Mast cells mediate malignant pleural effusion formation
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
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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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 14

MC-derived IL-1β promotes effusion development via IκB kinase (IKK) β.

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MC-derived IL-1β promotes effusion development via IκB kinase (IKK) β. (...
(A) Bioluminescence of C57BL/6 (n = 14) and c-KitWsh (n = 12) mice 14 days after pleural LLC cells expressing constitutive (pCAG-Luc) or NF-κB-dependent (pNF-κΒ-Luc) reporters. (B) Validation of adenocarcinoma cells overexpressing pEGFP and pEGFP.Ikbkb. (C) Bioluminescence of pNF-κΒ-Luc LLC cells expressing pEGFP or pEGFP.Ikbkb in response to 100 ng/ml IL-1β, with comparisons of pEGFP.Ikbkb with pEGFP cells (n = 3/data-point). Shown is 1 representative of 3 experiments. (D) MPEs of C57BL/6 (n = 36), c-KitWsh (n = 21), and Cpa3Cre/+ (n = 15) mice 14 days after pleural pEGFP- or pEGFP.Ikbkb-expressing LLC cells. Shown are MPEs (dashed lines), lungs (l), and pleural tumors (t). Numbers below columns indicate percentile MPE inhibition of c-KitWsh (gray font) and Cpa3Cre/+ (black font) mice. Data presented as data points, mean ± SD. Numbers in boxes indicate sample size. NS, P > 0.05; *P < 0.05; **P < 0.01; and ***P < 0.001, by Student’s t test (A), 1-way (D), or 2-way (C) ANOVA with Bonferroni post hoc tests.