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

• Type of Material: Article
• Authors: Juan Li, University of Alabama Birmingham; Qianying Pan, University of Alabama Birmingham; Patrick D. Rowan, University of Alabama Birmingham; Timothy N. Trotter, University of Alabama Birmingham; Deniz Peker, Emory University; Kellie M. Regal, University of Alabama Birmingham; Amjad Javed, University of Alabama Birmingham; Larry J. Suva, Texas A&M University; Yang Yang, University of Alabama Birmingham
• Language: English
• Date: 2016-03-08
• Publisher: IMPACT JOURNALS LLC
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Li et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.7170
• Title of Journal or Parent Work: ONCOTARGET
• Volume: 7
• Issue: 10
• Start Page: 11299
• End Page: 11309
• Grant/Funding Information: This work was supported by National Institutes of Health (NIH) grant R01CA151538 (YY), a Multiple Myeloma Research Foundation Senior Award (YY), an International Myeloma Foundation Senior Award (YY), UAB Center for Metabolic Bone Disease (CMBD) pilot grant (YY), and Chinese Government Studying Abroad Scholarship (QP).
• Keywords: PROTEOGLYCANS; tumor microenvironment; TRANSITION; BONE; bone dissemination; Cell Biology; EXPRESSION; heparanase; MULTIPLE-MYELOMA; Life Sciences & Biomedicine; BREAST-CANCER METASTASIS; mesenchymal marker; Science & Technology; Oncology; TUMOR-GROWTH; ANGIOGENESIS; PLASMA-CELLS; DISEASE; multiple myeloma
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology; Biology, Cell

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.