Chemotherapy-Induced Tunneling Nanotubes Mediate Intercellular Drug Efflux in Pancreatic Cancer.
Snider DesirPatrick O'HareRachel Isaksson VogelWilliam SperdutoAkshat SarkariElizabeth L DicksonPhillip WongAndrew C NelsonYuman FongClifford J SteerSubbaya SubramanianEmil LouPublished in: Scientific reports (2018)
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.
Keyphrases
- single cell
- induced apoptosis
- cell therapy
- chemotherapy induced
- squamous cell carcinoma
- endothelial cells
- single molecule
- drug induced
- emergency department
- stem cells
- cancer therapy
- signaling pathway
- optical coherence tomography
- papillary thyroid
- radiation therapy
- cell death
- bone marrow
- cell proliferation
- locally advanced
- smoking cessation
- label free
- fine needle aspiration