Abstract
Small GTPases are pivotal regulators of several aspects of tumor progression. Their implication in angiogenesis, vascular permeability and tumor-associated inflammatory responses is relevant to the pathobiology of Malignant Pleural Effusion (MPE). Inhibition of isoprenylcysteine carboxylmethyltransferase (Icmt) abrogates small GTPase activation. We therefore hypothesized that cysmethynil, an Icmt inhibitor would limit pleural fluid accumulation in two models, a lung-adenocarcinoma and a mesothelioma-induced MPE. Cysmethynil significantly reduced MPE volume in both models and tumor burden in the adenocarcinoma model. It inhibited pleural vascular permeability and tumor angiogenesis in vivo and reduced endothelial cell proliferation, migration and tube formation in vitro. Cysmethynil also promoted M1 anti-tumor macrophage homing in the pleural space in vivo, and inhibited tumor-induced polarization of macrophages towards a M2 phenotype in vitro. In addition, the inhibitor promoted adenocarcinoma cell apoptosis in vivo. Inhibition of small GTPase might thus represent a valuable strategy for pharmacotherapy of MPE.
Highlights
Malignant pleural effusion (MPE) i.e. the accumulation of fluid in the pleural cavity resulting from tumor cell infiltration of the pleura, is a common manifestation of a wide range of malignancies and is related to short life expectancy and significant morbidity [1, 2]
We demonstrated that the inhibitor significantly reduced pleural vascular permeability (Figure 2A) and tumor angiogenesis in both models (Figure 2B and 2C)
In the studies presented here we aimed at examining whether cysmethynil, a small GTPase inhibitor, possesses an MPE-limiting capacity, using two experimental MPE models established by our group
Summary
Malignant pleural effusion (MPE) i.e. the accumulation of fluid in the pleural cavity resulting from tumor cell infiltration of the pleura, is a common manifestation of a wide range of malignancies and is related to short life expectancy and significant morbidity [1, 2]. Small GTPases are G-proteins involved in the transduction of signals that promote epithelial cell transformation and cancer cell proliferation, survival, migration and invasion being critical to tumor initiation, progression and metastasis [5, 6]. Besides their role in tumor cell biology, they orchestrate several hostrelated tumor-promoting phenomena such as angiogenesis [7,8,9], vascular permeability [10, 11], and tumorassociated inflammatory responses [12]. We hypothesized that cysmethynil would block MPE accumulation by inhibiting angiogenesis and pleural vascular permeability and by modulating tumor-initiated host immune response
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