Abstract
9510 Background: Both CXCR4/SDF-1 and c-Met/HGF axes promote invasive growth of RMS cells in experimental models, but no data are available on their expression and significance in RMS tumors. Expression for CXCR4 and c-Met (and their ligands) was evaluated in primary RMS tumors and correlated with clinical features, marrow involvement at diagnosis, overall (OS) and progression-free survival (PFS). Methods: Forty newly diagnosed pts, aged 2–180 months (median 58), with embryonal (n. 20) or alveolar (n. 20) RMS admitted between 1994 and 2004 were retrospectively enrolled. The only selection criterion was availability of data on marrow involvement at diagnosis as assessed by cytomorphology and immunocytochemistry for MyoD1 and myogenin. Primary site was favorable (orbit, paratesticular, uterus/vagina) in 7 pts and unfavorable (all the others) in 33. Pts were entered as group I/II (n. 5), III (n. 28) or IV (n. 7) (IRS grouping system). Marrow was infiltrated at diagnosis in 16 pts. Treatment was according to Italian RMS protocols. Expression for CXCR4, SDF-1, c-Met and HGF proteins was investigated by immunohistochemistry. Three separate counts (each >5,000 tumor cells) were performed without knowledge of clinical features and outcome; results expressed as mean percentage of immunostained tumor cells. Student t test, log-rank test, Kaplan-Meier survival analysis were applied. Institutional informed consent and ethical approval were obtained. Results: As of December 2006, median follow-up was 60 months, with 25 pts DF, 1 AWD and 14 DOD. CXCR4 and c-Met were expressed in =5% of tumor cells in all cases, but 14/40 tumors showed =50% tumor cell positivity (high expression) for either markers. 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), shorter OS and PFS (p<0.001). High c- Met expression with alveolar histology (p=0.005), advanced group (p=0.04), marrow involvement (p=0.02). SDF-1 and HGF were expressed by a lower percentage of tumor cells (1–95% of cells positive for the correspondent receptor). Conclusions: CXCR4/SDF-1 and c-Met/HGF pathways are clinically relevant in children with RMS and represent novel targets for disease-directed therapy. No significant financial relationships to disclose.
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