Concurrent Blockade of Endothelial EGFR and VEGF Signaling on Malignant Associated Pleural Fluid Induced Angiogenesis: From Clinic to Bench
Wei-Teing Chen,
Yu-Huei Lin,
Chih-Ying Changchien,
Ying Chen,
Hsin-Han Chang,
Wen-Chiuan Tsai,
Hao-Chung Tsai,
Chieh-Yung Wang,
Ming-Sheng Shen,
Li-Ting Cheng,
Chen-Liang Tsai
Affiliations
Wei-Teing Chen
Division of Chest Medicine, Department of Medicine, Cheng-Hsin General Hospital, Taipei 112, Taiwan
Yu-Huei Lin
Post-Baccalaureate Program in Nursing, College of Nursing, Taipei Medical University, Taipei 110, Taiwan
Chih-Ying Changchien
Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
Ying Chen
Department of Biology and Anatomy, National Defense Medical Center, Taipei 114, Taiwan
Hsin-Han Chang
Department of Biology and Anatomy, National Defense Medical Center, Taipei 114, Taiwan
Wen-Chiuan Tsai
Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
Hao-Chung Tsai
Division of Chest Medicine, Department of Internal Medicine, Tri-Service General Hospital Songshan Branch, Taipei 105, Taiwan
Chieh-Yung Wang
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
Ming-Sheng Shen
Department of Internal Medicine, Taichung Armed Force General Hospital, Taichung 411, Taiwan
Li-Ting Cheng
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
Chen-Liang Tsai
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
Malignant-associated pleural fluid (MAPF) represented an unsolved problem in advanced lung cancer. Our previous work characterized increased pleural angiogenesis in lung adenocarcinoma and the propensity of MAPF on endothelial angiogenesis. This study investigated the combined efficacy of the tyrosine kinase inhibitor (gefitinib) and bevacizumab in opposing MAPF-induced angiogenesis. In lung adenocarcinoma patients with malignant pleural effusion (MPE), Kaplan–Meier analysis revealed the benefit of cotreatment with target therapy and bevacizumab. Increased EGFR expression was observed in the pleural microvessels of patients with lung adenocarcinoma both with and without mutations in EGFR. MAPF was obtained from lung adenocarcinoma patients both wild-type and mutant EGFRs. Total and phosphorylated EGFR were upregulated in HUVEC cultured with MAPF. Treatment with gefitinib as an EGFR inhibitor suppressed MAPF-induced endothelial migration and partially attenuated endothelial proliferation in both wild-type and mutant EGFR lung adenocarcinoma. Cotreatment with gefitinib and bevacizumab produced better inhibition of MAPF-induced endothelial angiogenesis than gefitinib alone in the mutant EGFR subgroup. Protein analysis of MAPF-derived exosomes revealed abundant EGFR and p-EGFR components that implied possible transfer to endothelial cells. Concluding Kaplan–Meier analysis and in vitro studies, the results indicated that the addition of bevacizumab on gefitinib treatment could suppress MAPF-induced angiogenesis in lung adenocarcinoma patients.
