title: Heparin-like polysaccharides reduce osteolytic bone destruction and tumor growth in a mouse model of breast cancer bone metastasis.
abstract: TGF-β regulates several steps in cancer metastasis, including the establishment of bone metastatic lesions. TGF-β is released from bone during osteoclastic bone resorption and it stimulates breast cancer cells to produce osteolytic factors such as interleukin 11 (IL-11). We conducted a cell-based siRNA screen and identified heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) as a critical gene for TGF-β-induced IL-11 production in highly bone metastatic MDA-MB-231(SA) breast cancer cells. HS6ST2 attaches sulfate groups to glucosamine residues in heparan sulfate glycosaminoglycans. We subsequently showed how heparin and a high-molecular-weight Escherichia coli K5-derived heparin-like polysaccharide (K5-NSOS) inhibited TGF-β-induced IL-11 production in MDA-MB-231(SA) cells. In addition, K5-NSOS inhibited bone resorption activity of human osteoclasts in vitro. We evaluated the therapeutic potential of K5-NSOS and fragmin in a mouse model of breast cancer bone metastasis. MDA-MB-231(SA) cells were inoculated into the left cardiac ventricle of athymic nude mice which were treated with fragmin, K5-NSOS, or vehicle once a day for four weeks. Both heparin-like glycosaminoglycans inhibited weight reduction, decreased osteolytic lesion area, and reduced tumor burden in bone. In conclusion, our data imply novel mechanisms involved in TGF-β induction and support the critical role of heparan sulfate glycosaminoglycans in cancer metastasis as well as indicate that K5-NSOS is a potential antimetastatic and antiresorptive agent for cancer therapy. This study illustrates the potential to translate in vitro siRNA screening results toward in vivo therapeutic concepts.
authors.affiliation: VTT Technical Research Centre of Finland and Turku Centre for Biotechnology, University of Turku, PO Box 106, Turku 20520, Finland. sielpo@utu.fi
authors.forename: Sirkku
authors.initials: S
authors.lastname: Pollari
authors.forename: Rami S
authors.initials: RS
authors.lastname: Käkönen
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Mohammad
authors.forename: Jukka P
authors.initials: JP
authors.lastname: Rissanen
authors.forename: Jussi M
authors.initials: JM
authors.lastname: Halleen
authors.forename: Anni
authors.initials: A
authors.lastname: Wärri
authors.forename: Liisa
authors.initials: L
authors.lastname: Nissinen
authors.forename: Marjo
authors.initials: M
authors.lastname: Pihlavisto
authors.forename: Anne
authors.initials: A
authors.lastname: Marjamäki
authors.forename: Merja
authors.initials: M
authors.lastname: Perälä
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Guise
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.forename: Sanna-Maria
authors.initials: SM
authors.lastname: Käkönen
mesh_terms: D000818:Animals; D016667:Bacterial Capsules / Q000737:chemistry; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary; D001862:Bone Resorption / Q000235:genetics / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D017370:Interleukin-11 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010010:Osteoclasts / Q000187:drug effects*; D034741:RNA, Small Interfering; D015238:Sulfotransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D017370:Interleukin-11; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; C050673:capsular polysaccharide K5; D006493:Heparin; C485758:Hs6st2 protein, mouse; D015238:Sulfotransferases