1. Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China;
2. Department of General Surgery, No. 411 Hospital of Navy, People's Liberation Army, Shanghai, China.
Int J Biol Sci. 2015 Feb 15;11(4):370-9. doi: 10.7150/ijbs.10666. eCollection 2015.
Stromal fibroblasts play an important role in chronic cancer-related inflammation and the development as well as progression of malignant diseases. However, the difference and relationship between inflammation-associated fibroblasts (IAFs) and cancer-associated fibroblasts (CAFs) are poorly understood. In this study, gastric cancer-associated fibroblasts (GCAFs) and their corresponding inflammation-associated fibroblasts (GIAFs) were isolated from gastric cancer (GC) with chronic gastritis and cultured in vitro. These activated fibroblasts exhibited distinct secretion and tumor-promoting behaviors in vitro. Using proteomics and bioinformatics techniques, caveolin-1 (Cav-1) was identified as a major network-centric protein of a sub-network consisting of 121 differentially expressed proteins between GIAFs and GCAFs. Furthermore, immunohistochemistry in a GC cohort showed significant difference in Cav-1 expression score between GIAFs and GCAFs and among patients with different grades of chronic gastritis. Moreover, silencing of Cav-1 in GIAFs and GCAFs using small interfering RNA increased the production of pro-inflammatory and tumor-enhancing cytokines and chemokines in conditioned mediums that elevated cell proliferation and migration when added to GC cell lines AGS and MKN45 in vitro. In addition, Cav-1 status in GIAFs and GCAFs independently predicted the prognosis of GC. Our findings indicate that Cav-1 loss contributes to the distinct activation statuses of fibroblasts in GC microenvironment and gastritis mucosa, and Cav-1 expression in both GCAFs and GIAFs may serve as a potential biomarker for GC progression.
基质成纤维细胞在慢性癌症相关炎症以及恶性疾病的发生和发展中起着重要作用。然而，炎症相关成纤维细胞（IAFs）和癌症相关成纤维细胞（CAFs）之间的差异和关系仍知之甚少。在这项研究中，从慢性胃炎伴胃癌（GC）患者中分离出胃癌相关成纤维细胞（GCAFs）及其相应的炎症相关成纤维细胞（GIAFs），并在体外进行培养。这些激活的成纤维细胞在体外表现出明显不同的分泌和促肿瘤行为。利用蛋白质组学和生物信息学技术，鉴定出窖蛋白-1（Cav-1）是 GIAFs 和 GCAFs 之间差异表达蛋白的 121 个蛋白子组成的子网络的主要网络中心蛋白。此外，在 GC 队列中进行的免疫组织化学分析显示，GIAFs 和 GCAFs 之间以及不同慢性胃炎严重程度患者之间 Cav-1 表达评分存在显著差异。此外，使用小干扰 RNA 沉默 GIAFs 和 GCAFs 中的 Cav-1 会增加条件培养基中促炎和促肿瘤细胞因子和趋化因子的产生，当将其添加到 GC 细胞系 AGS 和 MKN45 中时，会体外促进细胞增殖和迁移。此外，GIAFs 和 GCAFs 中的 Cav-1 状态独立预测了 GC 的预后。我们的研究结果表明，Cav-1 的缺失导致 GC 微环境和成胃炎黏膜中成纤维细胞的独特激活状态，并且 GCAFs 和 GIAFs 中的 Cav-1 表达可能成为 GC 进展的潜在生物标志物。
