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 hinders progress. We evaluated the potential of primary RCC cultures (derived from tumors and tumorgrafts) to signal to endothelial cells (and fibroblasts) in vitro and to stimulate angiogenesis ex vivo in chorioallantoic membrane (CAM) assays. From 65 patients, 27 primary cultures were established including several from patients with sunitinib-resistant RCC. RCC cultures supported endothelial cell (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 VEGF production. RCC caused paracrine ERK activation in EC which was inhibited by sunitinib in sensitive, but not resistant tumors. As determined by FRS2 phosphorylation in fibroblasts, RCC broadly induced low level FGFR signaling. Whereas ERK activation in EC was uniformly inhibited by combined VEGF/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.
Pharmacology, Toxicology and Pharmaceutical Science
1
3%
Other
1
3%
Unknown
14
39%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 04 May 2016.
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#31,219,024
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#13,859
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#406,341
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