast Growth Factor Receptor-Dependent and -Independent Paracrine Signaling by Sunitinib-Resistant Renal Cell Carcinoma
Molecular and cellular biology, Vol.36(13), pp.1836-1855
07/01/2016
DOI: 10.1128/MCB.00189-16
PMCID: PMC4911743
PMID: 27141054
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.
Details
- Title: Subtitle
- Fibroblast Growth Factor Receptor-Dependent and -Independent Paracrine Signaling by Sunitinib-Resistant Renal Cell Carcinoma
- Creators
- Tram Anh Tran - The University of Texas Southwestern Medical CenterHon Sing Leong - Translational Prostate Cancer Research Group, London Regional Cancer Program, Cancer Research Laboratory Program, Western University, London, ON, CanadaAndrea Pavia-Jimenez - The University of Texas Southwestern Medical CenterSlavic Fedyshyn - Translational Prostate Cancer Research Group, London Regional Cancer Program, Cancer Research Laboratory Program, Western University, London, ON, CanadaJuan YangBlanka Kucejova - The University of Texas Southwestern Medical CenterSharanya Sivanand - The University of Texas Southwestern Medical CenterPatrick Spence - 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, USAXian-Jin Xie - 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, USASamuel Peña-Llopis - The University of Texas Southwestern Medical CenterNicholas Power - Department of Surgery, Division of Urology, Western University, London, ON, CanadaJames Brugarolas - The University of Texas Southwestern Medical Center
- Resource Type
- Journal article
- Publication Details
- Molecular and cellular biology, Vol.36(13), pp.1836-1855
- Publisher
- United States
- DOI
- 10.1128/MCB.00189-16
- PMID
- 27141054
- PMCID
- PMC4911743
- ISSN
- 0270-7306
- eISSN
- 1098-5549
- Grant note
- R01 CA129387 / NCI NIH HHS T32 CA124334 / NCI NIH HHS P30 CA142543 / NCI NIH HHS
- Language
- English
- Date published
- 07/01/2016
- Academic Unit
- Preventive and Community Dentistry; Biostatistics; Dental Research
- Record Identifier
- 9983917662802771
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