Abstract
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.
Highlights
Intercellular communication has gained increasing attention as a critical factor to induce heterogeneity in the tumor microenvironments
tunneling nanotubes (TNTs) can be visualized in intact malignant pancreatic tumors resected from human patients: supportive evidence that TNTs are an in vivo phenomenon
Our studies were designed to evaluate the formation of TNTs — a unique form of cellular protrusion implicated in long-distance cell communication — as a cellular stress response
Summary
Intercellular communication has gained increasing attention as a critical factor to induce heterogeneity in the tumor microenvironments. The effects of direct cell-to-cell transfer of signals (via horizontal transfer) have long been understood to occur via soluble signals such as chemokines and cytokines They have been investigated via cellular channels or carriers such as gap junctions and extracellular vesicles (EVs), including exosomes and microvesicles. These physical modes of cellular communication are responsible for transmission of key signals of cellular proliferation and growth that permit tumor progression. A relatively new form of intercellular communication known as tunneling nanotubes (TNTs) represents an addition to the cadre of physical mechanisms of cellular signaling[5,6] Such redistribution via TNTs could be a potential mechanism for emergence of chemotherapeutic drug resistance in cancer
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