Heparanase promotes myeloma progression by inducing mesenchymal features and motility of myeloma cells

Abstract

Bone dissemination and bone disease occur in approximately 80% of patients with multiple myeloma (MM) and are a major cause of patient mortality. We previously demonstrated that MM cell-derived heparanase (HPSE) is a major driver of MM dissemination to and progression in new bone sites. However the mechanism(s) by which HPSE promotes MM progression remains unclear. In the present study, we investigated the involvement of mesenchymal features in HPSE-promoted MM progression in bone. Using a combination of molecular, biochemical, cellular, and in vivo approaches, we demonstrated that (1) HPSE enhanced the expression of mesenchymal markers in both MM and vascular endothelial cells; (2) HPSE expression in patient myeloma cells positively correlated with the expression of the mesenchymal markers vimentin and fibronectin. Additional mechanistic studies revealed that the enhanced mesenchymal-like phenotype induced by HPSE in MM cells is due, at least in part, to the stimulation of the ERK signaling pathway. Finally, knockdown of vimentin in HPSE expressing MM cells resulted in significantly attenuated MM cell dissemination and tumor growth in vivo. Collectively, these data demonstrate that the mesenchymal features induced by HPSE in MM cells contribute to enhanced tumor cell motility and bone-dissemination.

Mechanisms of heparanase inhibitors in cancer therapy

“…95 These findings support that heparanase promotes angiogenesis and metastasis in multiple myeloma by supporting the mesenchymal transition of both tumor and endothelial cells. 95 …”

“…95 Specifically, increased heparanase expression in both myeloma and endothelial cells correlates with the augmented expression of mesenchymal markers vimentin and fibronectin. 95 Mechanistically, the alteration in mesenchymal markers is thought to be promoted by the ERK signaling pathway.…”

“…95 Specifically, increased heparanase expression in both myeloma and endothelial cells correlates with the augmented expression of mesenchymal markers vimentin and fibronectin. 95 Mechanistically, the alteration in mesenchymal markers is thought to be promoted by the ERK signaling pathway. 95 These findings support that heparanase promotes angiogenesis and metastasis in multiple myeloma by supporting the mesenchymal transition of both tumor and endothelial cells.…”

“…95 Mechanistically, the alteration in mesenchymal markers is thought to be promoted by the ERK signaling pathway. 95 These findings support that heparanase promotes angiogenesis and metastasis in multiple myeloma by supporting the mesenchymal transition of both tumor and endothelial cells. 95 …”

Game of Bones: How Myeloma Manipulates Its Microenvironment

“…Myeloma cells also produce heparanase, an enzyme that cleaves heparanase sulfate chains of adhesive proteoglycans such as syndecan-1. Production of heparanase increases motility of myeloma cells and induces a migratory phenotype ( 168 ). In part, heparanase and syndecan appear to regulate one another throughout the progression of myeloma and EMM ( Figure 2B ).…”