Abstract
Prostate cancer (CaP) metastasis to bone results in mixed osteolytic and osteoblastic lesions associated with high morbidity and there is mounting evidence that the urokinase-type plasminogen (uPA) system is causatively involved in the progression of CaP. Adult mesenchymal stem cells (MSCs) are promising tools for cell-mediated gene therapy with the advantage of osteogenic potential, a critical issue in the case of osteolytic metastases. In this study, we evaluated the therapeutic use of engineered murine MSCs for in vivo delivery of the uPA antagonist amino-terminal fragment (hATF) in order to impair osteolytic CaP cells progression in bone and to repair bone lesions. Bioluminescence imaging (BLI) revealed that both primary MSCs (pMSCs) and MSC line C3H10T1/2 (C3) expressing hATF (MSC-hATF) inhibited significantly intra-tibial PC-3-Luc growth following co-injection in SCID mice. Furthermore, micro-computed tomography (microCT) imaging of vascular network clearly demonstrated a significant decrease of tumor-associated angiogenesis and a protection from tumor-induced osteolysis in MSC-hATF treated mice. Importantly, the osteogenic potential of MSC-hATF cells was unaffected and area of new bone formation was evidenced in 60% of animals. Altogether, these data support the concept of MSC-based therapy of tumor osteolysis disease, indicating that MSCs may combine properties of vehicle for angiostatic agent with osteogenic potential. ______________________________________________________________________________ Author contributions: V.F.: Conception and design, Collection and/or assembly of data, Data analysis and interpretation, Manuscript writing, Final approval of manuscript; D.N.: Conception and design, Collection and/or assembly of data, Data analysis and interpretation, Manuscript writing, Final approval of manuscript; C.Bouquet: Provision of study material or patients, Data analysis and interpretation, Manuscript writing, Final approval of manuscript; P.O.: Data analysis and interpretation, Final approval of manuscript; R.V.: Data analysis and interpretation, Final approval of manuscript; F.A.: Conception and design, Manuscript writing, Final approval of manuscript; P.L.-P.: Conception and design, Manuscript writing, Final approval of manuscript; C.Bouffi: Data analysis and interpretation, Final approval of manuscript; H.D.: Conception and design, Data analysis and interpretation, Manuscript writing, Final approval of manuscript; C.X.: Collection and/or assembly of data, Data analysis and interpretation, Manuscript writing, Final approval of manuscript; M.P.: Final approval of manuscript; R.M.: Conception and design, Data analysis and interpretation, Final approval of manuscript; E.S.: Conception and design, Manuscript writing, Final approval of manuscript; C.J.: Conception and design, Financial support, Data analysis and interpretation, Manuscript writing, Final approval of manuscript.