Intercellular communication plays a critical role in the ever-evolving landscape of invasive cancers. Recent studies have elucidated the potential role of tunneling nanotubes (TNTs) in this function. TNTs are long, filamentous, actin-based cell protrusions that mediate direct cell-to-cell communication between malignant cells. In this study, we investigated the formation of TNTs in response to variable concentrations of the chemotherapeutic drug doxorubicin, which is used extensively in the treatment of cancer patients. Doxorubicin stimulated an increased formation of TNTs in pancreatic cancer cells, and this occurred in a dose-dependent fashion. Furthermore, TNTs facilitated the intercellular redistribution of this drug between connected cells in both pancreatic and ovarian cancer systems in vitro. To provide supportive evidence for the relevance of TNTs in pancreatic cancer in vivo, we performed multiphoton fluorescence microscopy and imaged TNTs in tumor specimens resected from three human patients with pancreatic adenocarcinoma, and one with neuroendocrine carcinoma. In sum, TNT formation was upregulated in aggressive forms of pancreatic carcinoma, was further stimulated after chemotherapy exposure, and acted as a novel method for drug efflux. These findings implicate TNTs as a potential novel mechanism of drug resistance in chemorefractory forms of cancer.
Bibliographical noteFunding Information:
We would like to thank Guillermo Marques, Ph.D., and Mark Sanders, Ph.D., for assistance with confocal microscopy performed at the University Imaging Centers at the University of Minnesota; Michael Franklin, M.S., for helpful critiques and editorial suggestions; and Beshay Zordoky, Ph.D., for helpful discussion regarding pharmacologic activity and properties of doxorubicin. This research was supported by a National Pancreas Foundation Research Grant (provided in partnership with the National Pancreas Foundation, several NPF Chapters and the Horvitz/Lebovitz Research Fund) (E.L.); the University of Minnesota Deborah E. Powell for Women’s Health Interdisciplinary Seed Grant support (Grant #PCWH-2013-002) (E.L.); Institutional Research Grant #118198-IRG-58-001-52-IRG94 from the American Cancer Society (E.L.); the Mezin-Koats Colon Cancer Research Award (E.L.); The Randy Shaver Cancer Research and Community Fund (E.L.); the Litman Family Fund for Cancer Research; Family and Friends of G. Huntington; Central Society for Clinical and Translational Research Early Career Development Award (E.L.); Minnesota Masonic Charities; Minnesota Medical Foundation/University of Minnesota Foundation (E.L.); the Masonic Cancer Center and Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota (E.L.); and the NIH Clinical and Translational Science KL2 Scholar Award 8UL1TR000114 (to E.L.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.