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.
| Original language | English (US) |
|---|---|
| Article number | e33093 |
| Journal | PloS one |
| Volume | 7 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 9 2012 |
Bibliographical note
Funding Information:The authors gratefully acknowledge the Baker Street Foundation for its generous funding and support of this project. We wish to thank Zsolt Lazar, Ph.D., Tao Tong, Sanghoon Oh, Ph.D. and Jiang-Cheng Wang, Ph.D. of the Molecular Cytology Core Facility at the Memorial Sloan-Kettering Cancer Center (MSKCC) for their helpful suggestions, expertise, and assistance with time-lapse imaging and immunofluorescence; Mesruh Turkekul and Ning Fan for assistance with immunofluorescent staining; Nina Lampen for preparation of cells for electron microscopy evaluation; Alan Hall, Ph.D for helpful discussion; Yuman Fong, M.D. for providing mesothelioma cell lines; Valerie Rusch, M.D., Robert J. Downey, M.D., and David Finley, M.D. of the Thoracic Surgery Service at MSKCC, for providing primary pleural effusion specimens; Prasad Adusumilli, M.D. for providing an additional MSTO-211H GFP-transduced cell line; and Ms. Katherine DeBeer for administrative assistance and support.
