Temsirolimus targets multiple hallmarks of cancer to impede mesothelioma growth <i>in vivo</i>

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

doi:10.1111/resp.12604

Cited by 16 publications

(11 citation statements)

References 44 publications

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“…In order to create experimental MPM, we injected versican-deficient (shvcan) or versican-expressing (vector) AE17 or AB1 (5X10 5 ) cells into the pleural cavity of sex-, weight-and age-matched syngeneic C57Bl/6 and Balb/c mice, respectively. 33 Mice were euthanized 14 days upon tumor cell inoculation. Following sacrifice, pleural fluid was retrieved and quantified, tumor mass was collected and weighed and tumor vascular permeability was assessed using the in vivo Evans Blue assay.…”

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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Section: In Vivo Studiesmentioning

confidence: 99%

Versican modulates tumor-associated macrophage properties to stimulate mesothelioma growth

et al. 2018

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“…It is therefore unlikely that different sensitivity to the compound can explain the divergent in vivo responses. Since adenocarcinoma pleural growth is characterized by disseminated small foci [ 16 ] while mesothelioma forms massive tumors [ 17 ] it could be speculated that different pharmacokinetics may play a role in the observed different response in vivo . The observation that the MPE size was independent of the effects of the inhibitor in tumor burden, supports the assumption that the mechanisms determining the pleural fluid accumulation and the tumor growth are different.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of the Icmt enzyme prevents post-translational modification of GTPases that is required for their activation and this might be the most effective way to block GTPase activity [ 14 ]. In the studies presented here, we aimed at investigating the effects of the Icmt inhibitor cysmethynil [ 15 ] in experimental MPE [ 16 , 17 ] and explore the underlying mechanisms. We hypothesized that cysmethynil would block MPE accumulation by inhibiting angiogenesis and pleural vascular permeability and by modulating tumor-initiated host immune response.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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“…Among targeted therapies are agents that inhibit mammalian target of rapamycin. Using a syngeneic murine mesothelioma model, temsirolimus (mammalian target of rapamycin inhibitor) curtailed mesothelioma growth by inducing tumour cell apoptosis, inhibiting tumour angiogenesis and modulating host immune response . Whether temsirolimus combined with standard chemotherapy (cisplatin with pemetrexed) would improve overall survival of mesothelioma patients has yet to be explored.…”

Section: Pleural Diseasementioning

confidence: 99%

Year in review 2015: Lung cancer, pleural diseases, respiratory infections, bronchiectasis and tuberculosis, bronchoscopic intervention and imaging

et al. 2016

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Temsirolimus targets multiple hallmarks of cancer to impede mesothelioma growth in vivo

Abstract: In conclusion, temsirolimus apart from inducing tumour cell apoptosis, targets tumour angiogenesis and influences inflammatory tumour microenvironment to halt experimental mesothelioma growth in vivo.

Cited by 16 publications

References 44 publications

Versican modulates tumor-associated macrophage properties to stimulate mesothelioma growth

Versican modulates tumor-associated macrophage properties to stimulate mesothelioma growth

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

Year in review 2015: Lung cancer, pleural diseases, respiratory infections, bronchiectasis and tuberculosis, bronchoscopic intervention and imaging

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