152 Insights into the pathogenesis of HHV8-driven body cavity-based lymphoma

Abstract

Human herpesvirus 8 is associated with the development of primary effusion lymphoma (PEL), an aggressive non-Hodgkin’s lymphoma characterized by the proliferation of the malignant lymphocytes almost exclusively in large serous cavities. The mechanisms involved in the preferential tropism for serous cavities and in the aggressive course of PEL remain to be fully clarified. To study the role of host microenvironment in PEL progression, we previously compared the antineoplastic activity of a murine interferon◊-expressing lentiviral vector (mIFN-◊-LV) to that of a human IFN-◊-LV in a murine model of peritoneal PEL. We demonstrated that in vivo targeting of the murine microenvironment showed an antineoplastic activity comparable to that observed with the hIFN-◊-LV. These findings highlighted the relevant role of body cavity environment in PEL growth and indicated that modulation of microenvironment may impair PEL growth in vivo. By using cocultures of PEL cell lines with human mesothelial cells (HMC), we mimicked the interactions existing in body cavities to analyze the mechanisms involved in PEL progression. PEL cells induced a myofibroblastic morphology in HMC, paralleled by an expression profile indicative of the occurrence of epithelial-mesenchymal transition (EMT). Moreover, HMC increased proliferation and resistance to apoptosis of PEL cells. These data indicate that PEL cells induce EMT in HMC and fibrosis of serous membranes. In turn, HMC modulate PEL cell turnover, thus providing a milieu favorable to PEL progression. These findings open new perspectives into the mechanisms involved in PEL progression and may indicate new targets for PEL treatment.