Unit:
Faculty of MedicineLibrary of the School of Health Sciences
Dissertation committee:
Σπυρίδων Ζακυνθινός, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Νικόλαος Κουλούρης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Στυλιανός Λουκίδης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Χριστίνα Ρούτση, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Ιωάννης Καλομενίδης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Γρηγόριος Στρατάκος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Πέτρος Μπακάκος, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Original Title:
Ο ρόλος του versican στο μεσοθηλίωμα υπεζωκότα
Translated title:
Role of versican in malignant pleural mesothelioma
Summary:
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 intrapleurally 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.
Main subject category:
Health Sciences
Keywords:
Chondroitin sulfate proteoglycan core protein 2, Pleural neoplasms, Monocytes / macrophages, Extra-cellular matrix, Tumor-immunology
Number of references:
166
