CXCR4-CXCL12 axis: Pivotal role as a metastatic mediator in small cell sarcoma

Abstract

10569 Background: The chemokine CXCL12, and its receptor CXCR4, are expressed in over 23 different types of cancers, and have been associated with the metastatic phenotype and inferior clinical outcomes. Given the poor prognosis after failure of front-line therapy for patients with metastatic Ewing's sarcoma (EWS) and rhabdomyosarcoma (RMS), we examined the functional role of CXCR4 in these small cell sarcoma in vitro. Methods: Human EWS and RMS cell lines and tissue were used to study CXCR4 expression and activation. Immunoblotting techniques were used to evaluate CXCR4 activation and inhibition. Cell viability, cell cycle, apoptosis, chemosensitivity, migration, and invasion assays were utilized to assess the effects of the small peptide CXCR4 antagonist, CTCE-9908 (Chemokine Therapeutics) on cultured cells. Results: CXCR4 was highly expressed on 46 % of human RMS tumor samples. CXCR4 underwent phosphorylation after stimulation with CXCL12 in EWS and RMS cell lines with downstream activation of Akt, p42/44 MAPK, JAK2 and PLCγ1 in select cell lines. CTCE-9908 was able to specifically inhibit downstream signaling of Akt, p42/44 MAPK and JAK2. Decrease in cell proliferation (20–30%, p < .05), increase in cell apoptosis (20–40 %, p < .05) and cell cycle arrest was also observed with CXCR4 blockade. CTCE-9908 significantly inhibited migration and invasion (68–93 %, p < .05) in our cell lines. Conclusions: CXCR4-CXCL12 axis may be important in EWS and RMS metastasis. These results provide evidence that CTCE-9908 may be a novel therapy for these sarcomas. No significant financial relationships to disclose.