BAFF and APRIL as TNF superfamily molecules and angiogenesis parallel progression of human multiple myeloma

Abstract

Tumour necrosis factor alpha (TNF-α) is an inflammatory cytokine with a wide spectrum of biological activity, including angiogenesis. B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are members of the TNF-α family. Vascular endothelial growth factor (VEGF), on the other hand, is one of the most characteristic pro-angiogenic cytokines produced by multiple cell types in multiple myeloma (MM). We have analysed BAFF and APRIL concentrations in parallel with pro-angiogenic cytokines in serum and trephine biopsy, and the bone marrow microvascular density (MVD) in 50 patients with newly diagnosed IgG MM and 24 healthy volunteers. The study showed statistically higher concentrations of BAFF, APRIL and TNF-α, as well as VEGF and its receptor, in MM patients compared to healthy volunteers and patients in advanced stages of the disease. A statistically positive correlation between the concentration of TNF-α and the expression of VEGF was demonstrated, and so was a positive link between BAFF, APRIL, MVD and lactate dehydrogenase (LDH). Furthermore, we observed a significant decrease in all studied cytokines after anti-angiogenic therapy, with meaningful differences between responders (at least partial remission) and patients with stable disease. It was also established that APRIL, but not BAFF, correlated with pro-angiogenic cytokines such as VEGF with its receptor, MVD and syndecan-1. Finally, our results showed that serum BAFF and APRIL levels could be useful biomarkers of MM disease activity and its progression which suggests that APRIL could be a possible novel therapeutic target in MM.

Soluble B-Cell Maturation Antigen Mediates Tumor-Induced Immune Deficiency in Multiple Myeloma

“…The highest absorbance occurred at concentrations of 100 ng/mL BCMA and 1 ng/mL BAFF (Fig. 1A), which are similar to those found in plasma from multiple myeloma patients (28,29).…”

Phase 1 Study of Tabalumab, a Human Anti-B-Cell Activating Factor Antibody, and Bortezomib in Patients with Relapsed/Refractory Multiple Myeloma

“…Our data suggested that BAFF was produced by the stromal compartment, specifically the osteoclast compartment, and that treatment with an anti-BAFF antibody resulted in antitumor activity and decreased osteoclast numbers (4). Others have shown that elevated BAFF and APRIL levels are associated with poorer outcome and more aggressive disease (9,10). This association of elevated BAFF levels with poorer outcomes, along with the role of BAFF in the survival of multiple myeloma cells, provided the rationale for targeting BAFF in relapsed/refractory multiple myeloma.…”

APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment

“…These results further support a recent study showing that APRIL, but not BAFF, is correlated with expression of VEGF and its receptors, MVD and CD138, and with progression of human MM. 19 Furthermore, in a xenogeneic model where MM cells were subcutaneously injected into SCID mice deficient in APRIL, APRIL by itself was shown to be essential for in vivo MM development. 25 Moreover, the lack of APRIL equally impaired U266 (TACI Because BCMA overexpression by itself is sufficient to augment MM cell proliferation and survival, the majority of MM cell lines (also TACI low/neg ) may bypass APRIL-induced proliferation.…”

“…[15][16][17] It is elevated in the circulation of MM patients vs normal donors. 18,19 Besides binding to BCMA, APRIL also binds to the receptor transmembrane activator and calcium modulator (TACI), which is also overexpressed on malignant PCs from patients vs normal donors. 20 Despite its association with survival of MM cells on the BM microenvironment, 20,21 TACI expression on MM cell lines and patient MM cells is reported to be variable and lower compared with BCMA.…”