Abstract
The peculiar localization of body cavity lymphomas implies a specific contribution of the intracavitary microenvironment to the pathogenesis of these tumors. In this study, primary effusion lymphoma (PEL) was used as a model of body cavity lymphoma to investigate the role of mesothelial cells, which line the serous cavities, in lymphoma progression. The crosstalk between mesothelial and lymphomatous cells was studied in cocultures of primary human mesothelial cells (HMC) with PEL cells and a xenograft mouse model of peritoneal PEL. PEL cells were found to induce type 2 epithelial–mesenchymal transition (EMT) in HMC, which converted into a myofibroblastic phenotype characterized by loss of epithelial markers (pan cytokeratin and E-cadherin), expression of EMT-associated transcriptional repressors (Snail1, Slug, Zeb1, Sip1), and acquisition of α-smooth muscle actin (α-SMA), a mesenchymal protein. A progressive thickening of serosal membranes was observed in vivo, accompanied by loss of cytokeratin staining and appearance of α-SMA-expressing cells, confirming that fibrosis occurred during intracavitary PEL development. On the other hand, HMC were found to modulate PEL cell turnover in vitro, increasing their resistance to apoptosis and proliferation. This supportive activity on PEL cells was retained after transdifferentiation, and was impaired by interferon-α2b treatment. On the whole, our results indicate that PEL cells induce type 2 EMT in HMC, which support PEL cell growth and survival, providing a milieu favorable to lymphoma progression. Our findings provide new clues into the mechanisms involved in lymphoma progression and may indicate new targets for effective treatment of malignant effusions growing in body cavities.
Highlights
Body cavity lymphomas are a heterogeneous group of non-Hodgkin’s lymphomas that primarily grow as recurrent effusions in large serous body cavities generally in the absence of a solid tissue mass
Coculture with primary effusion lymphoma (PEL) cells induces a myofibroblastic morphology in mesothelial cells As mesothelium may go through different architectural alterations in response to numerous stimuli, we first assessed whether coculture with the CRO-AP/3 PELderived cell line could affect human mesothelial cells (HMC) morphology
We previously showed that murine mesothelial cells treated with murine interferon-a1 (mIFN-a1)-induced apoptosis in cocultured PEL cells in a tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)-dependent manner [25], suggesting that the targeting of body cavity microenvironment may interfere with PEL growth
Summary
Body cavity lymphomas are a heterogeneous group of non-Hodgkin’s lymphomas that primarily grow as recurrent effusions in large serous body cavities generally in the absence of a solid tissue mass. These lymphomas include primary effusion lymphoma (PEL), associated with human herpesvirus 8 (HHV8) infection [1,2,3], pyothoraxassociated lymphoma, linked to Epstein–Barr virus (EBV) infection, and characterized by pleural effusion and/or a a 2013 The Authors. Cases of body cavity lymphoma not associated with viral infections have been described [6, 7] Why these lymphomatous entities preferentially develop in body cavities is not fully understood. While the influence of bone marrow milieu in malignant hematopoietic disorders is well studied [8], the role of serous cavities, and the mesothelium, in initiation and progression of body cavity lymphomas has not yet been elucidated in depth
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