Docetaxel causes lymphatic endothelial cell apoptosis and impairs lymphatic function and gene expression in vitro

Abstract

Introduction: Recent studies have shown that taxanes — chemotherapeutic agents commonly used for breast cancer treatment—may increase the risk of lymphedema development in breast cancer survivors. The purpose of this study was to analyze the effects of docetaxel on lymphatic endothelial cells (LEC) and define the cellular mechanisms that may account for this clinical relationship. Methods: Human dermal LECs were cultured in vitro with varying concentrations of docetaxel and LEC viability, proliferation, migration, tubule formation and lymphatic gene expression were analyzed. Results: Docetaxel, at a concentration of 100 µM, was cytotoxic to LECs resulting in impaired proliferation. At the lower concentrations (1 and 10 µM), docetaxel impaired LEC function by decreasing LEC migration and tubule formation. The expression of lymphatic markers podoplanin, LYVE1 and FLT4, but not PROX-1 were down-regulated in LECs following high concentration of docetaxel treatment (100 µM). Conclusion: High concentration of docetaxel induces LEC death and impair LEC proliferation and lymphatic gene expression. In contrast, low concentration of docetaxel significantly impairs LEC migration and tubule formation. These adverse effects of docetaxel may therefore provide a cellular mechanism underlying the clinical observation that taxane therapy increases the risk of lymphedema development in cancer patients.