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肿瘤微环境中由信号转导与转录激活因子3（STAT3）介导的胰岛素样生长因子2（IGF-2）分泌引发了对抗胰岛素样生长因子1受体（IGF-1R）抗体的天然抗性。

STAT3-mediated IGF-2 secretion in the tumour microenvironment elicits innate resistance to anti-IGF-1R antibody.

作者信息

Lee Ji-Sun, Kang Ju-Hee, Boo Hye-Jin, Hwang Su-Jung, Hong Sungyoul, Lee Su-Chan, Park Young-Jun, Chung Tae-Moon, Youn Hyewon, Mi Lee Seung, Jae Kim Byoung, Chung June-Key, Chung Yeonseok, William William N, Kee Shin Young, Lee Hyo-Jong, Oh Seung-Hyun, Lee Ho-Young

机构信息

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151 742, Korea.

National Cancer Center, Goyang-si, Gyeonggi-do 410 769, Korea.

出版信息

Nat Commun. 2015 Oct 14;6:8499. doi: 10.1038/ncomms9499.

DOI:10.1038/ncomms9499
PMID:26465273
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4608384/
Abstract

Drug resistance is a major impediment in medical oncology. Recent studies have emphasized the importance of the tumour microenvironment (TME) to innate resistance, to molecularly targeted therapies. In this study, we investigate the role of TME in resistance to cixutumumab, an anti-IGF-1R monoclonal antibody that has shown limited clinical efficacy. We show that treatment with cixutumumab accelerates tumour infiltration of stromal cells and metastatic tumour growth, and decreases overall survival of mice. Cixutumumab treatment stimulates STAT3-dependent transcriptional upregulation of IGF-2 in cancer cells and recruitment of macrophages and fibroblasts via paracrine IGF-2/IGF-2R activation, resulting in the stroma-derived CXCL8 production, and thus angiogenic and metastatic environment. Silencing IGF-2 or STAT3 expression in cancer cells or IGF-2R or CXCL8 expression in stromal cells significantly inhibits the cancer-stroma communication and vascular endothelial cells' angiogenic activities. These findings suggest that blocking the STAT3/IGF-2/IGF-2R intercellular signalling loop may overcome the adverse consequences of anti-IGF-1R monoclonal antibody-based therapies.

摘要

耐药性是医学肿瘤学中的一个主要障碍。最近的研究强调了肿瘤微环境（TME）对固有耐药性以及分子靶向治疗的重要性。在本研究中，我们调查了TME在对西妥昔单抗耐药中的作用，西妥昔单抗是一种抗IGF-1R单克隆抗体，临床疗效有限。我们发现，用西妥昔单抗治疗会加速基质细胞的肿瘤浸润和转移性肿瘤生长，并降低小鼠的总生存期。西妥昔单抗治疗通过旁分泌IGF-2/IGF-2R激活刺激癌细胞中IGF-2的STAT3依赖性转录上调以及巨噬细胞和成纤维细胞的募集，导致基质来源的CXCL8产生，从而形成血管生成和转移环境。沉默癌细胞中的IGF-2或STAT3表达或基质细胞中的IGF-2R或CXCL8表达可显著抑制癌-基质通讯和血管内皮细胞的血管生成活性。这些发现表明，阻断STAT3/IGF-2/IGF-2R细胞间信号环可能克服基于抗IGF-1R单克隆抗体治疗的不良后果。

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