Hepatic Radiofrequency Ablation-induced Stimulation of Distant Tumor Growth Is Suppressed by c-Met Inhibition
Hepatic Radiofrequency Ablation-induced Stimulation of Distant Tumor Growth Is Suppressed by c-Met Inhibition
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DOI：
10.1148/radiol.2015150080
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发表时间：
2016-04-01
期刊：
影响因子：
19.7
通讯作者：
Goldberg, S. Nahum
中科院分区：
文献类型：
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作者：
Ahmed, Muneeb;Kumar, Gaurav;Goldberg, S. Nahum
目的：阐明肝脏射频（RF）消融如何通过两个关键分子途径影响远处肝外肿瘤的生长。材料和方法：在这项经机构动物护理和使用委员会批准的研究中使用了大鼠。首先，评估了肝脏射频消融对远处皮下原位 R3230 和 MATBIII 乳腺肿瘤的影响。动物被随机分配接受标准化射频消融、假手术或不治疗。测量31/2至7天的肿瘤生长率。然后，收获组织用于Ki-67增殖指数和CD34微血管密度。其次，在消融后 24 小时至 7 天进行肝脏射频消融，测量消融周围、血清和远处肿瘤中的肝细胞生长因子 (HGF)、血管内皮生长因子 (VEGF) 和 c-Met 受体表达。第三，肝脏射频消融与 c-Met 抑制剂 (PHA-665752) 或 VEGF 受体抑制剂 (semaxanib) 组合，并与假手术组或单独药物组进行比较，以评估远处肿瘤生长和生长因子水平。最后，对 c-Met 阴性 R3230 肿瘤大鼠进行肝脏射频消融，以与天然 c-Met 阳性细胞系进行比较。将第 0 天和处死时的肿瘤大小和免疫组织化学定量与方差分析和双尾学生 t 检验进行比较。采用线性回归分析法对治疗前后的肿瘤生长曲线进行分析，以确定每个肿瘤治疗前和治疗后生长曲线的平均斜率，并与方差分析和配对双尾t检验进行比较。结果：正常肝脏射频消融后，7天时远处的R3230肿瘤比假手术治疗的肿瘤和未治疗的肿瘤明显更大，具有更高的生长速率和肿瘤细胞 扩散。在 MATBIII 肿瘤中也观察到类似的结果。肝脏射频消融主要增加了消融周围和血清 HGF 以及下游远处肿瘤 VEGF 水平。与单独射频消融相比，射频消融联合辅助 PHA-665752 或 Semaxanib 可减少远处肿瘤的生长、增殖和微血管密度。对于c-Met阴性肿瘤，与假治疗相比，肝脏射频消融并没有增加远处肿瘤的生长、增殖或微血管密度。结论：正常肝脏的射频消融可以刺激HGF/c-Met通路和VEGF激活介导的远处皮下肿瘤生长。在 c-Met 阴性肿瘤中没有观察到这种效应，并且可以用辅助 c-Met 和 VEGF 抑制剂来阻断。 (C) 北美放射学会，2015
Purpose: To elucidate how hepatic radiofrequency (RF) ablation affects distant extrahepatic tumor growth by means of two key molecular pathways.Materials and Methods: Rats were used in this institutional animal care and use committee-approved study. First, the effect of hepatic RF ablation on distant subcutaneous in situ R3230 and MATBIII breast tumors was evaluated. Animals were randomly assigned to standardized RF ablation, sham procedure, or no treatment. Tumor growth rate was measured for 31/2 to 7 days. Then, tissue was harvested for Ki-67 proliferative indexes and CD34 microvascular density. Second, hepatic RF ablation was performed for hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and c-Met receptor expression measurement in periablational rim, serum, and distant tumor 24 hours to 7 days after ablation. Third, hepatic RF ablation was combined with either a c-Met inhibitor (PHA-665752) or VEGF receptor inhibitor (semaxanib) and compared with sham or drug alone arms to assess distant tumor growth and growth factor levels. Finally, hepatic RF ablation was performed in rats with c-Met-negative R3230 tumors for comparison with the native c-Met-positive line. Tumor size and immunohistochemical quantification at day 0 and at sacrifice were compared with analysis of variance and the two-tailed Student t test. Tumor growth curves before and after treatment were analyzed with linear regression analysis to determine mean slopes of pre- and posttreatment growth curves on a per-tumor basis and were compared with analysis of variance and paired two-tailed t tests.Results: After RF ablation of normal liver, distant R3230 tumors were substantially larger at 7 days compared with tumors treated with the sham procedure and untreated tumors, with higher growth rates and tumor cell proliferation. Similar findings were observed in MATBIII tumors. Hepatic RF ablation predominantly increased periablational and serum HGF and downstream distant tumor VEGF levels. Compared with RF ablation alone, RF ablation combined with adjuvant PHA-665752 or semaxanib reduced distant tumor growth, proliferation, and microvascular density. For c-Met-negative tumors, hepatic RF ablation did not increase distant tumor growth, proliferation, or microvascular density compared with sham treatment.Conclusion: RF ablation of normal liver can stimulate distant subcutaneous tumor growth mediated by HGF/c-Met pathway and VEGF activation. This effect was not observed in c-Metnegative tumors and can be blocked with adjuvant c-Met and VEGF inhibitors. (C) RSNA, 2015