Pentraxin 3 Inhibits the Angiogenic Potential of Multiple Myeloma Cells.

Abstract

Simple SummaryBone marrow (BM) angiogenesis represents a key aspect in the progression of multiple myeloma (MM) and is strictly linked to the balance between pro-angiogenic and anti-angiogenic players produced by both neoplastic and stromal components. It has been shown that Fibroblast Growth Factors (FGFs) play a pivotal role in the angiogenic switch occurring during MM progression. Accordingly, the natural FGF antagonist Long Pentraxin 3 (PTX3) is able to reduce the activation of BM stromal components induced by FGFs. This work explores, for the first time, the anti-angiogenic role of PTX3 produced by MM cells demonstrating that the inducible expression of PTX3 is able to impair MM neovascularization, the onset of a proficient BM vascular niche and, ultimately, to impair tumor growth and dissemination.During multiple myeloma (MM) progression the activation of the angiogenic process represents a key step for the formation of the vascular niche, where different stromal components and neoplastic cells collaborate and foster tumor growth. Among the different pro-angiogenic players, Fibroblast Growth Factor 2 (FGF2) plays a pivotal role in BM vascularization occurring during MM progression. Long Pentraxin 3 (PTX3), a natural FGF antagonist, is able to reduce the activation of stromal components promoted by FGF2 in various in vitro models. An increased FGF/PTX3 ratio has also been found to occur during MM evolution, suggesting that restoring the “physiological” FGF/PTX3 ratio in plasma cells and BM stromal cells (BMSCs) might impact MM. In this work, taking advantage of PTX3-inducible human MM models, we show that PTX3 produced by tumor cells is able to restore a balanced FGF/PTX3 ratio sufficient to prevent the activation of the FGF/FGFR system in endothelial cells and to reduce the angiogenic capacity of MM cells in different in vivo models. As a result of this anti-angiogenic activity, PTX3 overexpression causes a significant reduction of the tumor burden in both subcutaneously grafted and systemic MM models. These data pave the way for the exploitation of PTX3-derived anti-angiogenic approaches in MM.