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 8

MCs are required for MPEs.

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MCs are required for MPEs. (A) MPEs and pleural tumors of C57BL/6 mice a...
(A) MPEs and pleural tumors of C57BL/6 mice at day 14 after pleural BMMCs (n = 5), B16F10 cells (n = 11), or both (n = 12). (B and C) MPEs, pleural tumors, and TB-stained pleural fluid cells including MCs of C57BL/6 (n = 45), c-KitWsh (n = 37), and Cpa3Cre/+ (n = 14) mice at day 14 after pleural LLC (B) and MC38 (C) cells. (D) PCNA immunoreactivity of pleural tumors from B and C (n = 7/group). (E) MPEs (graph) and TB-stained pleural tumor MCs (images) of irradiated C57BL/6 and c-KitWsh recipients of BM transplants from C57BL/6 and c-KitWsh donors at day 14 after pleural LLC cells (n = 6–7/group). (F) BMMC yield of C57BL/6 and c-KitWsh mice (n = 6 each) at 1 month; data summary, TB-staining, and flow cytometry of c-KitWsh BMMCs. Arrows indicate shift toward c-KIT–Lin+ phenotype, as compared with Figure 4B. Shown throughout are MPEs (dashed lines), lungs (l), pleural tumors (t), and MCs (arrows). Numbers below columns: percentile MPE inhibition and pleural MCs (thousands) 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 2-tailed Student’s t-test (D) or 1-way ANOVA with Bonferroni post hoc tests (all other graphs).