Mast cells mediate malignant pleural effusion formation
Anastasios D. Giannou, … , Theodora Agalioti, Georgios T. Stathopoulos
Anastasios D. Giannou, … , Theodora Agalioti, Georgios T. Stathopoulos
Published April 27, 2015
Citation Information: J Clin Invest. 2015;125(6):2317-2334. https://doi.org/10.1172/JCI79840.
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Research Article Oncology

Mast cells mediate malignant pleural effusion formation

Abstract

Mast cells (MCs) have been identified in various tumors; however, the role of these cells in tumorigenesis remains controversial. Here, we quantified MCs in human and murine malignant pleural effusions (MPEs) and evaluated the fate and function of these cells in MPE development. Evaluation of murine MPE-competent lung and colon adenocarcinomas revealed that these tumors actively attract and subsequently degranulate MCs in the pleural space by elaborating CCL2 and osteopontin. MCs were required for effusion development, as MPEs did not form in mice lacking MCs, and pleural infusion of MCs with MPE-incompetent cells promoted MPE formation. Once homed to the pleural space, MCs released tryptase AB1 and IL-1β, which in turn induced pleural vasculature leakiness and triggered NF-κB activation in pleural tumor cells, thereby fostering pleural fluid accumulation and tumor growth. Evaluation of human effusions revealed that MCs are elevated in MPEs compared with benign effusions. Moreover, MC abundance correlated with MPE formation in a human cancer cell–induced effusion model. Treatment of mice with the c-KIT inhibitor imatinib mesylate limited effusion precipitation by mouse and human adenocarcinoma cells. Together, the results of this study indicate that MCs are required for MPE formation and suggest that MC-dependent effusion formation is therapeutically addressable.

Authors

Anastasios D. Giannou, Antonia Marazioti, Magda Spella, Nikolaos I. Kanellakis, Hara Apostolopoulou, Ioannis Psallidas, Zeljko M. Prijovich, Malamati Vreka, Dimitra E. Zazara, Ioannis Lilis, Vassilios Papaleonidopoulos, Chrysoula A. Kairi, Alexandra L. Patmanidi, Ioanna Giopanou, Nikolitsa Spiropoulou, Vaggelis Harokopos, Vassilis Aidinis, Dionisios Spyratos, Stamatia Teliousi, Helen Papadaki, Stavros Taraviras, Linda A. Snyder, Oliver Eickelberg, Dimitrios Kardamakis, Yoichiro Iwakura, Thorsten B. Feyerabend, Hans-Reimer Rodewald, Ioannis Kalomenidis, Timothy S. Blackwell, Theodora Agalioti, Georgios T. Stathopoulos

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Figure 3

MC topology in experimental MPEs.

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MC topology in experimental MPEs. Whole thoracic sections from mice with...
Whole thoracic sections from mice with pleural tumors and effusions induced by LLC and MC38 adenocarcinomas stained with TB. MCs (arrows) were found in parietal pleural tumors (ppt) and mediastinal tumors (mat), but not in visceral pleural tumors (vpt) (A–H). MCs appeared to stream in from intercostals vessels, sequentially invading intercostal tissues (fat and muscle) and ppt, forming chains invading into tumors or rings strategically positioned around tumors (I–Q). MCs were exclusively located in viable (vt), but not necrotic (nt), tumor tissues (R–T). All scale bars = 300 μm. B, D, F, H, J, L, N, and O, Q, and S and T: magnified inlays from A, C, E, G, I, K, M, P, and R, respectively. c, rib cartilage; cw, chest wall; ppm, parietal pleural mesothelium; pc, pleural cavity; bm, rib BM; scf, subcutaneous fat; icm, intercostal muscle; thy, thymus; sca, scalene muscle; tra, trachea; vpm, visceral pleural mesothelium; pv, pulmonary vein; icv, intercostal vein; d, dermis; r, rib; maf, mediastinal fat; mas, mediastinum.