title: Tunneling nanotubes provide a unique conduit for intercellular transfer of cellular contents in human malignant pleural mesothelioma.
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.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Emil
authors.initials: E
authors.lastname: Lou
authors.forename: Sho
authors.initials: S
authors.lastname: Fujisawa
authors.forename: Alexei
authors.initials: A
authors.lastname: Morozov
authors.forename: Afsar
authors.initials: A
authors.lastname: Barlas
authors.forename: Yevgeniy
authors.initials: Y
authors.lastname: Romin
authors.forename: Yildirim
authors.initials: Y
authors.lastname: Dogan
authors.forename: Sepideh
authors.initials: S
authors.lastname: Gholami
authors.forename: André L
authors.initials: AL
authors.lastname: Moreira
authors.forename: Katia
authors.initials: K
authors.lastname: Manova-Todorova
authors.forename: Malcolm A S
authors.initials: MA
authors.lastname: Moore
mesh_terms: D001692:Biological Transport / Q000502:physiology; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008654:Mesothelioma / Q000378:metabolism*; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D043942:Nanotubes / Q000737:chemistry* / Q000648:ultrastructure*; D010997:Pleural Neoplasms / Q000378:metabolism*; D059008:Time-Lapse Imaging