Mast cells mediate malignant pleural effusion formation.
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.
Anastasios D
AD
Giannou
Antonia
A
Marazioti
Magda
M
Spella
Nikolaos I
NI
Kanellakis
Hara
H
Apostolopoulou
Ioannis
I
Psallidas
Zeljko M
ZM
Prijovich
Malamati
M
Vreka
Dimitra E
DE
Zazara
Ioannis
I
Lilis
Vassilios
V
Papaleonidopoulos
Chrysoula A
CA
Kairi
Alexandra L
AL
Patmanidi
Ioanna
I
Giopanou
Nikolitsa
N
Spiropoulou
Vaggelis
V
Harokopos
Vassilis
V
Aidinis
Dionisios
D
Spyratos
Stamatia
S
Teliousi
Helen
H
Papadaki
Stavros
S
Taraviras
Linda A
LA
Snyder
Oliver
O
Eickelberg
Dimitrios
D
Kardamakis
Yoichiro
Y
Iwakura
Thorsten B
TB
Feyerabend
Hans-Reimer
HR
Rodewald
Ioannis
I
Kalomenidis
Timothy S
TS
Blackwell
Theodora
T
Agalioti
Georgios T
GT
Stathopoulos
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D010879:Piperazines / Q000494:pharmacology; D035422:Pleural Cavity / Q000378:metabolism / Q000473:pathology; D016066:Pleural Effusion, Malignant / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D053802:Tryptases / Q000235:genetics / Q000378:metabolism
D001549:Benzamides; C508585:IL1B protein, human; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; C509222:Tpsab1 protein, mouse; D053802:Tryptases