Icmt inhibition exerts anti-angiogenic and anti-hyperpermeability activities impeding malignant pleural effusion

Magkouta, Sophia; Pappas, Apostolos; Moschos, Charalampos; Vazakidou, Maria-Eleni; Psarra, Katherina; Kalomenidis, Ioannis

doi:10.18632/oncotarget.7912

Cited by 10 publications

(8 citation statements)

References 35 publications

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“…The results are consistent with the clinical results. As we all know, invasion and metastasis of tumor cells are associated with angiogenesis and lymphangiogenesis, which are also important factors contributing to the formation of pleural effusion . However, negative results of relative cell biology experiments (migration, proliferation, angiogenesis assay, cell cycle, and apoptosis) were shown in miR‐93 inhibitor group.…”

Section: Discussionmentioning

confidence: 95%

The role of microRNA‐93 regulating angiopoietin2 in the formation of malignant pleural effusion

et al. 2017

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The biological roles of miRNAs in the development of malignant pleural effusion (MPE) are unclear. In this study, the miRNA microarray analysis was performed in two different prognosis groups of lung adenocarcinoma patients. Expression profiles of miRNAs in MPEs were identified. With the help of quantification PCR, we confirmed the expression differences of miRNAs and further analyzed their biological functions and relative target genes in vitro. The target gene of miR‐93 was estimated by online database, and also, the protein was tested. The target gene and the binding sites of specific miRNA were estimated by online database. The combining capacity of binding sites was verified by luciferase reporter gene assay, and the target gene protein was tested by western blot. We detected 107 miRNAs with expression differences (n = 10) and confirmed significant expression differences in miR‐93 and miR‐146a in two groups of patients (n = 84). By manipulating miR‐93 expression of human lymphatic endothelial cells (HLEC) and human umbilical vein endothelial cells (HUVEC), we discovered that high expression of miR‐93 inhibited migration, proliferation, and angiogenesis. And also, miR‐93 increased not only apoptosis, but also G1 phase cell block. By using luciferase reporter gene assay and western blot, we confirmed that angiopoietin2 (Ang2) was the target of miR‐93. The data showed that miR‐93 has an inhibiting effect on pleural effusion. By targeting Ang2, miR‐93 regulates angiogenesis and lymphangiogenesis and plays a role in pathogenetic mechanism of MPE. MiR‐93/Ang2 may shed light on potential new targets in cancer treatment.

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Section: Discussionmentioning

confidence: 95%

The role of microRNA‐93 regulating angiopoietin2 in the formation of malignant pleural effusion

et al. 2017

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“…Versicandeficient mesothelioma stable clones were created using plasmid vectors (online data supplement) and maintained as described elsewhere. 32 C57Bl/6 and Balb/c mice were purchased from BSRC Al. Fleming or Hellenic Pasteur Institute, while Tomato C57Bl/6 mice were kindly offered to us by Dr. GT Stathopoulos (Patras, Greece) and were housed at the Animal Model Research Unit of "Evangelismos" Hospital (EL25BIO015, Athens, Greece), receiving food and water ad libitum.…”

Section: Cells and Animalsmentioning

confidence: 99%

“…Tumor tissue and cell culture lysates were analyzed by western immunoblotting in order to assess versican expression (online data supplement). 32 Nucleated cells isolated from mesotheliomas and pleural effusions from C57Bl/6 mice were analyzed by flow cytometry (online data supplement).…”

Section: In Vivo Studiesmentioning

confidence: 99%

Versican modulates tumor-associated macrophage properties to stimulate mesothelioma growth

et al. 2018

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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. ARTICLE HISTORY

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“…Tumor tissue paraffin sections were immunohistochemically analyzed for Ki-67 (clone D385, Cell Signaling, Danvers, MA) for evaluation of tumor cell proliferation. Tumor cell apoptosis was estimated by TUNEL as previously described [ 25 ]. For immunofluorescence analysis, tumor sections were fixed and stained for the presence of CD31 (clone MEC 13.3, BD Biosciences, Athens, Greece) and a-SMA (clone 1A4, Sigma-Aldrich, Steinheim, Germany) for endothelial and pericyte staining, respectively.…”

Section: Methodsmentioning

confidence: 99%

Targeting Tie-2/angiopoietin axis in experimental mesothelioma confers differential responses and raises predictive implications

et al. 2018

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Malignant pleural mesothelioma is resistant to currently used treatment. Angiopoieitn-1 directly promotes mesothelioma cell growth in a Tie-2-dependent fashion. Angiopoietin/Tie-2 axis may thus be valid targets for therapeutic interventions against mesothelioma. We hypothesized that a soluble angiopoietin inhibitor (Murine Tek-deltaFc) would halt mesothelioma progression in vivo by enhancing mesothelioma cell proliferation and inhibiting tumor angiogenesis. Our hypothesis was challenged on two syngeneic mesothelioma in vivo models (AB1 cells-Balb/c mice and AE17 cells-C57BL/6 mice. Even though both mesothelioma cell lines express the Angiopoietin-1/-2 and Tie-2, murine Tek-deltaFc hampered AB1 but not AE17 mesothelioma growth in vivo by enhancing tumor cell apoptosis and limiting tumor angiogenesis. Neither angiopoietins (Angs)-1 and -2 nor the inhibitor affected mesothelioma cell growth in vitro. AB1 (responding) tumors were more vascularized and displayed higher endothelial Tie-2 and lower tumor Ang-1 expression than the (non-responding) AE17 tumors. Angiopoietins-1 and -2 are expressed in tumors and pleural cavity of mesothelioma patients demonstrating the clinical relevance of our experimental observations. In conclusion, disrupting Ang-Tie-2 signaling limits mesothelioma angiogenesis and halts tumor progression. Tumor vascularity, endothelial Tie-2 expression and tumor Ang-1 expression may predict mesothelioma response to Tek-deltaFc.

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Icmt inhibition exerts anti-angiogenic and anti-hyperpermeability activities impeding malignant pleural effusion

Cited by 10 publications

References 35 publications

The role of microRNA‐93 regulating angiopoietin2 in the formation of malignant pleural effusion

The role of microRNA‐93 regulating angiopoietin2 in the formation of malignant pleural effusion

Versican modulates tumor-associated macrophage properties to stimulate mesothelioma growth

Targeting Tie-2/angiopoietin axis in experimental mesothelioma confers differential responses and raises predictive implications

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