Abstract
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.
Highlights
Recurrent symptomatic malignant pleural effusion (MPE) in non-small cell lung cancer (NSCLC) is a troublesome and unresolved clinical problem [1]
2010 to December 2019 to validate the outcome. Those included met the following criteria illustrate in Figure 1: (1) age 30 or over; (2) pathologic diagnosed with adenocarcinoma of lung; (3) presented MPE; (4) underwent target therapy (EGFR-TKI)
883 lung adenocarcinoma patients complicated with MPE were enrolled for analysis
Summary
Recurrent symptomatic MPE in non-small cell lung cancer (NSCLC) is a troublesome and unresolved clinical problem [1]. MPE is associated with excess lung fluid containing malignant cells and elevated lactate dehydrogenase (LDH) whether patients have actionable mutations or not [2]. The combination of epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) with vascular endothelial growth factor (VEGF) blockade has been shown to produce an improved progression-free survival in patients with advanced lung cancer [3,4,5]. EGFR and VEGFR2 are critical regulators in cancer progression, with the upregulation of VEGFA-VEGFR2 signaling pathways contributing to the resistance to EGFR-TKI treatment [7]. Double immunofluorescence has revealed phosphorylated (p-EGFR) and p-VEGFR upregulation in tumor endothelial cells [8]. In endothelial cells isolated from EGFR-TKI treated tumors, increased VEGFR2 mRNA and protein expression, suggesting heightened sensitivity to the inhibitor [9].
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