1. ¹Institute of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
2. ²Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
3. ³Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
4. ⁴Department of Radiotherapy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
5. ⁵Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Correspondence: Dr W-C Su, Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital and College of Medicine, 138 Sheng-Li Road, Tainan 704, Taiwan. E-mail: sunnysu@mail.ncku.edu.tw; H-S Liu, Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan. E-mail: a713@mail.ncku.edu.tw

Received 1 September 2005; Revised 27 December 2005; Accepted 13 January 2006; Published online 6 March 2006.

Abstract

Malignant pleural effusion (MPE) is a poor prognostic sign for patients with non-small-cell lung cancer (NSCLC). The generation of MPE is largely regulated by vascular endothelial growth factor (VEGF), and upregulation of VEGF by Stat3 has been observed in several types of tumor cells. In this study, we demonstrate constitutively activated Stat3 in several human lung cancer cell lines and in tumor cells infiltrated in the pleurae of patients with adenocarcinoma cell lung cancer (ADCLC) and MPE. The observations suggest that activated Stat3 plays a role in the pathogenesis of ADCLC. In PC14PE6/AS2 cells, a Stat3-positive human ADCLC cell line, autocrine IL-6 activated Stat3 via JAKs, not via Src kinase. PC14PE6/AS2 cells express higher VEGF mRNA and protein than do Stat3-negative PC14PE6/AS2/dnStat3 cells. In an animal model, PC14P6/AS2/dnStat3 cells produced no MPE and less lung metastasis than did PC14P6/AS2 cells. PC14PE6/AS2 cells also expressed higher VEGF protein, microvessel density, and vascular permeability in tumors than did PC14P6/AS2/dnStat3 cells. Therefore, we hypothesize that autocrine IL-6 activation of Stat3 in ADCLC may be involved in the formation of malignant pleural effusion by upregulating VEGF. Higher levels of IL-6 and VEGF were also found in the pleural fluids of patients with ADCLC than in patients with congestive heart failure. The autocrine IL-6/Stat3/VEGF signaling pathway may also be activated in patients with ADCLC and MPE. These findings provide novel targets for the management of MPE.