Biomedical Research Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Clin Cancer Res. 2011 Feb 1;17(3):505-13. doi: 10.1158/1078-0432.CCR-10-0166. Epub 2010 Dec 21.
Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children and can be divided into two main subtypes: embryonal and alveolar RMS. Patients with metastatic disease continue to have very poor prognosis although aggressive therapies and recurrences are common in advanced localized disease. The oncogenic potential of the Notch pathway has been established in some cancers of the adult and in some pediatric malignancies.
A real-time PCR assay was used to ascertain the expression of several Notch pathway components in a wide panel of RMS and cell lines. Four γ-secretase inhibitors (GSIs) were tested for pathway inhibition and the degree of inhibition was assessed by analysis of Hes1 and Hey1 expression. The putative effects of Notch pathway inhibition were evaluated by wound-healing, matrigel/transwell invasion, cell-cycle, and apoptosis assays.
The Notch pathway was widely expressed and activated in RMS and underwent substantial inhibition when treated with GSIs or transfected with a dominant negative form of MAML1. RMS cells showed a significant decrease in its mobility and invasiveness when the Notch pathway was properly inhibited; conversely, its inhibition had no noticeable effect on cell cycle or apoptosis.
Pharmacological or genetic blockage of the pathway significantly reduced invasiveness of RMS cell lines, thereby suggesting a possible role of the Notch pathway in the regulation of the metastatic process in RMS.
横纹肌肉瘤（RMS）是儿童中最常见的软组织肉瘤类型，可分为两个主要亚型：胚胎性和肺泡性 RMS。尽管转移性疾病患者的预后仍然非常差，但即使在晚期局限性疾病中也经常出现侵袭性治疗和复发。Notch 通路的致癌潜能已在一些成人癌症和一些儿科恶性肿瘤中得到证实。
使用实时 PCR 分析确定了 Notch 通路的几个成分在广泛的 RMS 和细胞系中的表达。测试了四种 γ-分泌酶抑制剂（GSIs）以抑制通路，并通过分析 Hes1 和 Hey1 的表达来评估抑制程度。通过划痕愈合、基质胶/Transwell 侵袭、细胞周期和凋亡测定评估 Notch 通路抑制的潜在作用。
Notch 通路在 RMS 中广泛表达并被激活，当用 GSIs 处理或转染显性负形式的 MAML1 时，它受到显著抑制。当 Notch 通路被适当抑制时，RMS 细胞的迁移和侵袭能力显著下降；相反，其抑制对细胞周期或凋亡没有明显影响。
该通路的药理学或遗传阻断显著降低了 RMS 细胞系的侵袭性，这表明 Notch 通路在 RMS 转移过程的调节中可能发挥作用。
