Tumor Necrosis Factor-α Promotes Malignant Pleural Effusion

Georgios T Stathopoulos,Richard W Light,Marilena Karatza,Dora Orphanidou,Spyros A Papiris,Charis Roussos,Daniel Graf,Taylor P Sherrill,Timothy S Blackwell,Ioannis Kalomenidis,Spyridoula Vassiliou,Charalampos Moschos,Androniki Kollintza,Emmanuel N Pitsinos,Ioannis Psallidas

doi:10.1158/0008-5472.can-07-1064

Abstract

Tumor necrosis factor (TNF)-alpha is present in the microenvironment of human tumors, including malignant pleural effusion (MPE). Although the cytokine is produced in the pleural cavity by both tumor and host cells, its effects on MPE formation are unknown. In these studies, we sought to determine the role of TNF-alpha in the pathogenesis of MPE and to assess the therapeutic effects of its neutralization in a preclinical model. For this, MPEs were generated in immunocompetent mice using intrapleural injection of mouse lung adenocarcinoma cells. The roles of tumor- and host-derived TNF-alpha were assessed using combined experimentation with TNF-alpha gene-deficient mice and in vivo TNF-alpha neutralization. To expand the scope of preclinical data, TNF-alpha and vascular endothelial growth factor (VEGF) expression were determined in human cancer cell lines and human MPE. In the MPE model, TNF-alpha of host and tumor origin was present. TNF-alpha neutralization significantly limited tumor dissemination, effusion formation, vascular hyperpermeability, TNF-alpha and VEGF expression, and angiogenesis, thereby improving survival. In contrast, these variables were not different between TNF-alpha gene-sufficient and TNF-alpha gene-deficient mice. In mouse cancer cells, TNF-alpha functioned via nuclear factor-kappaB- and neutral sphingomyelinase-dependent pathways to induce TNF-alpha and VEGF, respectively. These results were recapitulated in human cancer cells, and a correlation was detected between TNF-alpha and VEGF content of human MPE. We conclude that tumor-derived TNF-alpha is important in the development of MPE in mice, and provide preclinical evidence supporting the efficacy of TNF-alpha blockade against malignant pleural disease.

Highlights

A malignant pleural effusion (MPE) presents a frequent (f500 new cases per million population per year) and dismal event inNote: Supplementary data for this article are available at Cancer Research Online.I2007 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-07-1064 the course of various malignancies, predominantly adenocarcinomas of the lungs and other organs, signaling incurability, shortened life expectancy, and severely compromised quality of life [1,2,3,4]
Tumor cells produced Tumor necrosis factor (TNF)-a in vivo, because the cytokine was detected in MPE from tnfaÀ/À mice (Fig. 1C), and in vitro, because Tumor necrosis factor-a (TNF-a) was found in medium conditioned by confluent Lewis lung adenocarcinoma (LLC) cells (48 h: 9 F 1 pg/mL; 72 h: 16 F 1 pg/mL; n = 3/time point)
The cytokine was named after its ability to induce malignant cell death [47], recent studies on models of solid tumors have shown that TNF-a produced by either tumor [13] or host [25]

Summary

Introduction

A malignant pleural effusion (MPE) presents a frequent (f500 new cases per million population per year) and dismal event inNote: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).I2007 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-07-1064 the course of various malignancies, predominantly adenocarcinomas of the lungs and other organs, signaling incurability, shortened life expectancy, and severely compromised quality of life [1,2,3,4]. We recently developed a model of MPE in immunocompetent mice that recapitulates salient features of the human disease, including tumor-associated inflammation, angiogenesis, and vascular hyperpermeability, and is relevant for the study of its pathogenesis and potential treatment innovations [8]. The development of this and other models of cancer in immunocompetent hosts is vital, because recent evidence from human and animal studies has linked inflammation with enhanced formation, growth, and metastasis of tumors [9,10,11,12,13,14,15]. Human MPE contains inflammatory cells and mediators [1, 3, 18], but their role in disease progression is uncertain [19,20,21]

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