Cancer Sci. 2020 Jul 24. doi: 10.1111/cas.14584. Online ahead of print.
Malignant pleural effusion (MPE) and paramalignant pleural effusion (PPE) remain debilitating complication in lung cancer patients with poor prognosis and limited treatment options. The role of vascular endothelial cells had not been explored in pleural environment of lung cancer. By integrating MPE and PPE as malignant associated pleural fluid (MAPF), current study aimed to evaluate MAPF on cell proliferation, migration, and angiogenesis of human umbilical vein endothelial cell (HUVEC). First,
increased capillaries were identified in subpleural layer of lung adenocarcinoma. Compatible with pathological observation, ubiquitous elevation of HUVEC survival was identified in MAPF culture no matter underlying cancer type, driver gene mutation, prior treatments, and evidence of malignant cells in pleural fluid. Moreover, MAPF enhanced HUVEC motility with the formation of lamellipodia and filopodia and focal adhesion complex. Tube formation assayed revealed angiogenic behavior with the observation of sheet-like structures. HUVEC cultured with MAPF resulted in significant increase of MAPK phosphorylation. Accompanied with VEGFR2 upregulation in MAPF culture, there were increased expressions of p-STAT3, HIF-1α and Nf-kB. VEGF/VEGFR2 blockade demonstrated regress endothelial migration and angiogenesis, but not cell proliferation. Our data proposed the angiogenic activities of MAPF on vascular endothelial cells that disclosed increased pleural capillaries in lung cancer. Targeting VEGF/VEGFR2 pathway might modulate angiogenic propensity of MAPF in future clinical investigation.