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dc.contributor.authorDutta, Anindita
dc.contributor.authorLi, Jing
dc.contributor.authorLu, Huimin
dc.contributor.authorAkech, Jacqueline
dc.contributor.authorPratap, Jitesh
dc.contributor.authorWang, Tao
dc.contributor.authorZerlanko, Brad J.
dc.contributor.authorFitzgerald, Thomas J.
dc.contributor.authorJiang, Zhong
dc.contributor.authorBirbe, Ruth
dc.contributor.authorWixted, John J.
dc.contributor.authorViolette, Shelia M.
dc.contributor.authorStein, Janet L.
dc.contributor.authorStein, Gary S.
dc.contributor.authorLian, Jane B.
dc.contributor.authorLanguino, Lucia R.
dc.date2022-08-11T08:10:46.000
dc.date.accessioned2022-08-23T17:18:57Z
dc.date.available2022-08-23T17:18:57Z
dc.date.issued2014-03-01
dc.date.submitted2015-10-26
dc.identifier.citationCancer Res. 2014 Mar 1;74(5):1598-608. doi: 10.1158/0008-5472.CAN-13-1796. <a href="http://dx.doi.org/10.1158/0008-5472.CAN-13-1796">Link to article on publisher's site</a>.
dc.identifier.issn0008-5472 (Linking)
dc.identifier.doi10.1158/0008-5472.CAN-13-1796
dc.identifier.pmid24385215
dc.identifier.urihttp://hdl.handle.net/20.500.14038/47966
dc.description.abstractThe molecular circuitries controlling osseous prostate metastasis are known to depend on the activity of multiple pathways, including integrin signaling. Here, we demonstrate that the alphavbeta6 integrin is upregulated in human prostate cancer bone metastasis. In prostate cancer cells, this integrin is a functionally active receptor for fibronectin and latency-associated peptide-TGF-beta1; it mediates attachment and migration upon ligand binding and is localized in focal contacts. Given the propensity of prostate cancer cells to form bone metastatic lesions, we investigated whether the alphavbeta6 integrin promotes this type of metastasis. We show for the first time that alphavbeta6 selectively induces matrix metalloproteinase 2 (MMP2) in vitro in multiple prostate cancer cells and promotes osteolysis in vivo in an immunodeficient mouse model of bone metastasis through upregulation of MMP2, but not MMP9. The effect of alphavbeta6 on MMP2 expression and activity is independent of androgen receptor in the analyzed prostate cancer cells. Increased levels of parathyroid hormone-related protein (PTHrP), known to induce osteoclastogenesis, were also observed in alphavbeta6-expressing cells. However, by using MMP2 short hairpin RNA, we demonstrate that the alphavbeta6 effect on bone loss is due to upregulation of soluble MMP2 by the cancer cells, not due to changes in tumor growth rate. Another related alphav-containing integrin, alphavbeta5, fails to show similar responses, underscoring the significance of alphavbeta6 activity. Overall, these mechanistic studies establish that expression of a single integrin, alphavbeta6, contributes to the cancer cell-mediated program of osteolysis by inducing matrix degradation through MMP2. Our results open new prospects for molecular therapy for metastatic bone disease.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=24385215&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967411/
dc.subjectAnimals
dc.subjectAntigens, Neoplasm
dc.subjectBone Neoplasms
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectIntegrins
dc.subjectMale
dc.subjectMatrix Metalloproteinase 2
dc.subjectMatrix Metalloproteinase 9
dc.subjectMice
dc.subjectMice, SCID
dc.subjectOsteolysis
dc.subjectParathyroid Hormone-Related Protein
dc.subjectProstatic Neoplasms
dc.subjectReceptors, Androgen
dc.subjectTransforming Growth Factor beta1
dc.subjectUp-Regulation
dc.subjectCancer Biology
dc.subjectCell Biology
dc.subjectNeoplasms
dc.titleIntegrin alphavbeta6 promotes an osteolytic program in cancer cells by upregulating MMP2
dc.typeJournal Article
dc.source.journaltitleCancer research
dc.source.volume74
dc.source.issue5
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/radiationoncology_pubs/74
dc.identifier.contextkey7762706
html.description.abstract<p>The molecular circuitries controlling osseous prostate metastasis are known to depend on the activity of multiple pathways, including integrin signaling. Here, we demonstrate that the alphavbeta6 integrin is upregulated in human prostate cancer bone metastasis. In prostate cancer cells, this integrin is a functionally active receptor for fibronectin and latency-associated peptide-TGF-beta1; it mediates attachment and migration upon ligand binding and is localized in focal contacts. Given the propensity of prostate cancer cells to form bone metastatic lesions, we investigated whether the alphavbeta6 integrin promotes this type of metastasis. We show for the first time that alphavbeta6 selectively induces matrix metalloproteinase 2 (MMP2) in vitro in multiple prostate cancer cells and promotes osteolysis in vivo in an immunodeficient mouse model of bone metastasis through upregulation of MMP2, but not MMP9. The effect of alphavbeta6 on MMP2 expression and activity is independent of androgen receptor in the analyzed prostate cancer cells. Increased levels of parathyroid hormone-related protein (PTHrP), known to induce osteoclastogenesis, were also observed in alphavbeta6-expressing cells. However, by using MMP2 short hairpin RNA, we demonstrate that the alphavbeta6 effect on bone loss is due to upregulation of soluble MMP2 by the cancer cells, not due to changes in tumor growth rate. Another related alphav-containing integrin, alphavbeta5, fails to show similar responses, underscoring the significance of alphavbeta6 activity. Overall, these mechanistic studies establish that expression of a single integrin, alphavbeta6, contributes to the cancer cell-mediated program of osteolysis by inducing matrix degradation through MMP2. Our results open new prospects for molecular therapy for metastatic bone disease.</p>
dc.identifier.submissionpathradiationoncology_pubs/74
dc.contributor.departmentDepartment of Orthopedics and Physical Rehabiliation
dc.contributor.departmentDepartment of Pathology
dc.contributor.departmentDepartment of Radiation Oncology
dc.contributor.departmentDepartment of Cell Biology
dc.source.pages1598-608


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