title: Integrin αvβ6 promotes an osteolytic program in cancer cells by upregulating MMP2.
abstract: 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 αvβ6 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-β1; 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 αvβ6 integrin promotes this type of metastasis. We show for the first time that αvβ6 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 αvβ6 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 αvβ6-expressing cells. However, by using MMP2 short hairpin RNA, we demonstrate that the αvβ6 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 αv-containing integrin, αvβ5, fails to show similar responses, underscoring the significance of αvβ6 activity. Overall, these mechanistic studies establish that expression of a single integrin, αvβ6, 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.
authors.affiliation: Authors' Affiliations: Prostate Cancer Discovery and Development Program; Departments of Cancer Biology and Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Cell Biology, Radiation Oncology, Pathology, and Orthopedics, University of Massachusetts Medical School, Worcester; Biogen Idec, Inc., Cambridge, Massachusetts; and Department of Biochemistry, The University of Vermont, Burlington, Vermont.
authors.forename: Anindita
authors.initials: A
authors.lastname: Dutta
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Huimin
authors.initials: H
authors.lastname: Lu
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Akech
authors.forename: Jitesh
authors.initials: J
authors.lastname: Pratap
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Brad J
authors.initials: BJ
authors.lastname: Zerlanko
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: FitzGerald
authors.forename: Zhong
authors.initials: Z
authors.lastname: Jiang
authors.forename: Ruth
authors.initials: R
authors.lastname: Birbe
authors.forename: John
authors.initials: J
authors.lastname: Wixted
authors.forename: Shelia M
authors.initials: SM
authors.lastname: Violette
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stein
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
authors.forename: Lucia R
authors.initials: LR
authors.lastname: Languino
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D045744:Cell Line, Tumor; D006801:Humans; D016023:Integrins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D010014:Osteolysis / Q000235:genetics* / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*
chemical_list: C410798:AR protein, human; D000951:Antigens, Neoplasm; D016023:Integrins; D044162:Parathyroid Hormone-Related Protein; D011944:Receptors, Androgen; D053773:Transforming Growth Factor beta1; C073878:integrin alphavbeta6; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9