Tumor progression in osteosarcoma (OS): Role of the chemokine receptor CXCR4 and of its ligand stromal-cell derived factor 1 (SDF-1)

9021 Background. Despite intensive chemotherapy and surgery treatment, lung and bone metastases develop in about 30% of OS patients. Mechanisms for this preferential metastatic behaviour are largely unknown. The CXCR4/SDF-1 system was shown to play a role in the homing of neoplastic cells in breast cancer as well as in rabdhomyosarcoma. This hypothesis was tested in vitro and in vivo in a mouse model. Methods. Human OS cell lines MG-63, SJSA, U2-OS and HOS were studied in standard colture conditions. Cell lines were evaluated for: CXCR4 expression by FACS analysis (mAb anti-CXCR4, BD Pharmingen); SDF-1 levels in conditioned medium (antibody sandwich ELISA, R&D Systems); modulation of CXCR4 expression on OS cells by exposure to recombinant human SDF-1 (rhSDF-1). The adhesion and migration of SJSA cells were tested on a monolayer of bone marrow stromal cells in response to rhSDF-1. We evaluated lung metastasis development in mouse model (Balb-c nu/nu) with and without monoclonal antibody anti-CXCR4 (T134) treatment. Results. CXCR4 was detected in about 40% of SJSA cell lines. On the contrary SDF-1 expression was lowest in SJSA cells compared to other OS cell lines. Moreover, SDF-1 down-regulated receptor expression on CXCR4 positive cell lines from 86% positivity to 8%. A migration assay showed cell locomotion was SDF-1 dependent. SJSA cells had the highest migration in response to SDF-1. Also cell adhesion was CXCR4/SDF-1 system dependent. In vitro, neutralization of CXCR4/SDF-1 interactions significantly impairs migration and adhesion of OS cells. In vivo: lung metastasis development, after SJSA cells injection, was prevented by T134 (5 μM) administration. Conclusions. These data suggest a possible mechanism to explain and to prevent the preferential metastatic development into bone marrow and lung tissue, where SDF-1 concentration are highest, and suggest how inhibiting CXCR4/SDF-1 axis prevents dissemination of OS cells. No significant financial relationships to disclose.