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

Lignitto, Laura; Mattiolo, Adriana; Negri, Elena; Persano, Luca; Gianesello, Lisa; Chieco‐Bianchi, Luigi; Calabrò, Maria Luisa

doi:10.1002/cam4.159

Cited by 11 publications

(14 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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 ).…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2015

Self Cite

View full text Add to dashboard Cite

PEL is a B-cell non-Hodgkin lymphoma, occurring predominantly as a lymphomatous effusion in body cavities, characterized by aggressive clinical course, with no standard therapy. Based on previous reports that PEL cells display a Warburg phenotype, we hypothesized that the highly hypoxic environment in which they grow in vivo makes them more reliant on glycolysis, and more vulnerable to drugs targeting this pathway. We established here that indeed PEL cells in hypoxia are more sensitive to glycolysis inhibition. Furthermore, since PI3K/Akt/mTOR has been proposed as a drug target in PEL, we ascertained that pathway-specific inhibitors, namely the dual PI3K and mTOR inhibitor, PF-04691502, and the Akt inhibitor, Akti 1/2, display improved cytotoxicity to PEL cells in hypoxic conditions. Unexpectedly, we found that these drugs reduce lactate production/extracellular acidification rate, and, in combination with the glycolysis inhibitor 2-deoxyglucose (2-DG), they shift PEL cells metabolism from aerobic glycolysis towards oxidative respiration. Moreover, the associations possess strong synergistic cytotoxicity towards PEL cells, and thus may reduce adverse reaction in vivo, while displaying very low toxicity to normal lymphocytes. Finally, we showed that the association of 2-DG and PF-04691502 maintains its cytotoxic and proapoptotic effect also in PEL cells co-cultured with human primary mesothelial cells, a condition known to mimic the in vivo environment and to exert a protective and pro-survival action. All together, these results provide a compelling rationale for the clinical development of new therapies for the treatment of PEL, based on combined targeting of glycolytic metabolism and constitutively activated signaling pathways.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Primary Effusion Lymphomamentioning

confidence: 99%

“… 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.…”

Section: Primary Effusion Lymphomamentioning

confidence: 99%

Human Herpesvirus 8 and Lymphoproliferative Diseases

Calabrò¹,

Sarid²

2018

Mediterr J Hematol Infect Dis

Self Cite

View full text Add to dashboard Cite

The spectrum of lymphoproliferative disorders linked to human herpesvirus 8 (HHV-8) infection has constantly been increasing since the discovery of its first etiologic association with primary effusion lymphoma (PEL). PEL is a rapidly progressing non-Hodgkin’s B-cell lymphoma that develops in body cavities in an effusional form. With the increase in the overall survival of PEL patients, as well as the introduction of HHV-8 surveillance in immunocompromised patients, the extracavitary, solid counterpart of PEL was later identified. Moreover, virtually all plasmablastic variants of multicentric Castleman’s disease (MCD) developing in HIV-1-infected individuals harbor HHV-8, providing a strong etiologic link between MCD and this oncogenic herpesvirus. Two other pathologic conditions develop in HIV-1-infected persons concomitantly with MCD: MCD with plasmablastic clusters and HHV-8-positive diffuse large B-cell lymphoma not otherwise specified (HHV-8+ DLBCL NOS), the first likely representing an intermediate stage preceding the full neoplastic form. MCD in leukemic phase has also been described, albeit much less commonly. The germinotropic lymphoproliferative disorder (GLPD) may resemble extracavitary PEL, but develops in immune competent HHV8-infected individuals, and, unlike the other disorders, it responds well to conventional therapies. Almost all HHV-8-mediated lymphoproliferative disorders are the result of an interaction between HHV-8 infection and a dysregulated immunological system, leading to the formation of inflammatory niches in which B cells, at different developmental stages, are infected, proliferate and may eventually shift from a polyclonal state to a monoclonal/neoplastic disorder. Herein, we describe the association between HHV-8 and lymphoproliferative disorders and highlight the predominant distinctive features of each disease.

show abstract

Development of a novel cell line‐derived xenograft model of primary herpesvirus 8‐unrelated effusion large B‐cell lymphoma and antitumor activity of birabresib in vitro and in vivo

et al. 2021

View full text Add to dashboard Cite

Background Primary human herpesvirus 8 (HHV8)‐unrelated effusion large B‐cell lymphoma is a clinical disease entity distinct from HHV8‐positive primary effusion lymphoma (PEL). However, the lack of experimental HHV8‐unrelated effusion large B‐cell lymphoma models continues to hinder the pathophysiologic and therapeutic investigations of this disorder. Methods The lymphoma cells were obtained from the pleural effusion of a patient with primary HHV8‐unrelated effusion large B‐cell lymphoma and cultured in vitro. Results We established a novel HHV8‐unrelated effusion large B‐cell lymphoma cell line, designated Pell‐1, carrying a c‐MYC rearrangement with features distinct from those of HHV8‐positive PEL. Moreover, we developed an HHV8‐unrelated effusion large B‐cell lymphoma cell line‐derived xenograft model. Pell‐1 cells induced profuse lymphomatous ascites and subsequently formed intra‐abdominal tumors after intraperitoneal implantation into irradiated nonobese diabetic/severe combined immunodeficient mice. Thus, this xenograft mouse model mimicked the clinical phenomena observed in patients and recapitulated the sequential stages of aggressive HHV8‐unrelated effusion large B‐cell lymphoma. The bromodomain and extraterminal domain (BET) inhibitors JQ1 and birabresib (MK‐8628/OTX015) reduced the proliferation of Pell‐1 cells in vitro through the induction of cell cycle arrest and apoptosis. The antitumor effect of BET inhibition was also demonstrated in vivo, as birabresib significantly reduced ascites and suppressed tumor progression without apparent adverse effects in the xenografted mice. Conclusion These preclinical findings suggest the therapeutic potential of targeting c‐MYC through BET inhibition in HHV8‐unrelated effusion large B‐cell lymphoma.

show abstract

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

Cited by 11 publications

References 42 publications

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

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

Human Herpesvirus 8 and Lymphoproliferative Diseases

Development of a novel cell line‐derived xenograft model of primary herpesvirus 8‐unrelated effusion large B‐cell lymphoma and antitumor activity of birabresib in vitro and in vivo

Contact Info

Product

Resources

About