Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, 55455, USA.
Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, 55455, USA.
Sci Rep. 2018 Jun 21;8(1):9484. doi: 10.1038/s41598-018-27649-x.
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.
细胞间通讯在不断演变的侵袭性癌症领域中起着至关重要的作用。最近的研究阐明了隧道纳米管（TNTs）在这一功能中的潜在作用。TNTs 是长而丝状的、基于肌动蛋白的细胞突起，介导恶性细胞之间的直接细胞间通讯。在这项研究中，我们研究了 TNTs 的形成对化疗药物阿霉素的可变浓度的反应，阿霉素广泛用于癌症患者的治疗。阿霉素刺激胰腺癌细胞中 TNTs 的形成增加，并且这种增加呈剂量依赖性。此外，TNTs 促进了体外胰腺和卵巢癌细胞系统中连接细胞之间的这种药物的细胞间重新分布。为了提供 TNTs 在体内胰腺癌中相关性的支持证据，我们进行了多光子荧光显微镜检查，并在从三个人类胰腺腺癌患者和一个神经内分泌癌患者切除的肿瘤标本中成像 TNTs。总之，TNT 的形成在上皮样胰腺癌的侵袭性形式中被上调，在化疗暴露后进一步受到刺激，并作为药物外排的新方法。这些发现表明 TNTs 是化疗耐药性癌症的潜在新型耐药机制。
