15357163mct180548-sup-202229_2_supp_5252121_pkp968.pptx (338.67 kB)

Supplementary Figure 1 from Inhibition of Sphingosine Phosphate Receptor 1 Signaling Enhances the Efficacy of VEGF Receptor Inhibition

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posted on 2023-04-03, 15:02 authored by Anthony S. Fischl, Xiaoen Wang, Beverly L. Falcon, Rowena Almonte-Baldonado, Diane Bodenmiller, Glenn Evans, Julie Stewart, Takako Wilson, Philip Hipskind, Jason Manro, Mark T. Uhlik, Sudhakar Chintharlapalli, Damien Gerald, David C. Alsop, Laura E. Benjamin, Rupal S. Bhatt

Figure S1: Impedance barrier function assay: The effect of S1P and Ex82 was analyzed using a transendothelial electrical impedance assay. S1P treatment (10 nM) of an endothelial monolayer strongly increases electrical impedance (B) vs control (A) whereas Ex82 has the opposite effect and significantly decreases electrical impedance (D). These results are consistent with the known barrier function of S1P1. In addition, pretreatment with Ex82 blocked the S1P dependent increase in electrical impedance (C).

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ARTICLE ABSTRACT

Inhibition of VEGFR signaling is an effective treatment for renal cell carcinoma, but resistance continues to be a major problem. Recently, the sphingosine phosphate (S1P) signaling pathway has been implicated in tumor growth, angiogenesis, and resistance to antiangiogenic therapy. S1P is a bioactive lipid that serves an essential role in developmental and pathologic angiogenesis via activation of the S1P receptor 1 (S1P1). S1P1 signaling counteracts VEGF signaling and is required for vascular stabilization. We used in vivo and in vitro angiogenesis models including a postnatal retinal angiogenesis model and a renal cell carcinoma murine tumor model to test whether simultaneous inhibition of S1P1 and VEGF leads to improved angiogenic inhibition. Here, we show that inhibition of S1P signaling reduces the endothelial cell barrier and leads to excessive angiogenic sprouting. Simultaneous inhibition of S1P and VEGF signaling further disrupts the tumor vascular beds, decreases tumor volume, and increases tumor cell death compared with monotherapies. These studies suggest that inhibition of angiogenesis at two stages of the multistep process may maximize the effects of antiangiogenic therapy. Together, these data suggest that combination of S1P1 and VEGFR-targeted therapy may be a useful therapeutic strategy for the treatment of renal cell carcinoma and other tumor types.