title: Prostate cancer cells home to bone using a novel in vivo model: modulation by the integrin antagonist GLPG0187.
abstract: Micrometastasis is a barrier to the development of effective cancer therapies for prostate cancer metastasis to bone. The mechanisms remain incompletely characterised, primarily due to an inability to adequately monitor the initial metastatic events in vivo. This study aimed to establish a new model, allowing the tracking of prostate cancer cells homing to bone, and furthermore, to evaluate the response of this approach to therapeutic modulation, using the integrin antagonist GLPG0187. A single murine metatarsal was engrafted into a dorsal skinfold chamber implanted on a SCID mouse. Fluorescently-labeled human prostate (PC3-GFP) or oral (SCC4-GFP) cancer cells were administered via intracardiac (i.c) injection, with simultaneous daily GLPG0187 or vehicle-control treatment (i.p. 100 mg/kg/day) for the experimental duration. Metatarsal recordings were taken every 48 h for up to 4 weeks. Tissue was harvested and processed for microCT, multiphoton analysis, histology and immunohistochemistry. Cell viability, proliferation and migration in vitro were also quantified following treatment with GLPG0187. Metatarsals rapidly revascularised by inosculation with the host vasculature (day 5-7). PC3-GFP cells adhered to the microvascular endothelium and/or metatarsal matrix 3 days after administration, with adhesion maintained for the experimental duration. GLPG0187 treatment significantly (p < 0.05) reduced PC3 cell number within the metatarsal in vivo and reduced migration (p < 0.05) and proliferation (p < 0.05) but not cell viability in vitro. This new model allows evaluation of the early events of tumour-cell homing and localisation to the bone microenvironment, in addition to determining responses to therapeutic interventions.
authors.affiliation: Microcirculation Research Group, Department of Oncology, CR-UK/YCR Sheffield Cancer Research Centre, Faculty of Medicine, Dentistry and Health, University of Sheffield, S10 2RX, United Kingdom; Bone Biology Group, Department of Human Metabolism, Medical School, University of Sheffield, Sheffield, S10 2RX, United Kingdom.
authors.forename: Kimberley J
authors.initials: KJ
authors.lastname: Reeves
authors.forename: Jack E
authors.initials: JE
authors.lastname: Hurrell
authors.forename: Marco
authors.initials: M
authors.lastname: Cecchini
authors.forename: Gabri
authors.initials: G
authors.lastname: van der Pluijm
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Down
authors.forename: Colby L
authors.initials: CL
authors.lastname: Eaton
authors.forename: Freddie
authors.initials: F
authors.lastname: Hamdy
authors.forename: Philippe
authors.initials: P
authors.lastname: Clement-Lacroix
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Brown
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000556:secondary*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016023:Integrins
keywords: bone; dorsal skinfold window chamber; integrin antagonist; micrometastasis; prostate cancer