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.
| Original language | English |
|---|---|
| Pages (from-to) | 597-604 |
| Journal | Molecular Cancer Research |
| Volume | 10 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2012 |
| MoE publication type | A1 Journal article-refereed |
Funding
This work was supported by Academy of Finland, Verein zur Förderung der Krebsforschung (TIME project), Finnish Cancer Organisations, and Sigrid Jusélius Foundation (to O. Kallioniemi); Drug Discovery Graduate School, Finnish Cultural Foundation, and Cancer Society of Southwestern Finland (to S. Pollari); NIH grants R01CA69158, R01DK067333, R01DK065837, and U01CA143057, the Mary Kay Ash Foundation, the V-Foundation, the Jerry W. and Peggy S. Throgmartin Endowment of Indiana University, the Indiana Economic Development Fund, and Susan Komen Foundation (to T.A. Guise).
