Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity.
Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity.
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DOI：
10.1038/ncomms14206
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发表时间：
2017-02-15
影响因子：
16.6
通讯作者：
Zanivan S
中科院分区：
文献类型：
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作者：
Hernandez-Fernaud JR;Ruengeler E;Casazza A;Neilson LJ;Pulleine E;Santi A;Ismail S;Lilla S;Dhayade S;MacPherson IR;McNeish I;Ennis D;Ali H;Kugeratski FG;Al Khamici H;van den Biggelaar M;van den Berghe PV;Cloix C;McDonald L;Millan D;Hoyle A;Kuchnio A;Carmeliet P;Valenzuela SM;Blyth K;Yin H;Mazzone M;Norman JC;Zanivan S
癌细胞和间质细胞的分泌体产生有助于肿瘤细胞侵袭和血管生成的微环境。在这里，我们比较了人类乳腺正常和癌症相关成纤维细胞(CAF)的分泌组。我们发现氯离子细胞内通道蛋白3(CLIC3)是CAF分泌组中丰富的成分。在体内和3D细胞培养模型中，分泌型CLIC3促进内皮细胞的侵袭行为以驱动血管生成，并增加癌细胞的侵袭性，这需要活性的转谷氨酰胺酶-2(TGM2)。CLIC3作为谷胱甘肽依赖的氧化还原酶，减少TGM2并调节TGM2与其辅因子的结合。最后，CLIC3也是由癌细胞分泌的，在侵袭性卵巢癌的间质和肿瘤间质中大量存在，其水平与不良的临床结果相关。这项工作揭示了一种以前未描述的侵袭机制，即谷胱甘肽依赖的氧化还原酶的分泌通过促进TGM2依赖的侵袭来驱动血管生成和癌症进展。来自癌症和间质细胞的分泌体有助于创造微环境，而微环境反过来又有助于侵袭和血管生成。在这里，作者比较了永生化的正常成纤维细胞和癌症来源的成纤维细胞的分泌体，并确定CLIC3是癌症进展的驱动因素。
The secretome of cancer and stromal cells generates a microenvironment that contributes to tumour cell invasion and angiogenesis. Here we compare the secretome of human mammary normal and cancer-associated fibroblasts (CAFs). We discover that the chloride intracellular channel protein 3 (CLIC3) is an abundant component of the CAF secretome. Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive angiogenesis and increases invasiveness of cancer cells both in vivo and in 3D cell culture models, and this requires active transglutaminase-2 (TGM2). CLIC3 acts as a glutathione-dependent oxidoreductase that reduces TGM2 and regulates TGM2 binding to its cofactors. Finally, CLIC3 is also secreted by cancer cells, is abundant in the stromal and tumour compartments of aggressive ovarian cancers and its levels correlate with poor clinical outcome. This work reveals a previously undescribed invasive mechanism whereby the secretion of a glutathione-dependent oxidoreductase drives angiogenesis and cancer progression by promoting TGM2-dependent invasion. The secretome from cancer and stromal cells contributes to the creation of a microenvironment, which in turn contributes to invasion and angiogenesis. Here, the authors compare the secretomes of immortalized normal fibroblasts and cancer-derived fibroblast and identify CLIC3 as a driver of cancer progression.