Viral IL-6 is also considered to contribute significantly to HHV-8-associated pathogenesis, since vIL-6 can promote cell proliferation, cell survival, and angiogenesis that are characteristic of HHV-8-associated Kaposi's sarcoma, PEL and multicentric Castleman's disease (MCD), in addition to proinflammatory activities observed in MCD-like "Kaposi's sarcoma-associated herpesvirus-induced cytokine syndrome."
Although we found the production of VEGF and IL-6, and the expression of IL-6Rα in PEL cell lines, bevacizumab and tocilizumab did not inhibit the proliferation of PEL cells in vitro.
Depletion of vIL-6 in PEL cells increased levels of the catalytically active, proteolytically cleaved form of CatD, corresponding with decreased PEL cell viability.
Recent advances in dissecting the pathogenesis of these diseases have indicated that the viral cytokine IL-6 and the cellular cytokines/growth factors IL-10, IL-6, stromal cell-derived factor 1, and vascular endothelial growth factor are important contributors to the growth, survival, and spread of PEL and MCD and are therefore potential targets for drug development.
We find that (1) rapamycin is efficacious against PEL in culture and in a murine xenograft model; (2) mTOR, its activator Akt, and its target p70S6 kinase are phosphorylated in PEL; (3) rapamycin inhibits mTOR signaling as determined by S6 phosphorylation; (4) KSHV transcription is unaffected; (5) inhibition of IL-10 signaling correlates with drug sensitivity; and (6) addition of exogenous IL-10 or IL-6 can reverse the rapamycin growth arrest.
To investigate whether HHV-8 may contribute to PEL development in the absence of EBV, the expression of seven potentially oncogenic HHV-8 open reading frames (ORFs) (ORF72/viral cyclin D, ORF16/viral bcl-2, ORF74/viral G-protein coupled receptor, ORFK2/viral IL-6, ORFK13/viral FLICE inhibitory protein, ORFK9/viral interferon regulatory factor, and ORFK1, equivalent to the gene encoding herpesvirus saimiri transforming protein) was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) in an EBV-negative PEL presenting in an HIV-negative patient.
Anti-IL6 neutralizing antibodies had no effect on PEL cell line proliferation; conversely, whereas anti-IL6R alone inhibited only weakly, anti-gp130 and anti-gp130 plus anti-IL6R showed strong inhibitory effects (>20% inhibition in 5/9 lines and >60% inhibition in 3/9 lines).
Immunomodulatory drugs target IKZF1-IRF4-MYC axis in primary effusion lymphoma in a cereblon-dependent manner and display synergistic cytotoxicity with BRD4 inhibitors.
STR-428 represents a unique, B-cell lymphoma cell line carrying concurrent rearrangement of BCL2 and c-MYC genes with features distinct from those of HHV-8-related primary effusion lymphoma.
These findings suggest that there may be an additional subcategory of primary effusion lymphoma that is not associated with HHV8 nor c-MYC(R) but is pathogenetically associated with the PAX-5 gene or hepatitis C virus.
The PELs share several features with acquired immunodeficiency syndrome (AIDS)-associated primary central nervous system lymphomas (1 degree CNS-L), including B-cell phenotype, infection with Epstein-Barr virus, and lack of c-myc gene rearrangements.
In a PEL xenograft mouse model that showed profuse ascites, bevacizumab suppressed ascites formation completely, indicating the critical role of VEGF for PEL fluid retention.
PEL effusions usually contain vIL-6 at high concentrations; since vIL-6 induces vascular endothelial growth factor, vIL-6 likely contributes to vascular permeability and formation of PEL effusions.
KSHV-associated primary effusion lymphomas (PELs) secrete high levels of vascular endothelial growth factor (VEGF) and viral interleukin-6 (vIL-6) in vitro and VEGF, vIL-6, and basic-fibroblast growth factor (b-FGF) in mouse xenografts.
Finally, we show that PEL cells extravasate through the endothelial barrier and that the specific tyrosine kinase inhibitor of VEGF receptors, PTK-787/ZK-222584, the anti-VEGF antibody, bevacizumab or the gap junction inhibitor 18-alpha-glycyrrhetinic acid, partially attenuate PEL cell extravasation.
Recent advances in dissecting the pathogenesis of these diseases have indicated that the viral cytokine IL-6 and the cellular cytokines/growth factors IL-10, IL-6, stromal cell-derived factor 1, and vascular endothelial growth factor are important contributors to the growth, survival, and spread of PEL and MCD and are therefore potential targets for drug development.
In particular, vascular endothelial growth factor (VEGF), whose stimulation of vascular permeability is thought to be critical to the pathogenesis of PEL, was also produced in large quantities.