Anti-transforming growth factor ß antibody treatment rescues bone loss and prevents breast cancer metastasis to bone
Breast cancer often metastasizes to bone causing osteolytic bone resorption which releases active TGFβ. Because TGFβ favors progression of breast cancer metastasis to bone, we hypothesized that treatment using anti-TGFβ antibody may reduce tumor burden and rescue tumor-associated bone loss in metast...
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| Veröffentlicht in: | PloS one 2011-11, Vol.6 (11), p.e27090-e27090 |
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| creator | Biswas, Swati Nyman, Jeffry S Alvarez, JoAnn Chakrabarti, Anwesa Ayres, Austin Sterling, Julie Edwards, James Rana, Tapasi Johnson, Rachelle Perrien, Daniel S Lonning, Scott Shyr, Yu Matrisian, Lynn M Mundy, Gregory R |
| description | Breast cancer often metastasizes to bone causing osteolytic bone resorption which releases active TGFβ. Because TGFβ favors progression of breast cancer metastasis to bone, we hypothesized that treatment using anti-TGFβ antibody may reduce tumor burden and rescue tumor-associated bone loss in metastatic breast cancer. In this study we have tested the efficacy of an anti-TGFβ antibody 1D11 preventing breast cancer bone metastasis. We have used two preclinical breast cancer bone metastasis models, in which either human breast cancer cells or murine mammary tumor cells were injected in host mice via left cardiac ventricle. Using several in vivo, in vitro and ex vivo assays, we have demonstrated that anti-TGFβ antibody treatment have significantly reduced tumor burden in the bone along with a statistically significant threefold reduction in osteolytic lesion number and tenfold reduction in osteolytic lesion area. A decrease in osteoclast numbers (p = 0.027) in vivo and osteoclastogenesis ex vivo were also observed. Most importantly, in tumor-bearing mice, anti-TGFβ treatment resulted in a twofold increase in bone volume (p |
| doi_str_mv | 10.1371/journal.pone.0027090 |
| format | Article |
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Because TGFβ favors progression of breast cancer metastasis to bone, we hypothesized that treatment using anti-TGFβ antibody may reduce tumor burden and rescue tumor-associated bone loss in metastatic breast cancer. In this study we have tested the efficacy of an anti-TGFβ antibody 1D11 preventing breast cancer bone metastasis. We have used two preclinical breast cancer bone metastasis models, in which either human breast cancer cells or murine mammary tumor cells were injected in host mice via left cardiac ventricle. Using several in vivo, in vitro and ex vivo assays, we have demonstrated that anti-TGFβ antibody treatment have significantly reduced tumor burden in the bone along with a statistically significant threefold reduction in osteolytic lesion number and tenfold reduction in osteolytic lesion area. A decrease in osteoclast numbers (p = 0.027) in vivo and osteoclastogenesis ex vivo were also observed. Most importantly, in tumor-bearing mice, anti-TGFβ treatment resulted in a twofold increase in bone volume (p<0.01). In addition, treatment with anti-TGFβ antibody increased the mineral-to-collagen ratio in vivo, a reflection of improved tissue level properties. Moreover, anti-TGFβ antibody directly increased mineralized matrix formation in calverial osteoblast (p = 0.005), suggesting a direct beneficial role of anti-TGFβ antibody treatment on osteoblasts. Data presented here demonstrate that anti-TGFβ treatment may offer a novel therapeutic option for tumor-induced bone disease and has the dual potential for simultaneously decreasing tumor burden and rescue bone loss in breast cancer to bone metastases. This approach of intervention has the potential to reduce skeletal related events (SREs) in breast cancer survivors.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0027090</identifier><identifier>PMID: 22096521</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animal models ; Animals ; Antibodies ; Antibodies - pharmacology ; Antibodies - therapeutic use ; Biocompatibility ; Biology ; Biomedical materials ; Bone and Bones - cytology ; Bone and Bones - drug effects ; Bone and Bones - metabolism ; Bone cancer ; Bone diseases ; Bone loss ; Bone Neoplasms - metabolism ; Bone Neoplasms - prevention & control ; Bone Neoplasms - secondary ; Bone resorption ; Breast cancer ; Breast Neoplasms - complications ; Calcification ; Cancer ; Cancer metastasis ; Cancer prevention ; Cancer research ; Cell Differentiation - drug effects ; Cell Line, Tumor ; Collagen ; Collagen - metabolism ; Cytokines ; Development and progression ; Female ; Growth factors ; Heart diseases ; Humans ; Lesions ; Ligands ; Mammary gland ; Medicine ; Metastases ; Metastasis ; Mice ; Mice, Nude ; Orthopedics ; Osteoblasts ; Osteoblasts - cytology ; Osteoblasts - drug effects ; Osteoclastogenesis ; Osteoclasts - cytology ; Osteoclasts - drug effects ; Osteogenesis - drug effects ; Osteolysis ; Osteoporosis ; Phosphatase ; Physicians ; Proteins ; Real-Time Polymerase Chain Reaction ; Reduction ; Statistical analysis ; Transforming growth factor ; Transforming Growth Factor beta - antagonists & inhibitors ; Transforming growth factors ; Trends ; Tumor cells ; Tumors ; Ventricle</subject><ispartof>PloS one, 2011-11, Vol.6 (11), p.e27090-e27090</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Biswas et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Biswas et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6060-e4929bddc9eb286ebef2eaedf5fd0f8d9e8b7e4f6872989a54450de3b0347d843</citedby><cites>FETCH-LOGICAL-c6060-e4929bddc9eb286ebef2eaedf5fd0f8d9e8b7e4f6872989a54450de3b0347d843</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3214031/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3214031/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22096521$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Biswas, Swati</creatorcontrib><creatorcontrib>Nyman, Jeffry S</creatorcontrib><creatorcontrib>Alvarez, JoAnn</creatorcontrib><creatorcontrib>Chakrabarti, Anwesa</creatorcontrib><creatorcontrib>Ayres, Austin</creatorcontrib><creatorcontrib>Sterling, Julie</creatorcontrib><creatorcontrib>Edwards, James</creatorcontrib><creatorcontrib>Rana, Tapasi</creatorcontrib><creatorcontrib>Johnson, Rachelle</creatorcontrib><creatorcontrib>Perrien, Daniel S</creatorcontrib><creatorcontrib>Lonning, Scott</creatorcontrib><creatorcontrib>Shyr, Yu</creatorcontrib><creatorcontrib>Matrisian, Lynn M</creatorcontrib><creatorcontrib>Mundy, Gregory R</creatorcontrib><title>Anti-transforming growth factor ß antibody treatment rescues bone loss and prevents breast cancer metastasis to bone</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Breast cancer often metastasizes to bone causing osteolytic bone resorption which releases active TGFβ. Because TGFβ favors progression of breast cancer metastasis to bone, we hypothesized that treatment using anti-TGFβ antibody may reduce tumor burden and rescue tumor-associated bone loss in metastatic breast cancer. In this study we have tested the efficacy of an anti-TGFβ antibody 1D11 preventing breast cancer bone metastasis. We have used two preclinical breast cancer bone metastasis models, in which either human breast cancer cells or murine mammary tumor cells were injected in host mice via left cardiac ventricle. Using several in vivo, in vitro and ex vivo assays, we have demonstrated that anti-TGFβ antibody treatment have significantly reduced tumor burden in the bone along with a statistically significant threefold reduction in osteolytic lesion number and tenfold reduction in osteolytic lesion area. A decrease in osteoclast numbers (p = 0.027) in vivo and osteoclastogenesis ex vivo were also observed. Most importantly, in tumor-bearing mice, anti-TGFβ treatment resulted in a twofold increase in bone volume (p<0.01). In addition, treatment with anti-TGFβ antibody increased the mineral-to-collagen ratio in vivo, a reflection of improved tissue level properties. Moreover, anti-TGFβ antibody directly increased mineralized matrix formation in calverial osteoblast (p = 0.005), suggesting a direct beneficial role of anti-TGFβ antibody treatment on osteoblasts. Data presented here demonstrate that anti-TGFβ treatment may offer a novel therapeutic option for tumor-induced bone disease and has the dual potential for simultaneously decreasing tumor burden and rescue bone loss in breast cancer to bone metastases. This approach of intervention has the potential to reduce skeletal related events (SREs) in breast cancer survivors.</description><subject>Animal models</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antibodies - pharmacology</subject><subject>Antibodies - therapeutic use</subject><subject>Biocompatibility</subject><subject>Biology</subject><subject>Biomedical materials</subject><subject>Bone and Bones - cytology</subject><subject>Bone and Bones - drug effects</subject><subject>Bone and Bones - metabolism</subject><subject>Bone cancer</subject><subject>Bone diseases</subject><subject>Bone loss</subject><subject>Bone Neoplasms - metabolism</subject><subject>Bone Neoplasms - prevention & control</subject><subject>Bone Neoplasms - secondary</subject><subject>Bone resorption</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - complications</subject><subject>Calcification</subject><subject>Cancer</subject><subject>Cancer metastasis</subject><subject>Cancer prevention</subject><subject>Cancer research</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Collagen</subject><subject>Collagen - metabolism</subject><subject>Cytokines</subject><subject>Development and progression</subject><subject>Female</subject><subject>Growth factors</subject><subject>Heart diseases</subject><subject>Humans</subject><subject>Lesions</subject><subject>Ligands</subject><subject>Mammary