胰岛素样生长因子/胰岛素系统与乳腺癌靶向治疗研究进展

Insulin and insulin-like growth factor signaling system in targeted therapy for breast cancer

目的胰岛素样生长因子／胰岛素系统参与乳腺癌肿瘤细胞的增殖、分化、浸润和转移过程，这为乳腺癌靶向治疗提供了一个新方向。本研究旨在总结国内外该系统抑制剂在乳腺癌靶向治疗方面的研究进展。方法利用PubMed、SciencceDirect和万方数据知识服务平台等数据库，以“胰岛素样生长因子／胰岛素系统、乳腺癌和靶向治疗”等为关键词，检索1995—10—2015—10的相关文献，其中英文文献1431条，中文文献46条。纳入标准：（1）关于胰岛素样生长因子／胰岛素系统抑制剂和乳腺癌靶向治疗的临床和基础研究；（2）胰岛素样生长因子／胰岛素系统与乳腺癌患病风险的流行病学调查；（3）胰岛素样生长因子/胰岛素系统的构成及信号通路的相关研究。剔除标准：（1）存在研究设计缺陷或统计方法错误，质量差；（2）数据不完整，结局效应不明确。根据上述标准纳入67篇文献进行分析。结果外周血的高胰岛素样生长因子水平、高配体结合蛋白水平与乳腺癌的患病风险相关，而乳腺癌组织中的胰岛素样生长因子受体也呈现高表达趋势。大量实验表明，作用于胰岛素样生长因子／胰岛素系统的配体、配体结合蛋白、受体及下游信号通路等的抑制剂，以及与其他相关系统的联合抑制剂，具有抗肿瘤作用，且部分抑制剂已进入临床Ⅰ～Ⅲ期研究，并取得有效成果。然而也出现了一些失败的例子，这可能与该系统的复杂性和多变性相关。结论以胰岛素样生长因子/胰岛素系统为靶点的药物研究是乳腺癌治疗领域的新热点，但对该系统的作用机制和如何更好地应用于临床的研究还有待进一步完善和深入。

OBJECTIVE The insulin and insulin-like growth factor （IGF） signaling system is implicated in breast cancer biology including proliferation, differentiation, infiltration and metastasis, it provides new insights into the targeted therapy against breast cancer. This review focuses on the advances in breast cancer treatment targeting this system both in China and abroad. METHODS All the references were searched in PubMed, SeienceDirect and Wanfang standards data- base through 1995.10 to 2015. 10. The docuterm were ＂Insulin and insulin-like growth factor signaling system, breast cancer, targeted therapy＂, and so on. There were 1 431 English and 46 Chinese literatures. Inclusion criteria： （1） pre- clinical and clinical studies about IGF/insulin system and targeting therapy for breast cancer; （2） epidemiological surveys about IGF/insulin system and breast cancer risk; （3） researches about structure and signaling pathway of IGF/insulin system. Exclusion criteria： （1） Those exists problems in research designs or statistical methods; （2） Those has incom- plete data or unclear results. Finally 67 papers were analyzed and reviewed. RESULTS Circulating concentrations of IGF and its binding proteins （IGFBPs） are associated with an increased risk of breast cancer, and the expression of IGF- I re ceptors （IGF-1R） in breast cancer tissues are higher than those in normal healthy individuals. Lots of preclinlcal studies have demonstrated of the anti-tumor effect of the inhibitions which target the IGF, IGFBPs, IGF-1R, downstream signa- ling pathways of the IGF/insulin signaling system, or the combinations with related signaling systems. So far, several phase I -- UI trials that targeted the system showed evidences of response, while the others have not shown clear clinical benefit. These disappointing results may be due to the complication and variability of the IGF/insulin system. CONCLU- SION Targeting IGF/insulin system has become a new hot spot in breast cancer treatment, but more researches need to do about the mechanism of the system and better clinical application.