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.

中文翻译：

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Versican调节与肿瘤相关的巨噬细胞特性，以刺激间皮瘤生长。

Versican通过细胞和非细胞自主机制促进实验性肿瘤生长。迄今为止，尚未研究其在间皮瘤进展中的作用。在这项研究中，我们调查了肿瘤来源的Versican对间皮瘤进展的影响及其作用的潜在机制。为此，将胸膜间皮瘤或对照的A17和Aβ1鼠间皮瘤细胞经胸膜内注射到同系小鼠中，以产生胸膜间皮瘤和胸腔积液。使用流式细胞仪评估肿瘤内和胸膜免疫亚群。间皮瘤细胞与同基因巨噬细胞共培养，以检查versican对其相互作用的影响，并评估内皮细胞对versican对内皮通透性的影响。在人间皮瘤和间皮瘤相关的胸腔积液以及良性胸膜组织和积液中评估了Versican表达。我们观察到，versican沉默通过影响体内肿瘤细胞的增殖和凋亡而减少了间皮瘤的质量和胸膜积液，而体外肿瘤细胞的生长仍保持完整，并限制了胸膜血管的通透性。与对照动物相比，携带versican缺陷型肿瘤的小鼠表现出较少的肿瘤/胸膜巨噬细胞和嗜中性白细胞，以及较少的胸膜T调节细胞。与与对照肿瘤细胞共培养的巨噬细胞相比，与versican缺陷型间皮瘤细胞共培养的巨噬细胞朝着M1抗肿瘤表型极化，并显示出增加的肿瘤细胞吞噬能力。在共同文化中 versican缺陷细胞对内皮细胞单层通透性的刺激作用不如对照细胞。Versican在人间皮瘤组织和间皮瘤相关积液中过表达。总之，肿瘤细胞衍生的versican主要通过钝化巨噬细胞的抗肿瘤活性来塑造肿瘤友好的炎症环境，从而刺激间皮瘤的进展。