Bioactive insulin-like growth factors as a possible molecular target for non-islet cell tumor hypoglycemia
Bioactive insulin-like growth factors as a possible molecular target for non-islet cell tumor hypoglycemia
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DOI：
10.4161/15384047.2014.961878
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发表时间：
2014-12
影响因子：
3.6
通讯作者：
T. Setoyama;S. Miyamoto;T. Horimatsu;T. Funakoshi;Mitsuhiro Nikaido;Y. Kodama;S. Minamiguchi;Tomoko Yamabata;M. Muto;T. Chiba
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文献类型：
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作者：
T. Setoyama;S. Miyamoto;T. Horimatsu;T. Funakoshi;Mitsuhiro Nikaido;Y. Kodama;S. Minamiguchi;Tomoko Yamabata;M. Muto;T. Chiba
非胰岛细胞瘤低血糖症（NICTH）是一种伴随肿瘤的综合征，其特征是各种实体瘤的持续严重低血糖。它被认为是通过增加循环胰岛素样生长因子（IGF）系统的胰岛素样生物活性而引起低血糖，然而，低血糖的确切机制仍不清楚。在这篇手稿中，我们报告了一个病人患NICTH引起的小细胞癌的结肠。这是第一份报告，重点是生物活性IGFs的作用，这种病理条件。首先，我们使用免疫组织化学分析证明，该肿瘤中的IGF信号途径已以自分泌和/或旁分泌方式被激活。第二，我们证实，在患者的血清中的生物活性IGFs的增加，使用一种改进的激酶受体活化试验，因此，生物活性IGFs（主要是IGF-2）可以被认为是发挥了主要的致病作用，在增强的降糖胰岛素样活性。第三，患者血清中增加的IGF生物活性在体外被抗IGF中和抗体完全抑制。这些结果表明，中和生物活性IGFs可能成为一种新的治疗策略，NICTH，以减轻低血糖症状和肿瘤抑制作用。
Non-islet cell tumor hypoglycemia (NICTH) is a paraneoplastic syndrome characterized by persistent, severe hypoglycemia with a wide variety of solid tumors. It is considered to cause hypoglycemia by increasing the insulin-like bioactivity of the circulating insulin-like growth factor (IGF) system, however, the precise mechanism of hypoglycemia remains unclear. In this manuscript, we report on a patient suffering from NICTH caused by a small cell carcinoma of the colon. This is the first report focusing on the role of bioactive IGFs for this pathological condition. First, we demonstrated that the IGF signal pathway has been activated in this tumor in an autocrine and/or paracrine manner using immunohistochemical analysis. Second, we confirmed that bioactive IGFs in the patient's serum were increased using a modified kinase receptor activation assay, thus bioactive IGFs (mainly IGF-2) could be considered to play a major pathogenic role in enhanced hypoglycemic insulin-like activity. Third, increased IGF bioactivity in the patient's serum was completely inhibited by an anti-IGF neutralizing antibody in vitro. These results suggest that neutralization of bioactive IGFs might become a novel therapeutic strategy for NICTH to relieve the hypoglycemic symptoms together with the tumor suppressive effect.