Tunneling nanotube formation is stimulated by hypoxia in ovarian cancer cells

// Snider Desir 1, 2, * , Elizabeth L. Dickson 3, * , Rachel I. Vogel 4 , Venugopal Thayanithy 2 , Phillip Wong 2 , Deanna Teoh 3 , Melissa A. Geller 3 , Clifford J. Steer 5 , Subbaya Subramanian 6 , Emil Lou 1, 2 1 Integrative Biology and Physiology Program, University of Minnesota, Minneapolis, MN, USA 2 Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA 3 Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Minnesota, Minneapolis, MN, USA 4 Biostatistics and Bioinformatics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA 5 Departments of Medicine and Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA 6 Department of Surgery, Division of Basic Science and Translational Research, University of Minnesota, Minneapolis, MN, USA * These authors contributed equally to this work and are co-first authors Correspondence to: Emil Lou, email: emil-lou@umn.edu Keywords: tunneling nanotubes, intercellular communication, hypoxia, chemoresistance, mTOR Received: November 04, 2015      Accepted: April 24, 2016      Published: May 20, 2016 ABSTRACT In this study, we demonstrated that hypoxic conditions stimulated an increase in tunneling nanotube (TNT) formation in chemoresistant ovarian cancer cells (SKOV3, C200).We found that suppressing the mTOR pathway using either everolimus or metformin led to suppression of TNT formation in vitro , verifying TNTs as a potential target for cancer-directed therapy. Additionally, TNT formation was detected in co-cultures including between platinum-resistant SKOV3 cells, between SKOV3 cells and platinum-chemosensitive A2780 cells, and between SKOV3 cells cultured with benign ovarian epithelial (IOSE) cells; these findings indicate that TNTs are novel conduits for malignant cell interactions and tumor cell interactions with other cells in the microenvironment. When chemoresistant C200 and parent chemosensitive A2780 cells were co-cultured, chemoresistant cells displayed a higher likelihood of TNT formation to each other than to chemosensitive malignant or benign epithelial cells. Hypoxia-induced TNT formation represents a potential mechanism for intercellular communication in ovarian cancer and other forms of invasive refractory cancers.