Is Sphingosine-1-Phosphate a Regulator of Tumor Vascular Functionality?

SIMPLE SUMMARY: Despite substantial theoretical and experimental support for using vascular normalization as cancer therapy, effectively achieving this strategy in the clinic remains complex. In the present paper, we propose a novel potential approach for the induction of tumor vascular normalization, reduction of hypoxia, and improvement of conventional treatment in cancer patients. This approach consists of the pharmacological modulation of a patient’s plasma S1P levels which through a PDGF signaling can enhance tumor vasculature functionality and reduce hypoxia. This approach is proposed following a clinical observation in pancreatic adenocarcinoma patients and pre-clinical data in different in vivo tumor models, and is supported by a review of the literature describing the biological role of S1P in vascular functionality regulation. ABSTRACT: Increasing evidence indicates that tumor vasculature normalization could be an appropriate strategy to increase therapies’ efficacy in solid tumors by decreasing hypoxia and improving drug delivery. We searched for a novel approach that reduces hypoxia and enhances chemotherapy efficacy in pancreatic adenocarcinoma which is characterized by disrupted blood vasculature associated with poor patient survival. Clinical significance of plasma levels of the angiogenic lipid sphingosine-1-phosphate (S1P) was assessed at baseline in 175 patients. High plasma S1P concentration was found to be a favorable prognostic/predictive marker in advanced/metastatic pancreatic adenocarcinoma patients treated by gemcitabine alone but not in patients receiving a combination gemcitabine and PDGFR-inhibitor. In pancreatic adenocarcinoma PDX models, oral administration of an S1P lyase inhibitor (LX2931) significantly increased plasma S1P levels, decreased tumor expression of the hypoxia marker (CA IX), and enhanced chemotherapy efficacy when combined with gemcitabine treatment. The direct effect of S1P on tumor oxygenation was assessed by administration of S1P onto tumor-grafted CAM model and measuring intra-tumoral pO2 using a tissue oxygen monitor. S1P increased pO2 in a tumor-CAM model. Thus, increasing plasma S1P is a promising strategy to decrease tumor hypoxia and enhance therapy efficacy in solid tumors. S1P may act as a tumor vasculature normalizer.