gland</subject><subject>Medicine</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Orthopedics</subject><subject>Osteoblasts</subject><subject>Osteoblasts - cytology</subject><subject>Osteoblasts - drug effects</subject><subject>Osteoclastogenesis</subject><subject>Osteoclasts - cytology</subject><subject>Osteoclasts - drug effects</subject><subject>Osteogenesis - drug effects</subject><subject>Osteolysis</subject><subject>Osteoporosis</subject><subject>Phosphatase</subject><subject>Physicians</subject><subject>Proteins</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Reduction</subject><subject>Statistical analysis</subject><subject>Transforming growth factor</subject><subject>Transforming Growth Factor beta - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Biswas, Swati</au><au>Nyman, Jeffry S</au><au>Alvarez, JoAnn</au><au>Chakrabarti, Anwesa</au><au>Ayres, Austin</au><au>Sterling, Julie</au><au>Edwards, James</au><au>Rana, Tapasi</au><au>Johnson, Rachelle</au><au>Perrien, Daniel S</au><au>Lonning, Scott</au><au>Shyr, Yu</au><au>Matrisian, Lynn M</au><au>Mundy, Gregory R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Anti-transforming growth factor ß antibody treatment rescues bone loss and prevents breast cancer metastasis to bone</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-11-11</date><risdate>2011</risdate><volume>6</volume><issue>11</issue><spage>e27090</spage><epage>e27090</epage><pages>e27090-e27090</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Breast cancer often metastasizes to bone causing osteolytic bone resorption which releases active TGFβ. Because TGFβ favors progression of breast cancer metastasis to bone, we hypothesized that treatment using anti-TGFβ antibody may reduce tumor burden and rescue tumor-associated bone loss in metastatic breast cancer. In this study we have tested the efficacy of an anti-TGFβ antibody 1D11 preventing breast cancer bone metastasis. We have used two preclinical breast cancer bone metastasis models, in which either human breast cancer cells or murine mammary tumor cells were injected in host mice via left cardiac ventricle. Using several in vivo, in vitro and ex vivo assays, we have demonstrated that anti-TGFβ antibody treatment have significantly reduced tumor burden in the bone along with a statistically significant threefold reduction in osteolytic lesion number and tenfold reduction in osteolytic lesion area. A decrease in osteoclast numbers (p = 0.027) in vivo and osteoclastogenesis ex vivo were also observed. Most importantly, in tumor-bearing mice, anti-TGFβ treatment resulted in a twofold increase in bone volume (p<0.01). In addition, treatment with anti-TGFβ antibody increased the mineral-to-collagen ratio in vivo, a reflection of improved tissue level properties. Moreover, anti-TGFβ antibody directly increased mineralized matrix formation in calverial osteoblast (p = 0.005), suggesting a direct beneficial role of anti-TGFβ antibody treatment on osteoblasts. Data presented here demonstrate that anti-TGFβ treatment may offer a novel therapeutic option for tumor-induced bone disease and has the dual potential for simultaneously decreasing tumor burden and rescue bone loss in breast cancer to bone metastases. This approach of intervention has the potential to reduce skeletal related events (SREs) in breast cancer survivors.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22096521</pmid><doi>10.1371/journal.pone.0027090</doi><tpages>e27090</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2011-11, Vol.6 (11), p.e27090-e27090 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1311931546 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animal models Animals Antibodies Antibodies - pharmacology Antibodies - therapeutic use Biocompatibility Biology Biomedical materials Bone and Bones - cytology Bone and Bones - drug effects Bone and Bones - metabolism Bone cancer Bone diseases Bone loss Bone Neoplasms - metabolism Bone Neoplasms - prevention & control Bone Neoplasms - secondary Bone resorption Breast cancer Breast Neoplasms - complications Calcification Cancer Cancer metastasis Cancer prevention Cancer research Cell Differentiation - drug effects Cell Line, Tumor Collagen Collagen - metabolism Cytokines Development and progression Female Growth factors Heart diseases Humans Lesions Ligands Mammary gland Medicine Metastases Metastasis Mice Mice, Nude Orthopedics Osteoblasts Osteoblasts - cytology Osteoblasts - drug effects Osteoclastogenesis Osteoclasts - cytology Osteoclasts - drug effects Osteogenesis - drug effects Osteolysis Osteoporosis Phosphatase Physicians Proteins Real-Time Polymerase Chain Reaction Reduction Statistical analysis Transforming growth factor Transforming Growth Factor beta - antagonists & inhibitors Transforming growth factors Trends Tumor cells Tumors Ventricle |
| title | Anti-transforming growth factor ß antibody treatment rescues bone loss and prevents breast cancer metastasis to bone |
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