title: 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.
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.|Department of Hematology, The First Affiliated Hospital of Sun Yat-Sen University, Guangdong, China.
authors: Juan
authors: J
authors: Li
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.|Department of Hematology, The First Affiliated Hospital of Sun Yat-Sen University, Guangdong, China.
authors: Qianying
authors: Q
authors: Pan
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Patrick D
authors: PD
authors: Rowan
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Timothy N
authors: TN
authors: Trotter
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Deniz
authors: D
authors: Peker
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Kellie M
authors: KM
authors: Regal
authors: Comprehensive Cancer Center and The Center for Metabolic Bone Disease, University of Alabama at Birmingham, Birmingham, AL, USA.|Department of Oral and Maxillofacial Surgery, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Amjad
authors: A
authors: Javed
authors: Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A & M University, College Station, TX, USA.
authors: Larry J
authors: LJ
authors: Suva
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.|Comprehensive Cancer Center and The Center for Metabolic Bone Disease, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Yang
authors: Y
authors: Yang
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary; D048708:Cell Growth Processes / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006493:Heparin / Q000031:analogs & derivatives / Q000494:pharmacology; D064593:Heterografts; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D015398:Signal Transduction; D059016:Tumor Microenvironment; D014746:Vimentin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D006493:Heparin; D014746:Vimentin; D000099175:Heparanase; C559639:SST 0001
keywords: bone dissemination; heparanase; mesenchymal marker; multiple myeloma; tumor microenvironment