Prostate cancer cells home to bone using a novel in vivo model: Modulation by the integrin antagonist GLPG0187

• Published in: International journal of cancer Vol. 136; no. 7; pp. 1731 - 1740
• Main Authors: Reeves, Kimberley J., Hurrell, Jack E., Cecchini, Marco, van der Pluijm, Gabri, Down, Jenny M., Eaton, Colby L., Hamdy, Freddie, Clement‐Lacroix, Philippe, Brown, Nicola J.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-04-2015
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; bone; Bone cancer; Bone Neoplasms - diagnosis; Bone Neoplasms - drug therapy; Bone Neoplasms - secondary; Cancer; Cancer therapies; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Disease Models, Animal; dorsal skinfold window chamber; Humans; integrin antagonist; Integrins - antagonists & inhibitors; Male; Medical research; Metastasis; Mice; micrometastasis; Neovascularization, Pathologic - drug therapy; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Xenograft Model Antitumor Assays; prostate cancer; bone; micrometastasis; dorsal skinfold window chamber; integrin antagonist
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.29165

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.
What's new?
Early detection of bone metastasis is critical for developing new therapeutic cancer treatments. The authors developed a novel in vivo model using the dorsal skinfold window chamber with an implanted bone graft in immunodeficient mice. This window implanted onto the dorsal mouse skinfold allowed longitudinal and spatial evaluation of the early homing, adhesion and localization of fluorescently labeled prostate cancer cells, following intra‐cardiac injection. Administration of the αv integrin antagonist GLPG0187 significantly reduced prostate cancer cell number and localization within the bone implant demonstrating the clinical applicability of the model.