RAGE expression in rhabdomyosarcoma cells modulates metastasis formation in vivo.

Rhabdomyosarcoma (RMS) is a highly malignant tumor of skeletal muscle origin accounting for more than 50% of soft tissue sarcomas in childhood, and characterized by uncontrolled proliferation in spite of the expression of muscle-specific markers (1). We reported that activation of RAGE (receptor for advanced glycation end-products) in RMS cells resulted in myogenic differentiation, reduced proliferation, migration and invasiveness in vitro, and reduced tumor growth in vivo (2). Herein we show that RAGE has a role in the metastatic potential of RMS cells in vivo. Intraperitoneal injection of embryonal (RAGE-) RMS TE671 cells stably transfected with RAGE (TE671/RAGE) (2) in irradiated athymic nude mice resulted in a reduced tumor growth and liver metastasis formation, compared to TE671/WT cells (50% vs 100% and 25% vs 75% tumor and metastasis formation, respectively). Interestingly, liver metastases in TE671/RAGE-injected tumor-bearing mouse resulted negative for RAGE expression by immunohistochemistry. Moreover, compared to TE671/WT cells TE671/RAGE cells in growth medium (GM) showed: i) increased expression and reduced polysialylation of neural cell adhesion molecule (NCAM), events reported to prevent the progression of tumor metastases; and, ii) altered expression pattern of ephrins and Eph receptors (3), with upregulation of ephrins A1,A2,A5,B1,B3 and Ephs A2,A7, and down-regulation of ephrins A3 and Ephs A4,B2, as investigated by RT-PCR. These data suggest that forced expression of RAGE in embryonal RMS cells reduces their metastatic potential in vivo by altering the pattern of surface molecules involved in cell migration, invasion and metastasis. 1) Parham DM, Ellison DA. 2006. Arch Pathol Lab Med 130:1454-65; 2) Riuzzi F et al. 2007. Am J Pathol 171:947–61; 3) Pasquale EB. 2010. Nat Rev Cancer 10:165-80.