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

Abstract

// Juan Li 1, 2, * , Qianying Pan 1, 2, * , Patrick D. Rowan 1, * , Timothy N. Trotter 1 , Deniz Peker 1 , Kellie M. Regal 1 , Amjad Javed 3, 4 , Larry J. Suva 5 , Yang Yang 1, 3 1 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA 2 Department of Hematology, the First Affiliated Hospital of Sun Yat-Sen University, Guangdong, China 3 Comprehensive Cancer Center and the Center for Metabolic Bone Disease, University of Alabama at Birmingham, Birmingham, AL, USA 4 Department of Oral and Maxillofacial Surgery, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL, USA 5 Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A & M University, College Station, TX, USA * These authors contributed equally to this work Correspondence to: Yang Yang, e-mail: yangyang@uab.edu Keywords: multiple myeloma, bone dissemination, heparanase, mesenchymal marker, tumor microenvironment Received: June 19, 2015      Accepted: January 21, 2016      Published: February 03, 2016 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.