Fibroblast growth factor receptor-dependent and -independent paracrine signaling by sunitinib-resistant renal cell carcinoma

Tram Anh Tran, Hon Sing Leong, Andrea Pavia-Jimenez, Slavic Fedyshyn, Juan Yang, Blanka Kucejova, Sharanya Sivanand, Patrick Spence, Xian Jin Xie, Samuel Peña-Llopis, Nicholas Power, James Brugarolas

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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.

Original languageEnglish (US)
Pages (from-to)1836-1855
Number of pages20
JournalMolecular and Cellular Biology
Volume36
Issue number13
DOIs
StatePublished - 2016

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Paracrine Communication
Fibroblast Growth Factor Receptors
Renal Cell Carcinoma
Endothelial Cells
Vascular Endothelial Growth Factor A
Extracellular Signal-Regulated MAP Kinases
Fibroblasts
Chorioallantoic Membrane
Platelet-Derived Growth Factor Receptors
Neoplasms
Cell Survival
Receptor, Fibroblast Growth Factor, Type 2
sunitinib
Coculture Techniques
Cell Culture Techniques
Phosphorylation
Transplants

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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Fibroblast growth factor receptor-dependent and -independent paracrine signaling by sunitinib-resistant renal cell carcinoma. / Tran, Tram Anh; Leong, Hon Sing; Pavia-Jimenez, Andrea; Fedyshyn, Slavic; Yang, Juan; Kucejova, Blanka; Sivanand, Sharanya; Spence, Patrick; Xie, Xian Jin; Peña-Llopis, Samuel; Power, Nicholas; Brugarolas, James.

In: Molecular and Cellular Biology, Vol. 36, No. 13, 2016, p. 1836-1855.

Research output: Contribution to journalArticle

Tran, TA, Leong, HS, Pavia-Jimenez, A, Fedyshyn, S, Yang, J, Kucejova, B, Sivanand, S, Spence, P, Xie, XJ, Peña-Llopis, S, Power, N & Brugarolas, J 2016, 'Fibroblast growth factor receptor-dependent and -independent paracrine signaling by sunitinib-resistant renal cell carcinoma', Molecular and Cellular Biology, vol. 36, no. 13, pp. 1836-1855. https://doi.org/10.1128/MCB.00189-16
Tran, Tram Anh ; Leong, Hon Sing ; Pavia-Jimenez, Andrea ; Fedyshyn, Slavic ; Yang, Juan ; Kucejova, Blanka ; Sivanand, Sharanya ; Spence, Patrick ; Xie, Xian Jin ; Peña-Llopis, Samuel ; Power, Nicholas ; Brugarolas, James. / Fibroblast growth factor receptor-dependent and -independent paracrine signaling by sunitinib-resistant renal cell carcinoma. In: Molecular and Cellular Biology. 2016 ; Vol. 36, No. 13. pp. 1836-1855.
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AU - Yang, Juan

AU - Kucejova, Blanka

AU - Sivanand, Sharanya

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AU - Peña-Llopis, Samuel

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AU - Brugarolas, James

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