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Clinical Significance of CXC Chemokine Receptor-4 and c-Met in Childhood Rhabdomyosarcoma

Authors' Affiliations: Divisions of ¹ Pathology, ² Oncology, and ³ Surgery, ⁴ Laboratory of Oncology, Bambino Gesù Children's Hospital, Departments of ⁵ Experimental Medicine and Pathology, and ⁶ Pediatrics, La Sapienza University, ⁷ Section of Toxicology and Biomedical Sciences, ENEA Research Center Casaccia, Rome, Italy, ⁸ Department of Oncology, Royal Liverpool Children's NHS Trust-Alder Hey and ⁹ Division of Child Health, School of Reproductive and Developmental Medicine, Liverpool University, Liverpool, United Kingdom

Requests for reprints: Carlo Dominici, Department of Pediatrics, La Sapienza University, Viale Regina Elena 324 I-00161, Rome, Italy. Phone: 39-06-4997-9212; Fax: 39-06-4997-2580; E-mail: Carlo.Dominici{at}uniroma1.it.

Purpose: The CXC chemokine receptor-4 (CXCR4)/stromal-derived factor-1 and c-Met/hepatocyte growth factor axes promote the metastatic potential of rhabdomyosarcoma cell lines in experimental models, but no data are available on their role in rhabdomyosarcoma tumors. The expressions of CXCR4 and c-Met were evaluated in primary tumors and isolated tumor cells in marrow, and were correlated with clinicopathologic variables and survival.

Experimental Design: Forty patients with recently diagnosed rhabdomyosarcoma were retrospectively enrolled. CXCR4 and c-Met expression was investigated in primary tumors by immunohistochemistry, in isolated marrow-infiltrating tumor cells using double-label immunocytology. Results were expressed as the mean percentage of immunostained tumor cells.

Results: CXCR4 and c-Met were expressed in 5% of tumor cells from 40 of 40 tumors, with 14 of 40 cases showing 50% of immunostained tumor cells (high expression). High CXCR4 expression correlated with alveolar histology (P = 0.006), unfavorable primary site (P = 0.009), advanced group (P < 0.001), marrow involvement (P = 0.007), and shorter overall survival and event-free survival (P < 0.001); high c-Met expression correlated with alveolar histology (P = 0.005), advanced group (P = 0.04), and marrow involvement (P = 0.02). In patients with a positive diagnosis for isolated tumor cells in marrow (n = 16), a significant enrichment in the percentage of CXCR4-positive (P = 0.001) and c-Met–positive (P = 0.003) tumor cells was shown in marrow aspirates compared with the corresponding primary tumors.

Conclusions: CXCR4 and c-Met are widely expressed in both rhabdomyosarcoma subtypes and, at higher levels, in isolated marrow-infiltrating tumor cells. High levels of expression are associated with unfavorable clinical features, tumor marrow involvement and, only for CXCR4, poor outcome. In rhabdomyosarcoma, CXCR4 and c-Met represent novel exploitable targets for disease-directed therapy.