Chemotherapy-Induced Tunneling Nanotubes Mediate Intercellular Drug Efflux in Pancreatic Cancer

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.

Tumor-Cell–Macrophage Fusion Cells as Liquid Biomarkers and Tumor Enhancers in Cancer

“…These protrusions enable exchange of specific signals by direct cell-to-cell contact over short (tens of microns) and long (hundreds of microns) distances. Thin and transient membrane protrusions have been found, both in vitro [102][103][104] and in vivo [105][106][107] in different tissues from various organisms and in several disease models. Each protrusion type possesses distinct structural and functional characteristics.…”

Rhes Tunnels: A Radical New Way of Communication in the Brain's Striatum?

“…[ 79 ] Pancreatic cancer cells and tissues were shown to produce TNTs. [ 80 ] TNTs were also observed between endothelial progenitor cells and osteoclast precursors cells. [ 79 ] TNT‐like protrusions were found to be involved in mRNA and protein transfer between keratinocyte and Langerhans cells in vivo.…”

Tyrosine kinase inhibitors and interferon‐α increase tunneling nanotube (TNT) formation and cell adhesion in chronic myeloid leukemia (CML) cell lines

“…Leukocytes, their leukemic counterparts and bone marrow stromal cells have all been reported to form TNTs in vitro . TNT is proposed to be a mechanism for chemo resistance by transport of oncoproteins between T and B cells as well as in colon cancer cells, by transfer of mitochondria from endothelial cells to chemotherapy exposed cancer cells, or by induced drug‐efflux in aggressive forms of pancreatic carcinoma . The impact of TNTs in vivo is so far not well characterized, but they have been described to connect myeloid cells in the cornea of mouse and in fresh resected tumor samples from patients with malignant pleural mesothelioma and lung adenocarcinoma .…”

“…[25][26][27][28][29][30][31][32] TNT is proposed to be a mechanism for chemo resistance by transport of oncoproteins between T and B cells as well as in colon cancer cells, by transfer of mitochondria from endothelial cells to chemotherapy exposed cancer cells, or by induced drug-efflux in aggressive forms of pancreatic carcinoma. [33][34][35][36][37][38] The impact of TNTs in vivo is so far not well characterized, but they have been described to connect myeloid cells in the cornea of mouse 39,40 and in fresh resected tumor samples from patients with malignant pleural mesothelioma and lung adenocarcinoma. 41 Subsequently, TNTs have been proposed to be implicated in disease and to play a role with respect to therapy response recently demonstrated by vesicle exchange from stromal cells to CML cells providing increased resistance to imatinib.…”