De Marco Paola, Lappano Rosamaria, De Francesco Ernestina Marianna, Cirillo Francesca, Pupo Marco, Avino Silvia, Vivacqua Adele, Abonante Sergio, Picard Didier, Maggiolini Marcello
Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.
Department of Cell Biology, Faculty of Sciences, and Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva Switzerland.
Sci Rep. 2016 Apr 13;6:24354. doi: 10.1038/srep24354.
Cancer-associated fibroblasts (CAFs) contribute to the malignant aggressiveness through secreted factors like IL1β, which may drive pro-tumorigenic inflammatory phenotypes mainly acting via the cognate receptor named IL1R1. Here, we demonstrate that signalling mediated by the G protein estrogen receptor (GPER) triggers IL1β and IL1R1 expression in CAFs and breast cancer cells, respectively. Thereby, ligand-activation of GPER generates a feedforward loop coupling IL1β induction by CAFs to IL1R1 expression by cancer cells, promoting the up-regulation of IL1β/IL1R1 target genes such as PTGES, COX2, RAGE and ABCG2. This regulatory interaction between the two cell types induces migration and invasive features in breast cancer cells including fibroblastoid cytoarchitecture and F-actin reorganization. A better understanding of the mechanisms involved in the regulation of pro-inflammatory cytokines by GPER-integrated estrogen signals may be useful to target these stroma-cancer interactions.
癌症相关成纤维细胞（CAFs）通过分泌如IL1β等因子促进恶性侵袭，这些因子可能主要通过名为IL1R1的同源受体驱动促肿瘤炎症表型。在此，我们证明由G蛋白雌激素受体（GPER）介导的信号分别触发CAFs和乳腺癌细胞中IL1β和IL1R1的表达。因此，GPER的配体激活产生了一个前馈环，将CAFs诱导的IL1β与癌细胞的IL1R1表达相耦合，促进IL1β/IL1R1靶基因如PTGES、COX2、RAGE和ABCG2的上调。这两种细胞类型之间的这种调节相互作用诱导乳腺癌细胞出现迁移和侵袭特征，包括成纤维样细胞结构和F-肌动蛋白重组。更好地理解GPER整合雌激素信号调节促炎细胞因子的机制可能有助于靶向这些基质-癌症相互作用。
