ABSTRACT
Versican promotes experimental tumor growth through cell- and non cell-autonomous mechanisms. Its role in mesothelioma progression has not been investigated so far. In this study we investigated the impact of tumor-derived versican in mesothelioma progression and the underlying mechanism of its action. For this purpose, versican-silenced or control ΑΕ17 and ΑΒ1 murine mesothelioma cells were intrapleuraly injected into syngeneic mice, in order to create pleural mesotheliomas and pleural effusions. Intratumoral and pleural immune subsets were assessed using flow cytometry. Mesothelioma cells were co-cultured with syngeneic macrophages to examine versican's impact on their interaction and endothelial cells to assess the effect of versican in endothelial permeability. Versican expression was assessed in human mesotheliomas and mesothelioma-related pleural effusions and benign pleural tissue and effusions. We observed that, versican silencing reduced mesothelioma mass and pleural fluid volume by affecting tumor cell proliferation and apoptosis in vivo, while tumor cell growth remained intact in vitro, and limited pleural vascular permeability. Mice harboring versican-deficient tumors presented fewer tumor/pleural macrophages and neutrophils, and fewer pleural T-regulatory cells, compared to the control animals. Macrophages co-cultured with versican-deficient mesothelioma cells were polarized towards M1 anti-tumor phenotype and demonstrated increased tumor cell phagocytic capacity, compared to macrophages co-cultured with control tumor cells. In co-culture, endothelial monolayer permeability was less effectively stimulated by versican-deficient cells than control cells. Versican was over-expressed in human mesothelioma tissue and mesothelioma-associated effusion. In conclusion, tumor cell-derived versican stimulates mesothelioma progression by shaping a tumor friendly inflammatory milieu, mainly by blunting macrophage anti-tumor activities.
ABSTRACT
BACKGROUND AND OBJECTIVE: Anti-angiogenic treatment has been recently shown to be clinically beneficial for mesothelioma patients. Angiopoietins-1 and -2 are key regulators of tumor angiogenesis. Ang-1 is mainly known to promote angiogenesis and vessel stability, while Ang-2 could serve as an antagonist of Ang-1 causing vessel regression and destabilization or enhance angiogenesis in a context-dependent manner. We hypothesized that Ang-1 would promote and Ang2 would halt experimental mesothelioma by affecting tumor angiogenesis. METHODS: To examine the effects of angiopoietins in mesothelioma angiogenesis and in vivo growth we constructed Ang-1 or Ang-2 overexpressing AE17 and AB1 mesothelioma cells and implanted them in the respective syngeneic animals. We also explored the clinical relevance of our observations using the human tumoral mRNAseq data available in the TCGA database. RESULTS AND CONCLUSIONS: Ang-1 promotes mesothelioma angiogenesis and growth while the effect of Ang-2 is context-dependent. Low Ang-1 levels in human mesotheliomas are associated with the epitheloid subtype. Tumors of high Ang-1, or concurrent high Ang-2 and VEGF expression present high PECAM-1 and CDH5 expression, markers of vascularity and vascular stability, respectively. Our results highlight the importance of angiopoietins in mesothelioma pathophysiology and pave the way for the clinical development of novel anti-angiogenic strategies.
Subject(s)
Angiopoietin-1/metabolism , Angiopoietin-2/metabolism , Mesothelioma/metabolism , Animals , Disease Progression , Female , Humans , Male , Mesothelioma/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , RNA, Messenger/metabolism , Signal Transduction/physiology , Vascular Endothelial Growth Factor A/metabolismABSTRACT
INTRODUCTION: Since its introduction, small bowel video capsule endoscopy (VCE) use has evolved considerably. AIM: Evaluation of the temporal changes of small bowel VCE utilization in three tertiary centers in Greece in Era 1 (2002-2009) and Era 2 (2010-2014) and the development a forecast model for future VCE use during 2015-2017. MATERIALS AND METHODS: Data from all small bowel VCE examinations were retrieved and analyzed in terms of the annual number of the performed examinations, their indications and the significance of their findings. RESULTS: Overall, we evaluated 3724 VCE examinations. The number of studies peaked in 2009 (n=595) and then decreased to reach 225 in 2014. Overall, more (53.8 vs. 51.4%) patients with iron-deficiency anemia and obscure gastrointestinal bleeding (IDA/OGIB) and fewer (10.7 vs. 14%) patients with chronic diarrhea were evaluated in Era 2 compared with Era 1 (P=0.046). In Era 2, there were more nondiagnostic examinations (39.5 vs. 29.3%, P<0.001), whereas the rate of cases with relevant findings decreased from 47.8 to 40.9%. According to the time trend analysis, we developed a forecast model with two scenarios: the pessimistic and the optimistic. Validation of the model with 2015 data showed that reality was close to the pessimistic scenario: the number of exams further decreased to 190, studies carried out for IDA/OGIB increased to 67%, and there were more negative than positive exams (40.7 vs. 39.2%). CONCLUSION: The number of VCE studies carried out after the emergence of the financial crisis decreased significantly and VCE indications were optimized. Our forecast model predicts lower numbers of VCE studies, with IDA/OGIB being the dominant indication. However, the predicted increase of negative exams requires further evaluation.
