Tunneling Nanotubes

Lou, Emil; Fujisawa, Sho; Barlas, Afsar; Romin, Yevgeniy; Manova‐Todorova, Katia; Moore, Malcolm A.S.; Subramanian, Subbaya

doi:10.4161/cib.20569

Cited by 110 publications

(76 citation statements)

References 37 publications

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“…Here we show that hypoxia-induced TNT formation is a novel mechanism of chemoresistance in cancer. In the past few years, in vitro studies have begun to elucidate the role of TNTs for facilitating intercellular trafficking of cellular signals between connected cancer cells [10, 12, 16, 24–26]. For example, our group has demonstrated in vitro direct cell-to-cell transfer of oncogenic genetic materials, including microRNAs, via TNTs connecting malignant ovarian cancer cells to each other as well as to stromal epithelial cells [10, 12, 16].…”

Section: Discussionmentioning

confidence: 99%

Tunneling nanotube formation is stimulated by hypoxia in ovarian cancer cells

et al. 2016

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In this study, we demonstrated that hypoxic conditions stimulated an increase in tunneling nanotube (TNT) formation in chemoresistant ovarian cancer cells (SKOV3, C200). We found that suppressing the mTOR pathway using either everolimus or metformin led to suppression of TNT formation in vitro, verifying TNTs as a potential target for cancer-directed therapy. Additionally, TNT formation was detected in co-cultures including between platinum-resistant SKOV3 cells, between SKOV3 cells and platinum-chemosensitive A2780 cells, and between SKOV3 cells cultured with benign ovarian epithelial (IOSE) cells; these findings indicate that TNTs are novel conduits for malignant cell interactions and tumor cell interactions with other cells in the microenvironment. When chemoresistant C200 and parent chemosensitive A2780 cells were co-cultured, chemoresistant cells displayed a higher likelihood of TNT formation to each other than to chemosensitive malignant or benign epithelial cells. Hypoxia-induced TNT formation represents a potential mechanism for intercellular communication in ovarian cancer and other forms of invasive refractory cancers.

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Section: Discussionmentioning

confidence: 99%

Tunneling nanotube formation is stimulated by hypoxia in ovarian cancer cells

et al. 2016

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“…TnTs are a novel candidate to explain how this communication process occurs (Lou et al, 2012a). Our prior and current work have consistently demonstrated TnTs in malignant mesothelioma and lung adenocarcinoma tumors from human patients (Lou et al, 2012b).…”

Section: Discussionmentioning

confidence: 99%

“…Our group focuses on investigation of TnTs in the context of invasive forms of cancer (Lou et al, 2012a,b). To investigate TnTs as a physiologically relevant structure in human solid tumor malignancies, our initial work successfully visualized TnTs in solid tumors resected from patients with mesothelioma and lung adenocarcinomas (Lou et al, 2012b), providing the first evidence of the potential in vivo relevance of these cellular structures in cancer.…”

Section: Introductionmentioning

confidence: 99%

Intercellular communication in malignant pleural mesothelioma: properties of tunneling nanotubes

et al. 2014

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Malignant pleural mesothelioma is a particularly aggressive and locally invasive malignancy with a poor prognosis despite advances in understanding of cancer cell biology and development of new therapies. At the cellular level, cultured mesothelioma cells present a mesenchymal appearance and a strong capacity for local cellular invasion. One important but underexplored area of mesothelioma cell biology is intercellular communication. Our group has previously characterized in multiple histological subtypes of mesothelioma a unique cellular protrusion known as tunneling nanotubes (TnTs). TnTs are long, actin filament-based, narrow cytoplasmic extensions that are non-adherent when cultured in vitro and are capable of shuttling cellular cargo between connected cells. Our prior work confirmed the presence of nanotube structures in tumors resected from patients with human mesothelioma. In our current study, we quantified the number of TnTs/cell among various mesothelioma subtypes and normal mesothelial cells using confocal microscopic techniques. We also examined changes in TnT length over time in comparison to cell proliferation. We further examined potential approaches to the in vivo study of TnTs in animal models of cancer. We have developed novel approaches to study TnTs in aggressive solid tumor malignancies and define fundamental characteristics of TnTs in malignant mesothelioma. There is mounting evidence that TnTs play an important role in intercellular communication in mesothelioma and thus merit further investigation of their role in vivo.

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“…Gap junctions, chemical messengers (eg, cytokines), and exosomes are well established forms of intercellular communication[1, 2]; however, tunneling nanotubes (TnTs), represent a novel mechanism by which intercellular components can be transferred from cell to cell in the complex tumor microenvironment[3, 4]. TnTs are long, thin, actin-based, cytoplasmic extensions that form de novo and can serve as conduits for intercellular shuttling of cargo such as proteins, Golgi vesicles, and mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Tumor-stromal cross talk: direct cell-to-cell transfer of oncogenic microRNAs via tunneling nanotubes

Thayanithy

Dickson

Steer

et al. 2014

Translational Research

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Tunneling nanotubes (TnTs) represent a novel mechanism by which intercellular components such as proteins, Golgi vesicles, and mitochondria can be transferred from cell to cell in the complex tumor microenvironment. Here, we report data showing that microRNAs (miRNAs) are transferred through TnTs in osteosarcoma and ovarian cancer as in vitro model systems. miRNA array analysis demonstrated significant upregulation of miR-19a in osteosarcoma tumors resected from human patients, and differential expression of miR-199a in ovarian cancer cell lines resistant or sensitive to platinum chemotherapy. K7M2 murine osteosarcoma cells were transfected with miR-19a and cultured with non-transfected K7M2 cells in low-serum, hyperglycemic medium for up to 72 hours to induce TnT formation. miRNA transfer via TnTs was detected by time-lapse microscopic imaging. miR-19 was also transported via TnTs connecting transfected K7M2 cells and non-transfected stromal MC3T3 murine osteoblast cells. Similar findings were observed in studies of TnT-mediated transport of miR-199a among SKOV3 ovarian cancer cells and non-malignant IOSE human ovarian epithelial cells. To quantify TnT-mediated transport of miRNAs, we used modified Boyden chambers to separate miR19a-transfected K7M2 cells (top chamber) and DiI-labeled MC3TC cells (bottom chamber) as compared to open culture of these cells. FACS analysis of cells collected after 48-hours of culture indicated that miR19a-positive MC3TC cells was 3-fold higher in open culture; this finding suggest that miR-19a occurred via TnTs, exclusive of other forms of cell-cell communication. These studies demonstrate that TnTs mediate direct transfer of genetic material between tumor and stromal cells.

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Tunneling Nanotubes

Cited by 110 publications

References 37 publications

Tunneling nanotube formation is stimulated by hypoxia in ovarian cancer cells

Tunneling nanotube formation is stimulated by hypoxia in ovarian cancer cells

Intercellular communication in malignant pleural mesothelioma: properties of tunneling nanotubes

Tumor-stromal cross talk: direct cell-to-cell transfer of oncogenic microRNAs via tunneling nanotubes

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