Modulating sphingosine‐1‐phosphate receptors to improve chemotherapy efficacy against Ewing sarcoma

• Published in: International journal of cancer Vol. 147; no. 4; pp. 1206 - 1214
• Main Authors: Marmonti, Enrica, Savage, Hannah, Zhang, Aiqian, Bedoya, Claudia A.F., Morrell, Miriam G., Harden, Avis, Buzbee, Meridith, Schadler, Keri
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 15-08-2020; Wiley Subscription Services, Inc
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; Antitumor activity; Bone Neoplasms - drug therapy; Bone Neoplasms - metabolism; Cancer; Capillary Permeability - drug effects; Cell Line, Tumor; Chemotherapy; chemotherapy efficacy; Doxorubicin - pharmacology; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Ewing sarcoma; Ewing's sarcoma; Ewings sarcoma; Humans; Medical research; Mice, Nude; Oxadiazoles - pharmacology; Permeability; Phenotypes; Pyrazoles - pharmacology; Pyridines - pharmacology; S1PR1; S1PR2; Sarcoma; Sarcoma, Ewing - drug therapy; Sarcoma, Ewing - metabolism; Sphingosine 1 Phosphate Receptor Modulators - pharmacology; Sphingosine-1-Phosphate Receptors - antagonists & inhibitors; Sphingosine-1-Phosphate Receptors - metabolism; Thiophenes - pharmacology; Treatment Outcome; Tumor cells; vascular permeability; Xenograft Model Antitumor Assays - methods; chemotherapy efficacy; S1PR1; Ewing sarcoma; S1PR2; vascular permeability
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32862

Tumor vasculature is innately dysfunctional. Poorly functional tumor vessels inefficiently deliver chemotherapy to tumor cells; vessel hyper‐permeability promotes chemotherapy delivery primarily to a tumor's periphery. Here, we identify a method for enhancing chemotherapy efficacy in Ewing sarcoma (ES) in mice by modulating tumor vessel permeability. Vessel permeability is partially controlled by the G protein‐coupled Sphinosine‐1‐phosphate receptors 1 and 2 (S1PR1 and S1PR2) on endothelial cells. S1PR1 promotes endothelial cell junction integrity while S1PR2 destabilizes it. We hypothesize that an imbalance of S1PR1:S1PR2 is partially responsible for the dysfunctional vascular phenotype characteristic of ES and that by altering the balance in favor of S1PR1, ES vessel hyper‐permeability can be reversed. In our study, we demonstrate that pharmacologic activation of S1PR1 by SEW2871 or inhibition of S1PR2 by JTE‐013 caused more organized, mature and functional tumor vessels. Importantly, S1PR1 activation or S1PR2 inhibition improved antitumor efficacy. Our data suggests that pharmacologic targeting of S1PR1 and S1PR2 may be a useful adjuvant to standard chemotherapy for ES patients.
What's new?
The inherently dysfunctional nature of tumor vasculature complicates the delivery of therapeutic agents to tumors, potentially undermining treatment efforts. Here, focusing of Ewing sarcoma (ES), the authors identify receptors for sphingosine‐1‐phosphate (S1P), a sphingolipid involved in regulating endothelial function, as novel targets for tumor vasculature remodeling and adjuvant therapy. In ES mouse models, S1P receptor 1 (S1PR1) activation promoted tumor vasculature normalization, marked by more elongated vessels with open lumens and layered with mural cells. Meanwhile, inhibition of S1PR2 slightly increased microvessel density and decreased vascular hyperpermeability. S1PR1 activation or S1PR2 inhibition further increased chemotherapeutic delivery, thereby improving therapeutic efficacy.