Extracellular vesicles of carcinoma-associated fibroblasts creates a pre-metastatic niche in the lung through activating fibroblasts

Jing Kong,Dong Jin,Xue Liu,Hongzhu Tian,Xuesong Yang,Xiancheng Li,Jiao Li,Fuyin Zhang,Yong Luo,Xiaojie Li,Zebing Zhang,Tingjiao Liu,Tao Guo,Yao Lu,Bingcheng Lin,Bo Sun,Jing Liu

doi:10.1186/s12943-019-1101-4

Abstract

ObjectivesCarcinoma-associated fibroblasts (CAFs) have been known to promote cancer progression by modifying the primary tumor microenvironment. We aimed to elucidate the intercellular communication between CAFs and secondary organs in salivary adenoid cystic carcinoma (SACC) metastasis.MethodsPre-metastatic and metastatic animal models of SACC were established using extracellular vesicles (EVs) from CAFs and SACC cells. Lung fibroblasts (LFs) were treated with EVs and their transcriptomic alterations were identified by RNA sequencing. ITRAQ were performed to analyze EV cargos. TC I-15 was used to inhibit EV uptake by LFs and SACC lung metastasis in vivo.ResultsHere, we show that CAF EVs induced lung pre-metastatic niche formation in mice and consequently increased SACC lung metastasis. The pre-metastatic niche induced by CAF EVs was different from that induced by SACC EVs. CAF EVs presented a great ability for matrix remodeling and periostin is a potential biomarker characterizing the CAF EV-induced pre-metastatic niche. We found that lung fibroblast activation promoted by CAF EVs was a critical event at the pre-metastatic niche. Integrin α2β1 mediated CAF EV uptake by lung fibroblasts, and its blockage by TC I-15 prevented lung pre-metastatic niche formation and subsequent metastasis. Plasma EV integrin β1 was considerably upregulated in the mice bearing xenografts with high risk of lung metastasis.ConclusionsWe demonstrated that CAF EVs participated in the pre-metastatic niche formation in the lung. Plasma EV integrin β1 might be a promising biomarker to predict SACC metastasis at an early stage. An integrated strategy targeting both tumor and stromal cells is necessary to prevent SACC metastasis.

Highlights

Carcinoma-associated fibroblasts (CAFs) are considered to be activated fibroblasts in the tumor stroma and contribute to malignant initiation and progression [1, 2]
Our results indicated that CAF extracellular vesicles (EVs) presented a great ability for extracellular matrix (ECM) remodeling by activating the Transforming growth factor-beta (TGF-β) signaling pathway in lung fibroblasts (LFs)
Immunohistochemical staining identified higher expression of fibroblast activation protein (FAP), a biomarker of CAFs, in the stroma of salivary adenoid cystic carcinoma (SACC) cases with lung metastasis than those without lung metastasis (Fig. 1a), suggesting that CAFs may contribute to SACC lung metastasis

Summary

Introduction

Carcinoma-associated fibroblasts (CAFs) are considered to be activated fibroblasts in the tumor stroma and contribute to malignant initiation and progression [1, 2]. Numerous experimental and clinical studies support that CAFs secrete growth factors, chemokines, matrix metalloproteinases (MMPs) and extracellular matrix (ECM) to regulate tumor growth, angiogenesis and the recruitment. Pre-metastatic niche formation is a spatio-temporal process that favors tumor cell colonization. Kong et al Molecular Cancer (2019) 18:175 stage of pre-metastatic niche formation, tumor-derived factors are transported by the blood flow and increase vascular permeability in the target organs [11]. These factors mobilize and recruit BMDCs to premetastatic sites through the upregulation of proinflammatory molecules [9, 10, 14]. Limited information is available about the role of CAFs in pre-metastatic niche formation

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