Expression of the ghrelin/growth hormone secretagogue receptor axis and its functional role in promoting tumor growth in primary central nervous system lymphomas
Expression of the ghrelin/growth hormone secretagogue receptor axis and its functional role in promoting tumor growth in primary central nervous system lymphomas
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DOI：
10.1111/neup.12634
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发表时间：
2020-06-01
期刊：
影响因子：
2.3
通讯作者：
Kakita, Akiyoshi
中科院分区：
文献类型：
--
作者：
Muta, Hiroko;Sugita, Yasuo;Kakita, Akiyoshi
Ghrelin及其受体生长激素促分泌素受体（GHS-R）广泛存在于多种恶性肿瘤组织中，提示Ghrelin/GHS-R轴在肿瘤的生长和发展中具有重要的生物学功能。在中枢神经系统肿瘤中，原发性中枢神经系统淋巴瘤（PCNSL）相对罕见，其特点是进展快，预后差。为了阐明Ghrelin的表达及其在促进PCNSL肿瘤生长和进展中的功能作用，我们对43例患者的Ghrelin和GHS-R表达进行了免疫组化研究，并测试了Ghrelin抑制对淋巴瘤细胞的影响。此外，我们研究了肿瘤血管生成的标志物CD 105的表达，以探讨其与ghrelin/GHS-R轴的关系。采用Kaplan-Meier法和考克斯比例风险回归模型分析ghrelin/GHS-R表达与总生存率的关系。免疫组化结果显示，分别有40例（93.0%）和39例（90.7%）患者的ghrelin和GHS-R细胞呈中/强免疫染色。Ghrelin抑制剂在体外对肿瘤细胞增殖无影响。ghrelin和GHS-R的表达水平根据中强染色细胞占肿瘤细胞的比例分为高、低两组。GHS-R高表达患者的生存率显著较低（对数秩检验P= 0.0368; Wilcoxon检验P= 0.0219）。此外，使用考克斯的比例风险回归模型的总生存率的多因素分析表明，GHS-R是一个重要的独立预后因素（P= 0.0426）。33例（33/37，89.2%）肿瘤血管CD 105表达阳性。Ghrelin的中强染色率与CD 105阳性血管计数呈正相关。这些结果表明，ghrelin/GHS-R轴在促进肿瘤的生长和发展中发挥了潜在的作用，通过新血管生成，而不是肿瘤细胞的增殖。
Ghrelin and its receptor, growth hormone secretagogue receptor (GHS-R), have been found in a variety of malignant tumor tissues, suggesting a biological function of the ghrelin/GHS-R axis in tumor growth and progression. Among central nervous system tumors, primary central nervous system lymphomas (PCNSLs) are relatively rare and characterized by a rapid progression and poor prognosis. In order to clarify ghrelin expression and its functional role in promoting tumor growth and progression in PCNSLs, we undertook an immunohistochemical investigation for ghrelin and GHS-R expression in 43 patients and tested the effect of ghrelin inhibition on lymphoma cells. Furthermore, we investigated the expression of CD105, a marker for tumor angiogenesis, to explore its association with the ghrelin/GHS-R axis. The Kaplan-Meier method and Cox's proportional hazards regression model were used to determine the association of ghrelin/GHS-R expression with overall survival rate. The immunohistochemical study showed moderate/strong immunostaining of cells for ghrelin and GHS-R in 40 patients (93.0%) and 39 patients (90.7%), respectively. A ghrelin inhibitor did not affect tumor cell proliferationin vitro. Expression levels of ghrelin and GHS-R were divided into high and low groups by the rate of moderate-strong staining cells to tumor cells. The survival rate was significantly lower in patients with high GHS-R expression (P= 0.0368 by log-rank test;P= 0.0219 by Wilcoxon test). In addition, multivariate analysis of overall survival using Cox's proportional hazards regression model indicated that GHS-R was a significant independent prognostic factor (P= 0.0426). CD105 expression on tumor vessels was positive in 33 patients (33/37, 89.2%). There was a positive correlation between the moderate-strong staining rate of ghrelin and CD105-positive vessel count. These results indicated that the ghrelin/GHS-R axis plays a potential role in promoting tumor growth and progression through neoangiogenesis, rather than the proliferation of tumor cells.