Agr2 Mediates Paracrine Effects on Stromal Fibroblasts That Promote Invasion by Gastric Signet-Ring Carcinoma Cells
Agr2 Mediates Paracrine Effects on Stromal Fibroblasts That Promote Invasion by Gastric Signet-Ring Carcinoma Cells
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DOI：
10.1158/0008-5472.can-14-1693
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发表时间：
2015-01-15
期刊：
影响因子：
11.2
通讯作者：
Tanaka, Masamitsu
中科院分区：
文献类型：
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作者：
Tsuji, Tadahiro;Satoyoshi, Rika;Tanaka, Masamitsu
Agr2 是一种存在于内质网 (ER) 中的二硫键异构酶，它在生理上调节蛋白质折叠并介导对 ER 应激的抵抗力。 Agr2在多种器官的腺癌中过度表达，参与肿瘤转化和转移，因此充当促癌蛋白。除了正常定位于内质网外，Agr2 还存在于癌症患者的血清和尿液中，尽管细胞外 Agr2 的生理意义尚不清楚。在这项研究中，我们证明细胞外Agr2可以激活基质成纤维细胞并促进Agr2高表达的胃印戒细胞癌（SRCC）中成纤维细胞相关的癌症侵袭。 SRCC细胞分泌的Agr2被周围的胃成纤维细胞吸收并促进这些细胞的侵袭。反过来，激活的成纤维细胞协调成纤维细胞和癌细胞的侵袭行为。我们的研究结果表明，Agr2 通过对肿瘤微环境中的成纤维细胞发挥旁分泌作用来驱动胃 SRCC 的进展，同时作为细胞自主效应，还可以增加 SRCC 细胞的生长和对氧化和缺氧应激的抵抗力。 (C) 2014 年 AACR。
Agr2 is a disulfide isomerase residing in the endoplasmic reticulum (ER), which physiologically regulates protein folding and mediates resistance to ER stress. Agr2 is overexpressed in adenocarcinomas of various organs, where it participates in neoplastic transformation and metastasis, therefore acts as a pro-oncogenic protein. Besides its normal localization in the ER, Agr2 is also found in the serum and urine of cancer patients, although the physiological significance of extracellular Agr2 is poorly understood. In this study, we demonstrated that extracellular Agr2 can activate stromal fibroblasts and promote fibroblast-associated cancer invasion in gastric signet-ring cell carcinoma (SRCC), where Agr2 is highly expressed. Agr2 secreted from SRCC cells was incorporated by the surrounding gastric fibroblasts and promoted invasion by these cells. In turn, activated fibroblasts coordinated the invasive behavior of fibroblasts and cancer cells. Our findings suggested that Agr2 drives progression of gastric SRCC by exerting paracrine effects on fibroblasts in the tumor microenvironment, acting also to increase the growth and resistance of SRCC cells to oxidative and hypoxic stress as cell autonomous effects. (C) 2014 AACR.