title: Targeting integrin α6 stimulates curative-type bone metastasis lesions in a xenograft model.
abstract: Laminin-binding integrin receptors are key mediators of epithelial cell migration and tumor metastasis. Recent studies have demonstrated a role for the α6 integrin (ITGA6/CD49f) in maintaining stem cell compartments within normal bone marrow and in residency of tumors metastatic to bone. In this study, we tested a function-blocking antibody specific for ITGA6, called J8H, to determine if preexisting cancer lesions in bone could be slowed and/or animal survival improved. Human prostate tumors were established by intracardiac injection into male SCID mice and treatment with J8H antibody was initiated after 1 week. Tumor progression was monitored by micro-computed tomography (CT) imaging of skeletal lesions. Animals that received weekly injections of the anti-ITGA6 antibody showed radiographic progression in only 40% of osseous tumors (femur or tibia), compared with control animals, where 80% of the lesions (femur or tibia) showed progression at 5 weeks. Kaplan-Meier survival analysis demonstrated a significant survival advantage for J8H-treated animals. Unexpectedly, CT image analysis revealed an increased proportion of bone lesions displaying a sclerotic rim of new bone formation, encapsulating the arrested lytic lesions in animals that received the anti-ITGA6 antibody treatment. Histopathology of the sclerotic lesions demonstrated well-circumscribed tumor within bone, surrounded by fibrosis. These data suggest that systemic targeting of the ITGA6-dependent function of established tumors in bone may offer a noncytotoxic approach to arrest the osteolytic progression of metastatic prostate cancer, thereby providing a new therapeutic strategy for advanced disease.
authors.affiliation: Authors' Affiliations: University of Arizona Cancer Center; Departments of Medicine, Medical Imaging, Pathology, and Cellular and Molecular Medicine, University of Arizona Cancer Center, Tucson, ArizonaAuthors' Affiliations: University of Arizona Cancer Center; Departments of Medicine, Medical Imaging, Pathology, and Cellular and Molecular Medicine, University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Terry H
authors.initials: TH
authors.lastname: Landowski
authors.affiliation: Authors' Affiliations: University of Arizona Cancer Center; Departments of Medicine, Medical Imaging, Pathology, and Cellular and Molecular Medicine, University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Jaime
authors.initials: J
authors.lastname: Gard
authors.affiliation: Authors' Affiliations: University of Arizona Cancer Center; Departments of Medicine, Medical Imaging, Pathology, and Cellular and Molecular Medicine, University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Erika
authors.initials: E
authors.lastname: Pond
authors.affiliation: Authors' Affiliations: University of Arizona Cancer Center; Departments of Medicine, Medical Imaging, Pathology, and Cellular and Molecular Medicine, University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Gerald D
authors.initials: GD
authors.lastname: Pond
authors.affiliation: Authors' Affiliations: University of Arizona Cancer Center; Departments of Medicine, Medical Imaging, Pathology, and Cellular and Molecular Medicine, University of Arizona Cancer Center, Tucson, ArizonaAuthors' Affiliations: University of Arizona Cancer Center; Departments of Medicine, Medical Imaging, Pathology, and Cellular and Molecular Medicine, University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Raymond B
authors.initials: RB
authors.lastname: Nagle
authors.affiliation: Authors' Affiliations: University of Arizona Cancer Center; Departments of Medicine, Medical Imaging, Pathology, and Cellular and Molecular Medicine, University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Geffre
authors.affiliation: Authors' Affiliations: University of Arizona Cancer Center; Departments of Medicine, Medical Imaging, Pathology, and Cellular and Molecular Medicine, University of Arizona Cancer Center, Tucson, ArizonaAuthors' Affiliations: University of Arizona Cancer Center; Departments of Medicine, Medical Imaging, Pathology, and Cellular and Molecular Medicine, University of Arizona Cancer Center, Tucson, Arizona cress@email.arizona.edu.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Cress
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D006801:Humans; D039503:Integrin alpha6 / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D010006:Osteoblasts / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; D058846:Antibodies, Monoclonal, Murine-Derived; D039503:Integrin alpha6
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