The IL-6/JAK/Stat3 Feed-Forward Loop Drives Tumorigenesis and Metastasis
The IL-6/JAK/Stat3 Feed-Forward Loop Drives Tumorigenesis and Metastasis
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DOI：
10.1593/neo.13706
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发表时间：
2013-07-01
期刊：
影响因子：
4.8
通讯作者：
Bromberg, Jacqueline
中科院分区：
文献类型：
--
作者：
Chang, Qing;Bournazou, Eirini;Bromberg, Jacqueline
我们研究了白介素6(IL-6)在促进肿瘤生长和转移中的重要性。在人类原发性乳腺癌中，IL-6水平在肿瘤前沿升高，且与晚期乳腺癌呈正相关，提示肿瘤细胞产生IL-6与肿瘤侵袭有关。为了支持这一假说，我们证明了IL-6/Janus Kinase(JAK)/信号转导和转录激活因子3(STAT3)通路通过间质和转移生态位驱动肿瘤进展。IL-6在肿瘤细胞系中的过表达促进了髓系细胞的募集、血管生成和诱导转移。我们证明了通过阻断IL-6受体或通过抑制其下游效应JAK1/2或STAT3来阻断这一途径的治疗潜力。这些临床相关的干预措施在体外并不抑制肿瘤细胞的增殖，但在体内对肿瘤的进展有深远的影响，广泛干扰肿瘤的支持间质功能，包括肿瘤和转移前的壁龛中的血管生成、成纤维细胞的渗透和髓系抑制细胞的募集。本研究首次提供了IL-6在人类乳腺浸润性肿瘤前沿表达的证据，并从机制上证明了IL-6/JAK/STAT3信号在协调促进生长、侵袭和转移的肿瘤微环境的组成中起着关键的和药理学靶向的作用。
We have investigated the importance of interleukin-6 (IL-6) in promoting tumor growth and metastasis. In human primary breast cancers, increased levels of IL-6 were found at the tumor leading edge and positively correlated with advanced stage, suggesting a mechanistic link between tumor cell production of IL-6 and invasion. In support of this hypothesis, we showed that the IL-6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (Stat3) pathway drives tumor progression through the stroma and metastatic niche. Overexpression of IL-6 in tumor cell lines promoted myeloid cell recruitment, angiogenesis, and induced metastases. We demonstrated the therapeutic potential of interrupting this pathway with IL-6 receptor blockade or by inhibiting its downstream effectors JAK1/2 or Stat3. These clinically relevant interventions did not inhibit tumor cell proliferation in vitro but had profound effects in vivo on tumor progression, interfering broadly with tumor-supportive stromal functions, including angiogenesis, fibroblast infiltration, and myeloid suppressor cell recruitment in both the tumor and pre-metastatic niche. This study provides the first evidence for IL-6 expression at the leading edge of invasive human breast tumors and demonstrates mechanistically that IL-6/JAK/Stat3 signaling plays a critical and pharmacologically targetable role in orchestrating the composition of the tumor microenvironment that promotes growth, invasion, and metastasis.