Pediatric Oncology Research Unit, Department of Pediatrics, Lausanne University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland.
PLoS One. 2012;7(8):e43665. doi: 10.1371/journal.pone.0043665. Epub 2012 Aug 20.
Neuroblastoma (NB) is a typical childhood and heterogeneous neoplasm for which efficient targeted therapies for high-risk tumors are not yet identified. The chemokine CXCL12, and its receptors CXCR4 and CXCR7 have been involved in tumor progression and dissemination. While CXCR4 expression is associated to undifferentiated tumors and poor prognosis, the role of CXCR7, the recently identified second CXCL12 receptor, has not yet been elucidated in NB. In this report, CXCR7 and CXCL12 expressions were evaluated using a tissue micro-array including 156 primary and 56 metastatic NB tissues. CXCL12 was found to be highly associated to NB vascular and stromal structures. In contrast to CXCR4, CXCR7 expression was low in undifferentiated tumors, while its expression was stronger in matured tissues and specifically associated to differentiated neural tumor cells. As determined by RT-PCR, CXCR7 expression was mainly detected in N-and S-type NB cell lines, and was slightly induced upon NB cell differentiation in vitro. The relative roles of the two CXCL12 receptors were further assessed by overexpressing CXCR7 or CXCR4 receptor alone, or in combination, in the IGR-NB8 and the SH-SY5Y NB cell lines. In vitro functional analyses indicated that, in response to their common ligand, both receptors induced activation of ERK1/2 cascade, but not Akt pathway. CXCR7 strongly reduced in vitro growth, in contrast to CXCR4, and impaired CXCR4/CXCL12-mediated chemotaxis. Subcutaneous implantation of CXCR7-expressing NB cells showed that CXCR7 also significantly reduced in vivo growth. Moreover, CXCR7 affected CXCR4-mediated orthotopic growth in a CXCL12-producing environment. In such model, CXCR7, in association with CXCR4, did not induce NB cell metastatic dissemination. In conclusion, the CXCR7 and CXCR4 receptors revealed specific expression patterns and distinct functional roles in NB. Our data suggest that CXCR7 elicits anti-tumorigenic functions, and may act as a regulator of CXCR4/CXCL12-mediated signaling in NB.
神经母细胞瘤（NB）是一种典型的儿童期异质性肿瘤，对于高危肿瘤，目前还没有有效的靶向治疗方法。趋化因子 CXCL12 及其受体 CXCR4 和 CXCR7 已被涉及到肿瘤的进展和扩散。虽然 CXCR4 的表达与未分化的肿瘤和不良预后相关，但 CXCR7 的作用，即最近发现的第二个 CXCL12 受体，在 NB 中的作用尚未阐明。在本报告中，使用包括 156 个原发和 56 个转移性 NB 组织的组织微阵列评估了 CXCR7 和 CXCL12 的表达。发现 CXCL12 与 NB 的血管和基质结构高度相关。与 CXCR4 相反，CXCR7 的表达在未分化的肿瘤中较低，而在成熟的组织中表达更强，并特异性地与分化的神经肿瘤细胞相关。通过 RT-PCR 确定，CXCR7 的表达主要在 N 和 S 型 NB 细胞系中检测到，并且在体外 NB 细胞分化时略有诱导。通过单独过表达 CXCR7 或 CXCR4 受体，或组合过表达，在 IGR-NB8 和 SH-SY5Y NB 细胞系中进一步评估了这两种 CXCL12 受体的相对作用。体外功能分析表明，两种受体在响应其共同配体时均诱导 ERK1/2 级联的激活，但不诱导 Akt 途径。与 CXCR4 相反，CXCR7 强烈地降低了体外生长，并损害了 CXCR4/CXCL12 介导的趋化性。CXCR7 表达的 NB 细胞的皮下植入表明，CXCR7 也显著降低了体内生长。此外，CXCR7 在产生 CXCL12 的环境中影响 CXCR4 介导的原位生长。在这种模型中，CXCR7 与 CXCR4 一起，不会诱导 NB 细胞的转移扩散。总之，CXCR7 和 CXCR4 受体在 NB 中表现出特定的表达模式和不同的功能作用。我们的数据表明，CXCR7 引发抗肿瘤功能，并可能作为 NB 中 CXCR4/CXCL12 介导的信号的调节剂。
