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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Animals
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Benzamides / pharmacology
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Cell Line, Tumor
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Colonic Neoplasms / drug therapy
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology
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Humans
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Imatinib Mesylate
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism
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Lung Neoplasms / diet therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Male
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Mast Cells / metabolism*
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Mast Cells / pathology
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Mice, Transgenic
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Piperazines / pharmacology
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Pleural Cavity / metabolism
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Pleural Cavity / pathology
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Pleural Effusion, Malignant / drug therapy
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Pleural Effusion, Malignant / genetics
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Pleural Effusion, Malignant / metabolism*
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Pleural Effusion, Malignant / pathology
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-kit / antagonists & inhibitors
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Proto-Oncogene Proteins c-kit / genetics
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Proto-Oncogene Proteins c-kit / metabolism
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Pyrimidines / pharmacology
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Tryptases / genetics
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Tryptases / metabolism
Substances
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Benzamides
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IL1B protein, human
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IL1B protein, mouse
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Interleukin-1beta
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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Imatinib Mesylate
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Proto-Oncogene Proteins c-kit
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Tpsab1 protein, mouse
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Tryptases