CXC趋化因子受体4和c-Met在儿童横纹肌肉瘤中的临床意义

Clinical significance of CXC chemokine receptor-4 and c-Met in childhood rhabdomyosarcoma.

作者信息

Diomedi-Camassei Francesca, McDowell Heather P, De Ioris Maria A, Uccini Stefania, Altavista Pierluigi, Raschellà Giuseppe, Vitali Roberta, Mannarino Olga, De Sio Luigi, Cozzi Denis A, Donfrancesco Alberto, Inserra Alessandro, Callea Francesco, Dominici Carlo

机构信息

Division of Pathology, Bambino Gesù Children's Hospital, Rome, Italy.

出版信息

Clin Cancer Res. 2008 Jul 1;14(13):4119-27. doi: 10.1158/1078-0432.CCR-07-4446.

DOI:10.1158/1078-0432.CCR-07-4446

PMID:18593989

Abstract

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.

摘要

目的

在实验模型中，CXC趋化因子受体4（CXCR4）/基质细胞衍生因子1和c-Met/肝细胞生长因子轴可促进横纹肌肉瘤细胞系的转移潜能，但尚无关于它们在横纹肌肉瘤肿瘤中作用的数据。评估原发性肿瘤和骨髓中分离出的肿瘤细胞中CXCR4和c-Met的表达，并将其与临床病理变量及生存率相关联。

实验设计

回顾性纳入40例新诊断的横纹肌肉瘤患者。通过免疫组织化学检测原发性肿瘤中CXCR4和c-Met的表达，使用双标记免疫细胞术检测分离出的骨髓浸润肿瘤细胞中的表达。结果以免疫染色肿瘤细胞的平均百分比表示。

结果

40例肿瘤中有40例肿瘤细胞中CXCR4和c-Met的表达≥5%，40例中有14例显示免疫染色肿瘤细胞≥50%（高表达）。CXCR4高表达与肺泡组织学（P = 0.006）、原发部位不佳（P = 0.009）、晚期组（P < 0.001）、骨髓受累（P = 0.007）以及总生存期和无事件生存期较短相关（P < 0.001）；c-Met高表达与肺泡组织学（P = 0.005）、晚期组（P = 0.04）和骨髓受累（P = 0.02）相关。在骨髓中分离出肿瘤细胞诊断为阳性的患者（n = 16）中，与相应原发性肿瘤相比，骨髓穿刺液中CXCR4阳性（P = 0.001）和c-Met阳性（P = 0.003）肿瘤细胞的百分比显著增加。