Intercellular communication in malignant pleural mesothelioma: properties of tunneling nanotubes

Our plain-English summary of Intercellular communication in malignant pleural mesothelioma: properties of tunneling nanotubes, by J.W. Ady, S. Desir, V. Thayanithy, et al (Frontiers in Physiology, 2014).

The study

• Authors: J.W. Ady, S. Desir, V. Thayanithy, R.I. Vogel, A.L. Moreira, R.J. Downey, Y. Fong, K. Manova-Todorova, M.A. Moore, E. Lou
• Journal: Frontiers in Physiology
• Published: 2014;5:400
• Cited by: 79 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This laboratory study examined tunneling nanotubes (TnTs), thin tubes connecting cells, in malignant pleural mesothelioma. It did not study asbestos or fiber exposure. The authors grew three mesothelioma cell lines (H2052, VAMT and MSTO-211H) and one benign mesothelial cell line (MeT5A) in a medium that encourages TnT formation. All three mesothelioma lines formed significantly more TnTs per cell than the benign line. In the mesothelioma lines, TnT length decreased over time, significantly at most time points. Malignant cells from the pleural fluid of 5 patients with malignant pleural mesothelioma or lung adenocarcinoma also formed TnTs. Migrastatin core ether, a synthetic analog of migrastatin, reduced TnTs in MSTO-211H cells at 24 and 72 hours. In mice, cells pre-grown in TnT medium produced less tumor by day 31. However, 2 of 10 of those mice died by day 31 and a third died just after imaging, compared with none of 10 controls. This survival difference was not statistically significant (p = 0.067). The authors concluded that their work challenges the view that gap junctions, exosomes and diffusible signals are the only ways mesothelioma cells communicate. They called for further studies in living animals.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of cultured cell lines and patient-derived cells, with a mouse xenograft experiment
• Who was studied: Three malignant pleural mesothelioma cell lines (H2052 epithelioid, VAMT sarcomatoid, MSTO-211H biphasic) and one normal immortalized human mesothelium cell line (MeT5A). Also pleural effusion cells from 5 patients with malignant pleural mesothelioma or lung adenocarcinoma, resected mesothelioma tumors, and NOG immunodeficient mice (10 per group).
• Exposure: No asbestos or fiber exposure was studied. Cells were grown in a low-serum, high-glucose 'TnT medium' (2.5% FBS, 50 mM glucose) to stimulate nanotube formation. They were also treated with drugs including migrastatin core ether (100 nM), tunicamycin, dextran sulfate, 4-methylumbelliferone and hyaluronidase.
• Main results:
  • All three malignant mesothelioma cell lines had a significantly higher average number of TnTs per cell than the benign MeT5A line
  • Ratio of malignant to mesothelial TnTs per cell from 48 to 72 hours: 26.73 to 78.16 for H2052, 9.80 to 42.66 for VAMT, and 9.80 to 18.84 for MSTO
  • TnT length decreased over time in all malignant cell lines; the changes were statistically significant at most time points
  • Malignant cells from pleural effusions of 5 patients with malignant pleural mesothelioma or lung adenocarcinoma formed TnTs connecting the patient-derived cells in culture
  • MSTO cells treated with migrastatin core ether (a synthetic analog of migrastatin) had significantly fewer TnTs than untreated controls at 24 hours and at 72 hours; the difference at 48 hours was not significant
  • 4-methylumbelliferone and hyaluronidase had no effect on TnTs, which the authors took as indicating that hyaluronic acid does not play a notable role in TnT formation
  • In MSTO cells grown in TnT medium, proliferation was about half that of cells grown in standard passage medium
  • By 31 days, mice injected with cells pre-conditioned in TnT medium had less tumor burden than mice injected with cells pre-conditioned in passage medium
  • None of the 10 control mice had died by day 31. In the TnT-medium group (n = 10), 2 mice had died by day 31 and 1 more died just after imaging. The overall survival comparison (Kaplan-Meier curve, log-rank test, censored at 40 days) gave p = 0.067, which is not significant at the authors' p < 0.05 threshold. In a repeat experiment, 5 of 10 TnT-medium mice and 0 of 10 controls died by day 31 (data not shown).
  • In MSTO cells grown in TnT medium, genes linked to invasion and migration (tenascin-C, CD44, osteopontin, fascin, mesothelin) were significantly induced. The TnT-associated genes M-Sec and LST1 were also upregulated.
• The authors' conclusion: The authors concluded that their work challenges the view that gap junctions, exosomes, cytokines and other diffusible signals are the only ways mesothelioma cells communicate with one another
• Limitations the authors state:
  • Further in vivo studies are needed to clarify whether TnT connections occur among mesothelioma cells invading the mesothelial lining
  • Examining TnTs in living organisms remains a major barrier to studying their function in cancer
  • TnTs were rare in the benign MeT5A cells, so the distribution of TnT length could not be plotted for that line

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, Mesothelioma, Histological Subtype, Mesothelial Cells.

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