The mechanism of resistance to cancer uncovered by Sipa1 deficiency

1.鉴定了三种不同的肿瘤间充质基质细胞亚群。它们在肿瘤组织中具有不同的功能，在正常组织中几乎检测不到它们的类似表型。结论：1.在Sipa1缺陷宿主的肿瘤组织中，网状成纤维细胞样瘤MSCs(FB/Fc亚型)的增殖和分化被激活，而成肌成纤维细胞样MSCs(FA亚型)的增殖和分化不受影响。在Sipa1缺陷宿主的肿瘤组织中，部分T细胞趋化因子的表达显著增加，并伴有T细胞浸润的显著增加。SIpa1缺陷宿主的肿瘤MSCs也表现出选择性趋化因子基因的表达增加。定量聚合酶链式反应分析证实，Sipa1缺陷宿主的肿瘤相关MSCs显示T细胞趋化因子基因(Cxcl9、10)的表达显著增加，这与肿瘤组织中T细胞的浸润增加有关。免疫染色分析还显示，Cxcl9在KO宿主肿瘤细胞周围的网状MSCs中有较强的表达，这与T细胞的显著聚集有关。在Sipa1缺陷的肿瘤MSCs中，干扰素-GAMA信号通路增强。这可能是肿瘤组织中Sipa1缺陷的MSCs T细胞趋化因子基因表达显著增强的基础。

1. Three distinct subsets of tumor mesenchymal stroma cells (MSCs) were identified. They had different functions in tumor tissues and their comparable phenotypes could be barely detectable in normal tissues. In the tumor tissues of Sipa1 deficient host, the proliferation and differentiation of reticular fibroblastic like tumor MSCs (FB/FC subtype) were activated, but myofibrobrastic like MSCs (FA subtype) were not be affected.2. Tumor tissues of Sipa1 deficient host showed a remarkably elevated expression of selected T cell-chemokines in association with a significant increase in T cell infiltration. Tumor MSCs of Sipa1 deficient host also showed an increased expression of selected chemokine genes. qPCR analysis confirmed that the tumor-associated MSCs of Sipa1 deficient host show a markedly increased expression of T cell-chemokine genes (Cxcl9, 10), and this was associated with the increased T cell infiltration in tumor tissues. Immunostaining analysis also reveals strong expression of Cxcl9 in the reticular MSCs surrounding tumor cells of KO hosts, which was associated with a significant accumulation of T cells.3. In Sipa1 deficient tumor MSCs IFN gama-signaling pathway was enhanced. It may underlie the remarkably augmented T-cell chemokine gene expression in Sipa1 deficient MSCs in tumor tissues.