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 6

Identification of SPP1 and CCL2 as candidate tumor-derived MC effectors.

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Identification of SPP1 and CCL2 as candidate tumor-derived MC effectors....
(A) Venn diagram of mouse cancer cell differential gene expression (ΔGE) assessed by 2 microarrays showing 39 transcripts overrepresented in adenocarcinomas (top 10 listed), including Ccl2 and Spp1 (biological n = 3). (B) SPP1 and CCL2 ELISA of cancer cells–CM. (C) SPP1 and CCL2 ELISA of C57BL/6 mouse sera at day 14 after pleural PBS or cancer cells. (D) SPP1 and CCL2 ELISA of CM from LLC cells stably expressing random (shC), anti-Spp1 (shSpp1), or anti-Ccl2 (shCcl2) shRNA, and MC38 cells stably expressing shC or shSpp1. Data represent 1 representative of 2 experiments and are presented as data points, mean ± SD. Numbers in boxes indicate the sample size. nd, not detected; NS, P > 0.05; **P < 0.01; and ***P < 0.001, by 1-way ANOVA with Bonferroni post hoc tests.