Abstract
Tunneling nanotubes are long, non-adherent F-actin-based cytoplasmic extensions which connect proximal or distant cells and facilitate intercellular transfer. The identification of nanotubes has been limited to cell lines, and their role in cancer remains unclear. We detected tunneling nanotubes in mesothelioma cell lines and primary human mesothelioma cells. Using a low serum, hyperglycemic, acidic growth medium, we stimulated nanotube formation and bidirectional transfer of vesicles, proteins, and mitochondria between cells. Notably, nanotubes developed between malignant cells or between normal mesothelial cells, but not between malignant and normal cells. Immunofluorescent staining revealed their actin-based assembly and structure. Metformin and an mTor inhibitor, Everolimus, effectively suppressed nanotube formation. Confocal microscopy with 3-dimensional reconstructions of sectioned surgical specimens demonstrated for the first time the presence of nanotubes in human mesothelioma and lung adenocarcinoma tumor specimens. We provide the first evidence of tunneling nanotubes in human primary tumors and cancer cells and propose that these structures play an important role in cancer cell pathogenesis and invasion.
Highlights
Intercellular communication is critical to cancer cell proliferation, coordination, and tumor invasion
Under normal acidity, the highest cell count was observed for the cells in high serum (10% fetal calf serum (FCS)) and normal glucose conditions, and with significantly less proliferation of cells grown in the low-serum (2.5% FCS), hyperglycemic medium which induced increased Tunneling nanotubes (TnTs) formation
We discovered that TnT formation is most effectively stimulated and accelerated in a hyperglycemic, low-serum, acidic environment
Summary
Intercellular communication is critical to cancer cell proliferation, coordination, and tumor invasion. The traditional paradigm of cancer cell communication is reliance on potentially inefficient diffusion of chemical signals between cells, transfer of materials responsible for stimulating growth of neighboring cells and coordinating tumor invasion. Tunneling nanotubes (TnTs) are fine, long, non-adherent, actin-based cytoplasmic extensions first described in PC12, a cell line of rat pheochromocytoma [4]. The authors demonstrated cellto-cell spread of endosomes via these extensions, which they termed tunneling nanotubules to distinguish them from adherent actin-based cell extensions, such as lamellopodia, filopodia, and invadopodia. Characteristic morphologic features distinguishing TnTs from other actin-based structures are their small diameter, cell-to-cell cytoplasmic connections, and non-adherence to the substratum when cultivated in vitro [4]. Cells can form multiple TnTs, and some form as many as 75 TnTs [5]
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