Division of Pediatric Hematology/Oncology, Children's Hospital and University Medical Group of the Greenville Hospital System, Greenville, SC 29605, USA.
BMC Cancer. 2009 Nov 25;9:411. doi: 10.1186/1471-2407-9-411.
c-Met is a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF), and both c-Met and its ligand are expressed in a variety of tissues. C-Met/HGF/SF signaling is essential for normal embryogenesis, organogenesis, and tissue regeneration. Abnormal c-Met/HGF/SF signaling has been demonstrated in different tumors and linked to aggressive and metastatic tumor phenotypes. In vitro and in vivo studies have demonstrated inhibition of c-Met/HGF/SF signaling by the small-molecule inhibitor PHA665752. This study investigated c-Met and HGF expression in two neuroblastoma (NBL) cell lines and tumor tissue from patients with NBL, as well as the effects of PHA665752 on growth and motility of NBL cell lines. The effect of the tumor suppressor protein PTEN on migration and proliferation of tumor cells treated with PHA665752 was also evaluated.
Expression of c-Met and HGF in NBL cell lines SH-EP and SH-SY5Y and primary tumor tissue was assessed by immunohistochemistry and quantitative RT-PCR. The effect of PHA665752 on c-Met/HGF signaling involved in NBL cell proliferation and migration was evaluated in c-Met-positive cells and c-Met-transfected cells. The transwell chemotaxis assay and the MTT assay were used to measure migration and proliferation/cell-survival of tumor cells, respectively. The PPAR-gamma agonist rosiglitazone was used to assess the effect of PTEN on PHA665752-induced inhibition of NBL cell proliferation/cell-survival and migration
High c-Met expression was detected in SH-EP cells and primary tumors from patients with advanced-stage disease. C-Met/HGF signaling induced both migration and proliferation of SH-EP cells. Migration and proliferation/cell-survival were inhibited by PHA665752 in a dose-dependent manner. We also found that induced overexpression of PTEN following treatment with rosiglitazone significantly enhanced the inhibitory effect of PHA665752 on NBL-cell migration and proliferation.
c-Met is highly expressed in most tumors from patients with advanced-stage, metastatic NBL. Furthermore, using the NBL cell line SH-EP as a model, PHA665752 was shown to inhibit cMet/HGF/SF signaling in vitro, suggesting c-Met inhibitors may have efficacy for blocking local progression and/or metastatic spread of c-Met-positive NBL in vivo. These are novel findings for this disease and suggest that further studies of agents targeting the c-Met/HGF axis in NBL are warranted.
c-Met 是肝细胞生长因子/分散因子（HGF/SF）的酪氨酸激酶受体，c-Met 及其配体均在多种组织中表达。c-Met/HGF/SF 信号对于正常胚胎发生、器官发生和组织再生至关重要。在不同的肿瘤中已经证明了异常的 c-Met/HGF/SF 信号，并与侵袭性和转移性肿瘤表型相关。体外和体内研究已经证明了小分子抑制剂 PHA665752 对 c-Met/HGF/SF 信号的抑制作用。本研究调查了两种神经母细胞瘤（NBL）细胞系和 NBL 患者肿瘤组织中的 c-Met 和 HGF 表达，以及 PHA665752 对 NBL 细胞系生长和运动性的影响。还评估了肿瘤抑制蛋白 PTEN 对用 PHA665752 处理的肿瘤细胞迁移和增殖的影响。
通过免疫组织化学和定量 RT-PCR 评估 NBL 细胞系 SH-EP 和 SH-SY5Y 以及原发性肿瘤组织中 c-Met 和 HGF 的表达。在 c-Met 阳性细胞和 c-Met 转染细胞中评估 PHA665752 对 NBL 细胞增殖和迁移涉及的 c-Met/HGF 信号的影响。使用 Transwell 趋化性测定和 MTT 测定分别测量肿瘤细胞的迁移和增殖/细胞存活。使用过氧化物酶体增殖物激活受体-γ激动剂罗格列酮来评估 PTEN 对 PHA665752 诱导的抑制 NBL 细胞增殖/细胞存活和迁移的影响
在 SH-EP 细胞和晚期疾病患者的原发性肿瘤中检测到高表达的 c-Met。c-Met/HGF 信号诱导 SH-EP 细胞的迁移和增殖。PHA665752 以剂量依赖性方式抑制迁移和增殖/细胞存活。我们还发现，在用罗格列酮治疗后诱导过表达的 PTEN 显著增强了 PHA665752 对 NBL 细胞迁移和增殖的抑制作用。
在大多数晚期、转移性 NBL 患者的肿瘤中高度表达 c-Met。此外，使用 NBL 细胞系 SH-EP 作为模型，体外显示 PHA665752 抑制 cMet/HGF/SF 信号，表明 c-Met 抑制剂可能在体内有效阻止 c-Met 阳性 NBL 的局部进展和/或转移扩散。这是该疾病的新发现，并表明有必要进一步研究针对 NBL 中 c-Met/HGF 轴的药物。
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