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Blood, 1 February 2005, Vol. 105, No. 3, pp. 1303-1309. Prepublished online as a Blood First Edition Paper on October 7, 2004; DOI 10.1182/blood-2004-06-2141. This Article Full Text (PDF) All Versions of this Article: 2004-06-2141v1 105/3/1303    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Yang, Y. Articles by Sanderson, R. D Search for Related Content PubMed PubMed Citation Articles by Yang, Y. Articles by Sanderson, R. D Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 8, 2004 Accepted September 23, 2004 Heparanase promotes the spontaneous metastasis of myeloma cells to bone Yang Yang, Veronica MacLeod, Manali Bendre, Yan Huang, Allison M Theus, Hua-Quan Miao, Paul Kussie, Shmuel Yaccoby, Joshua Epstein, Larry J Suva, Thomas Kelly, and Ralph D Sanderson* Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA; Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA; Center for Orthopaedic Research, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA ImClone Systems Incorporated, New York, New York, USA Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA; Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA; Center for Orthopaedic Research, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA; Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA; Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA; Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA * Corresponding author; email: RDSanderson{at}uams.edu. Although widespread skeletal dissemination is a critical step in the progression of myeloma, little is known regarding mechanisms that control metastasis of this cancer. Heparanase-1 (heparanase), an enzyme that cleaves heparan sulfate chains, is expressed at high levels in some myeloma patients, and promotes metastasis of some tumor types (e.g., breast, lymphoma). Using a SCID mouse model, we demonstrate that enhanced expression of heparanase by myeloma cells dramatically upregulates their spontaneous metastasis to bone. This occurs from primary tumors growing subcutaneously and also from primary tumors established in bone. Interestingly, tumors formed by subcutaneous injection of cells metastasize not only to bone, but to other sites including spleen, liver and lung. In contrast, tumors formed by injection of cells directly into bone exhibit a restricted pattern of metastasis that includes dissemination of tumor to other bones but not to extramedullary sites. In addition, expression of heparanase by myeloma cells: (i) accelerates the initial growth of the primary tumor, (ii) increases whole body tumor burden as compared to controls and (iii) enhances both the number and size of microvessels within the primary tumor. These studies describe a novel experimental animal model for examining the spontaneous metastasis of bone-homing tumors and indicate that heparanase is a critical determinant of myeloma dissemination and growth in vivo. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Regina, J.-B. Valentin, S. Lachot, E. Lemarie, J. Rollin, and Y. Gruel Increased Tissue Factor Expression Is Associated with Reduced Survival in Non-Small Cell Lung Cancer and with Mutations of TP53 and PTEN Clin. Chem., October 1, 2009; 55(10): 1834 - 1842. [Abstract] [Full Text] [PDF] A. C. Sprynski, D. Hose, L. Caillot, T. Reme, J. D. Shaughnessy Jr, B. Barlogie, A. Seckinger, J. Moreaux, M. Hundemer, M. Jourdan, et al. The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor Blood, May 7, 2009; 113(19): 4614 - 4626. [Abstract] [Full Text] [PDF] A. Purushothaman, L. Chen, Y. Yang, and R. D. Sanderson Heparanase Stimulation of Protease Expression Implicates It as a Master Regulator of the Aggressive Tumor Phenotype in Myeloma J. Biol. Chem., November 21, 2008; 283(47): 32628 - 32636. [Abstract] [Full Text] [PDF] Y. Yang, V. MacLeod, Y. Dai, Y. Khotskaya-Sample, Z. Shriver, G. Venkataraman, R. Sasisekharan, A. Naggi, G. Torri, B. Casu, et al. The syndecan-1 heparan sulfate proteoglycan is a viable target for myeloma therapy Blood, September 15, 2007; 110(6): 2041 - 2048. [Abstract] [Full Text] [PDF] K. Mahtouk, D. Hose, P. Raynaud, M. Hundemer, M. Jourdan, E. Jourdan, V. Pantesco, M. Baudard, J. De Vos, M. Larroque, et al. Heparanase influences expression and shedding of syndecan-1, and its expression by the bone marrow environment is a bad prognostic factor in multiple myeloma Blood, June 1, 2007; 109(11): 4914 - 4923. [Abstract] [Full Text] [PDF] Y. Yang, V. MacLeod, H.-Q. Miao, A. Theus, F. Zhan, J. D. Shaughnessy Jr., J. Sawyer, J.-P. Li, E. Zcharia, I. Vlodavsky, et al. Heparanase Enhances Syndecan-1 Shedding: A NOVEL MECHANISM FOR STIMULATION OF TUMOR GROWTH AND METASTASIS J. Biol. Chem., May 4, 2007; 282(18): 13326 - 13333. [Abstract] [Full Text] [PDF] A. G. Marguiles, V. S. Klimberg, S. Bhattacharrya, D. Gaddy, and L. J. Suva Genomics and Proteomics of Bone Cancer. Clin. Cancer Res., October 15, 2006; 12(20): 6217s - 6221s. [Abstract] [Full Text] [PDF] M. Smid, Y. Wang, J. G.M. Klijn, A. M. Sieuwerts, Y. Zhang, D. Atkins, J. W.M. Martens, and J. A. Foekens Genes Associated With Breast Cancer Metastatic to Bone J. Clin. Oncol., May 20, 2006; 24(15): 2261 - 2267. [Abstract] [Full Text] [PDF] Y. Dai, Y. Yang, V. MacLeod, X. Yue, A. C. Rapraeger, Z. Shriver, G. Venkataraman, R. Sasisekharan, and R. D. Sanderson HSulf-1 and HSulf-2 Are Potent Inhibitors of Myeloma Tumor Growth in Vivo J. Biol. Chem., December 2, 2005; 280(48): 40066 - 40073. [Abstract] [Full Text] [PDF] T. Kelly, L. J. Suva, Y. Huang, V. MacLeod, H.-Q. Miao, R. C. Walker, and R. D. Sanderson Expression of Heparanase by Primary Breast Tumors Promotes Bone Resorption in the Absence of Detectable Bone Metastases Cancer Res., July 1, 2005; 65(13): 5778 - 5784. [Abstract] [Full Text] [PDF]

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