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 11

Adenocarcinoma-primed MCs secrete TPSAB1 and IL-1β.

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Adenocarcinoma-primed MCs secrete TPSAB1 and IL-1β. (A) Microarray (Venn...
(A) Microarray (Venn and PCA diagrams, n = 2) and qPCR (n = 3) of BMMC differential gene expression (ΔGE) after tumor-CM exposure. Comparisons with naive BMMCs. (B) C57BL/6 BMMC-CM IL-1β ELISA after 4 hours of sham or tumor-CM exposure (n = 3/treatment). (C) MPE IL-1β ELISA of mice from Figure 8, B and C (n = 5/group). (D and E) IL-1β (D) and CD68 (E) immunolocalization in C57BL/6 BMMCs counterstained with Hoechst 33258 (nuclei) and avidin (granules). (F) IL-1β colocalization with c-KIT and CD68 in MPE cells. (G and H) MPEs of C57BL/6 (n = 45), c-KitWsh (G, n = 33), and Il1b–/– (H, n = 51) mice 14 days after pleural LLC cells with or without s.c. C57BL/6, c-KitWsh, or Il1b–/– BMMCs. (I) Proliferation of B16F10, LLC, and MC38 cells (n = 3/cell line) at 100 ng/ml IL-1β (top; comparisons of adenocarcinomas with melanoma) and at increasing BMMC-CM concentrations (bottom; comparisons of LLC [stars] and MC38 [number sign] cells with 0% BMMC-CM [control]). (J) C57BL/6 skin Evans’ blue leak (color-coded areas) induced by BSA or rm cytokines (comparisons with BSA, n = 6/group). (A, B, and I) Shown are 1 representative of 3 experiments. Data are 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 2-way (I) or 1-way (all other graphs) ANOVA with Bonferroni post hoc tests.