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

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

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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 languageEnglish
Pages (from-to)597-604
JournalMolecular Cancer Research
Volume10
Issue number5
DOIs
Publication statusPublished - 2012
MoE publication typeA1 Journal article-refereed

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

Cite this

Pollari, S., Käkönen, R. S., Mohammad, K. S., Rissanen, J. P., Halleen, J. M., Wärri, A., ... Käkönen, S-M. (2012). Heparin-like polysaccharides reduce osteolytic bone destruction and tumor growth in a mouse model of breast cancer bone metastasis. Molecular Cancer Research, 10(5), 597-604. https://doi.org/10.1158/1541-7786.MCR-11-0482
Pollari, Sirkku ; Käkönen, Rami S. ; Mohammad, Khalid S. ; Rissanen, Jukka P. ; Halleen, Jussi M. ; Wärri, Anni ; Nissinen, Liisa ; Pihlavisto, Marjo ; Marjamäki, Anne ; Perälä, Merja ; Guise, Theresa A. ; 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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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.",
author = "Sirkku Pollari and K{\"a}k{\"o}nen, {Rami S.} and Mohammad, {Khalid S.} and Rissanen, {Jukka P.} and Halleen, {Jussi M.} and Anni W{\"a}rri and Liisa Nissinen and Marjo Pihlavisto and Anne Marjam{\"a}ki and Merja Per{\"a}l{\"a} and Guise, {Theresa A.} and Olli Kallioniemi and Sanna-Maria K{\"a}k{\"o}nen",
year = "2012",
doi = "10.1158/1541-7786.MCR-11-0482",
language = "English",
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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, S-M 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

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

In: Molecular Cancer Research, Vol. 10, No. 5, 2012, p. 597-604.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Heparin-like polysaccharides reduce osteolytic bone destruction and tumor growth in a mouse model of breast cancer bone metastasis

AU - Pollari, Sirkku

AU - Käkönen, Rami S.

AU - Mohammad, Khalid S.

AU - Rissanen, Jukka P.

AU - Halleen, Jussi M.

AU - Wärri, Anni

AU - Nissinen, Liisa

AU - Pihlavisto, Marjo

AU - Marjamäki, Anne

AU - Perälä, Merja

AU - Guise, Theresa A.

AU - Kallioniemi, Olli

AU - Käkönen, Sanna-Maria

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

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DO - 10.1158/1541-7786.MCR-11-0482

M3 - Article

VL - 10

SP - 597

EP - 604

JO - Molecular Cancer Research

JF - Molecular Cancer Research

SN - 1541-7786

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ER -