Heparin-like polysaccharides reduce osteolytic bone destruction and tumor growth in a mouse model of breast cancer bone metastasis

Sirkku Pollari, Rami S. Käkönen, Khalid Mohammad, Jukka P. Rissanen, Jussi M. Halleen, Anni Wärri, Liisa Nissinen, Marjo Pihlavisto, Anne Marjamäki, Merja Perälä, Theresa Guise, Olli Kallioniemi, Sanna Maria Käkönen

Research output: Contribution to journalArticle

18 Citations (Scopus)

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. Weevaluated 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-b 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 languageEnglish
Pages (from-to)597-604
Number of pages8
JournalMolecular Cancer Research
Volume10
Issue number5
DOIs
StatePublished - May 2012

Fingerprint

Bone Neoplasms
Polysaccharides
Heparin
Interleukin-11
Breast Neoplasms
Neoplasm Metastasis
Bone and Bones
Glycosaminoglycans
Dalteparin
Growth
Heparitin Sulfate
Neoplasms
Bone Resorption
Nude Mice
Small Interfering RNA
Heart Ventricles
Bone Density Conservation Agents
Glucosamine
Osteoclasts
Tumor Burden

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

Heparin-like polysaccharides reduce osteolytic bone destruction and tumor growth in a mouse model of breast cancer bone metastasis. / Pollari, Sirkku; Käkönen, Rami S.; Mohammad, Khalid; Rissanen, Jukka P.; Halleen, Jussi M.; Wärri, Anni; Nissinen, Liisa; Pihlavisto, Marjo; Marjamäki, Anne; Perälä, Merja; Guise, Theresa; Kallioniemi, Olli; Käkönen, Sanna Maria.

In: Molecular Cancer Research, Vol. 10, No. 5, 05.2012, p. 597-604.

Research output: Contribution to journalArticle

Pollari, S, Käkönen, RS, Mohammad, K, Rissanen, JP, Halleen, JM, Wärri, A, Nissinen, L, Pihlavisto, M, Marjamäki, A, Perälä, M, Guise, T, Kallioniemi, O & Käkönen, SM 2012, 'Heparin-like polysaccharides reduce osteolytic bone destruction and tumor growth in a mouse model of breast cancer bone metastasis', Molecular Cancer Research, vol. 10, no. 5, pp. 597-604. https://doi.org/10.1158/1541-7786.MCR-11-0482
Pollari, Sirkku ; Käkönen, Rami S. ; Mohammad, Khalid ; Rissanen, Jukka P. ; Halleen, Jussi M. ; Wärri, Anni ; Nissinen, Liisa ; Pihlavisto, Marjo ; Marjamäki, Anne ; Perälä, Merja ; Guise, Theresa ; Kallioniemi, Olli ; Käkönen, Sanna Maria. / Heparin-like polysaccharides reduce osteolytic bone destruction and tumor growth in a mouse model of breast cancer bone metastasis. In: Molecular Cancer Research. 2012 ; Vol. 10, No. 5. pp. 597-604.
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