Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

: Pollari S, Käkönen RS, Mohammad KS, Rissanen JP, Halleen JM, Wärri A, Nissinen L, Pihlavisto M, Marjamäki A, Perälä M, Guise TA, Kallioniemi O, Käkönen SM

Publisher: AMER ASSOC CANCER RESEARCH

: 2012

: Molecular Cancer Research

: MOLECULAR CANCER RESEARCH

: MOL CANCER RES

: 5

: 10

: 5

: 597

: 604

: 8

: 1557-3125

DOI: https://doi.org/10.1158/1541-7786.MCR-11-0482(external)

TGF-beta regulates several steps in cancer metastasis, including the establishment of bone metastatic lesions. TGF-beta 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-beta-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-beta-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-beta 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. Mol Cancer Res; 10(5); 597-604. (C) 2012 AACR.