Crosstalk between the mesothelium and lymphomatous cells: insight into the mechanisms involved in the progression of body cavity lymphomas

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.

Reversal of the glycolytic phenotype of primary effusion lymphoma cells by combined targeting of cellular metabolism and PI3K/Akt/ mTOR signaling

“…Due to the recently demonstrated shielding effect of the mesothelium on lymphoma progression [ 69 ], we then asked whether the mesothelial microenvironment protects against 2-DG+PF-04691502-facilitated apoptosis. To mimic the physiological microenvironment, BCBL1 cells were co-cultured with primary human mesothelial cells (HMC) for 48 hours, a condition sufficient to highlight the pro-survival effect of HMC on BCBL1 cells (Figure 6F ).…”

“…Moreover, it is particularly important that the pro-apoptotic function of this drug association also prevails over the shielding action of the HMC in the HMC-BCBL1 co-culture performed to mimic the PEL microenvironment [ 69 ]. Finally, it is worth remembering that we have shown here that the above drug associations exert very low toxicity in normal human B and T lymphocytes, compared to PEL cells, suggesting some degree of specificity towards cancer cells.…”

“…Primary human mesothelial cells (HMC) were isolated and cultured as previously reported [ 69 ]. To evaluate the activity of 2-DG and PF on BCBL1 cells in a context mimicking the intracavitary environment, 2 × 10 5 BCBL1 cells were co-cultured with subconfluent cells first passage HMC in 6-well plates with or without drug treatment for 48 hours.…”

Human Herpesvirus 8 and Lymphoproliferative Diseases

“…Indeed, in vitro co-culture studies showed that mesothelial cells could modify the turnover of PEL cells by increasing their proliferation and their resistance to apoptotic stimuli, thus generating an environment favorable to PEL progression. 50 On the other hand, PEL cells, through the release of Transforming Growth Factor (TGF)-beta, induce type 2 epithelial-mesenchymal transition (EMT) in primary human mesothelial cells. 50 , 51 This can be observed in co-culture systems as well as in a preclinical animal model of SCID/PEL mimicking the aggressive nature of PEL in humans.…”

“… 50 On the other hand, PEL cells, through the release of Transforming Growth Factor (TGF)-beta, induce type 2 epithelial-mesenchymal transition (EMT) in primary human mesothelial cells. 50 , 51 This can be observed in co-culture systems as well as in a preclinical animal model of SCID/PEL mimicking the aggressive nature of PEL in humans. 28 Primary human mesothelial cells have a polygonal shape and form a regular monolayer in culture.…”