Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Am J Pathol. 2012 Jul;181(1):303-12. doi: 10.1016/j.ajpath.2012.03.028. Epub 2012 May 29.
New treatment targets need to be identified in gastrointestinal stromal tumors (GISTs) to extend the treatment options for patients experiencing failure with small-molecule tyrosine kinase inhibitors, such as imatinib. Insulin-like growth factor (IGF)-II acts as an autocrine factor in several tumor types by binding to IGF receptor type 1 (IGF-1R) and/or the insulin receptor (IR) isoform A. The aim of the present study was to investigate the putative role of unprocessed pro-IGF-II, called 'big'-IGF-II, in GISTs. The imatinib-sensitive GIST882 and imatinib-resistant GIST48 cell lines secrete high levels of big-IGF-II as demonstrated by ELISA and Western blotting analyses. IR isoform A mRNA and protein expression, but not that of IGF-1R, was found in these KIT mutant cell lines and in KIT and platelet-derived growth factor receptor α-mutant GIST specimens. Down-regulation of either big-IGF-II or IR affected AKT and MAPK signaling and reduced survival in both cell lines. Disruption of big-IGF-II signaling in combination with imatinib had additive cytotoxic effects on GIST882 cells. IGF-II mRNA as determined by in situ hybridization was present in 91% of 60 primary GISTs. Immunohistochemical analysis of big-IGF-II protein expression was associated with moderate- to high-risk tumors compared with tumors with a lower risk classification (P < 0.028). Our data put forth the big-IGF-II/IR isoform A axis as an autocrine survival pathway and potential therapeutic target in GISTs.
需要在胃肠道间质瘤 (GIST) 中确定新的治疗靶点，以延长对小分子酪氨酸激酶抑制剂（如伊马替尼）治疗失败的患者的治疗选择。胰岛素样生长因子 (IGF)-II 在几种肿瘤类型中作为自分泌因子发挥作用，通过与 IGF 受体 1 (IGF-1R) 和/或胰岛素受体 (IR) 同工型 A 结合。本研究旨在研究未加工的前胰岛素样生长因子 II（称为“大”胰岛素样生长因子 II）在 GIST 中的潜在作用。免疫印迹分析和 ELISA 分析表明，伊马替尼敏感的 GIST882 和伊马替尼耐药的 GIST48 细胞系分泌高水平的大胰岛素样生长因子 II。在这些 KIT 突变细胞系和 KIT 和血小板衍生生长因子受体 α 突变 GIST 标本中发现了 IR 同工型 A mRNA 和蛋白表达，但没有 IGF-1R。下调大胰岛素样生长因子 II 或 IR 均影响 AKT 和 MAPK 信号通路，并降低两种细胞系的存活率。大胰岛素样生长因子 II 信号中断与伊马替尼联合使用对 GIST882 细胞具有相加的细胞毒性作用。通过原位杂交确定的 IGF-II mRNA 存在于 60 例原发性 GIST 中的 91%。与风险较低的肿瘤相比，大胰岛素样生长因子 II 蛋白表达的免疫组织化学分析与中高危肿瘤相关（P < 0.028）。我们的数据提出了大胰岛素样生长因子 II/IR 同工型 A 轴作为 GIST 中的自分泌存活途径和潜在治疗靶点。
