title: A role for versican in the development of leiomyosarcoma.
abstract: Leiomyosarcoma (LMS) is a mesenchymal cancer that occurs throughout the body. Although LMS is easily recognized histopathologically, the cause of the disease remains unknown. Versican, an extracellular matrix proteoglycan, increases in LMS. Microarray analyses of 80 LMSs and 24 leiomyomas showed a significant elevated expression of versican in human LMS versus benign leiomyomas. To explore the importance of versican in this smooth muscle cell tumor, we used versican-directed siRNA to knock down versican expression in a LMS human cell line, SK-LMS-1. Decreased versican expression was accompanied by slower rates of LMS cell proliferation and migration, increased adhesion, and decreased accumulation of the extracellular matrix macromolecule hyaluronan. Addition of purified versican to cells expressing versican siRNA restored cell proliferation to the level of LMS controls, increased the pericellular coat and the retention of hyaluronan, and decreased cell adhesion in a dose-dependent manner. The presence of versican was not only synergistic with hyaluronan in increasing cell proliferation, but the depletion of versican decreased hyaluronan synthase expression and decreased the retention of hyaluronan. When LMS cells stably expressing versican siRNA were injected into nude mice, the resulting tumors displayed significantly less versican and hyaluronan staining, had lower volumes, and had reduced levels of mitosis as compared with controls. Collectively, these results suggest a role for using versican as a point of control in the management and treatment of LMS.
authors.affiliation: From the Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101, Department of Pathology, University of Washington, Seattle, Washington 98195.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Keire
authors.affiliation: From the Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Bressler
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington 98195.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Lemire
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, and.
authors.forename: Badreddin
authors.initials: B
authors.lastname: Edris
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington 98195.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.affiliation: James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul's Hospital, Room 166, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada, and Department of Pathology and Laboratory Medicine, University of British Columbia, Room G227, 2211 Wesbrook Mall, Vancouver, British Columbia V6T 2A1, Canada.
authors.forename: Maziar
authors.initials: M
authors.lastname: Rahmani
authors.affiliation: James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul's Hospital, Room 166, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada, and Department of Pathology and Laboratory Medicine, University of British Columbia, Room G227, 2211 Wesbrook Mall, Vancouver, British Columbia V6T 2A1, Canada.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: McManus
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, and.
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
authors.affiliation: From the Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101, Department of Pathology, University of Washington, Seattle, Washington 98195, twight@benaroyaresearch.org.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Wight
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000378:metabolism*; D007890:Leiomyosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D019042:Muscle Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D046888:Tissue Array Analysis; D053675:Versicans / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D034741:RNA, Small Interfering; D053675:Versicans; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases
keywords: Cell Migration; Cell Proliferation; Extracellular Matrix; Hyaluronan; Leiomyosarcoma; Small Interfering RNA (siRNA); Tumor Growth; Versican