Versican modulates tumor-associated macrophage properties to stimulate mesothelioma growth

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.

KEYWORDS:

• Chondroitin sulfate proteoglycan core protein 2
• pleural neoplasms
• monocytes/macrophages
• extra-cellular matrix
• tumor-immunology

Acknowledgments

We thank Dr E. Aravidou and Z. Kollia for professional veterinarian and animal care assistance, respectively.

Disclosure statement

Authors declare no conflict of interest.

Supplemental online material

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Availability of materials & data

Materials and data are available upon contact with the corresponding author.

Authors contribution

Supplemental data for this article can be access on the publisher’s website.

Authors contribution

A.G. Pappas did most of the experimental work and wrote the first draft. S. Magkouta, I. Pateras, C. Moschos, M.E. Vazakidou, K. Psarra and V. Gourgoulis contributed in different parts of the experimental work and reviewed the manuscript. I. Skianis conducted the statistical analysis and reviewed the manuscript. I. Kalomenidis conceived the idea of the study, designed and supervised the experiments and critically contributed in writing and reviewing the manuscript.

Additional information

Funding

The current project was funded by the Greek state Diretorate of Scholarships (ΙΚΥ), under the following sponsorship: “Research projects for excellence IKY/Siemens” [grant number: 2755].