Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation
Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation
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原发性肿瘤释放富含ITGBL1的细胞外囊泡，通过成纤维细胞微环境的形成促进远端转移性肿瘤的生长。
DOI：
10.1038/s41467-020-14869-x
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发表时间：
2020-03-05
影响因子：
16.6
通讯作者：
Li, Qi
中科院分区：
文献类型：
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作者：
Ji, Qing;Zhou, Lihong;Li, Qi
肿瘤转移是癌症的一个标志。转移性癌细胞常常以休眠状态存在于远端组织和器官中。转移前微环境形成的潜在机制了解甚少。在此我们在一个结直肠癌（CRC）模型中表明，原发肿瘤向循环中释放富含整合素β样1（ITGBL1）的细胞外囊泡（EVs），以激活远处器官中的驻留成纤维细胞。被激活的成纤维细胞通过分泌促炎细胞因子，如白细胞介素 - 6（IL - 6）和白细胞介素 - 8（IL - 8），诱导转移前微环境形成并促进转移性肿瘤生长。从机制上讲，源自原发性CRC的富含ITGBL1的EVs刺激TNFAIP3介导的核因子 - κB（NF - κB）信号通路来激活成纤维细胞。因此，被激活的成纤维细胞产生高水平的促炎细胞因子以促进转移性肿瘤生长。这些发现揭示了转移性肿瘤微环境中的肿瘤 - 基质相互作用，以及通过负载ITGBL1的EVs在原发肿瘤和转移瘤之间的紧密信号通讯。靶向EVs - ITGBL1 - 癌相关成纤维细胞（CAFs） - TNFAIP3 - NF - κB信号轴为治疗转移性疾病提供了一种有吸引力的方法。调节转移前微环境形成的机制仍然知之甚少。在此，作者表明源自原发性结直肠癌细胞的含ITGBL1的细胞外囊泡激活远处器官中驻留成纤维细胞产生炎性细胞因子，促进转移性肿瘤生长。
Tumor metastasis is a hallmark of cancer. Metastatic cancer cells often reside in distal tissues and organs in their dormant state. Mechanisms underlying the pre-metastatic niche formation are poorly understood. Here we show that in a colorectal cancer (CRC) model, primary tumors release integrin beta-like 1 (ITGBL1)-rich extracellular vesicles (EVs) to the circulation to activate resident fibroblasts in remote organs. The activated fibroblasts induce the pre-metastatic niche formation and promote metastatic cancer growth by secreting pro-inflammatory cytokine, such as IL-6 and IL-8. Mechanistically, the primary CRC-derived ITGBL1-enriched EVs stimulate the TNFAIP3-mediated NF-kappa B signaling pathway to activate fibroblasts. Consequently, the activated fibroblasts produce high levels of pro-inflammatory cytokines to promote metastatic cancer growth. These findings uncover a tumor-stromal interaction in the metastatic tumor microenvironment and an intimate signaling communication between primary tumors and metastases through the ITGBL1-loaded EVs. Targeting the EVs-ITGBL1-CAFs-TNFAIP3-NF-kappa B signaling axis provides an attractive approach for treating metastatic diseases. Mechanisms regulating the formation of pre-metastatic niches remain poorly understood. Here, the authors show that ITGBL1-containing extracellular vesicles derived from primary colorectal cancer cells activate the production of inflammatory cytokines by resident fibroblasts in distant organs, promoting metastatic cancer growth.