BACKGROUND Endothelial-to-mesenchymal transition (EndoMT) can provide a source of cancer-associated fibroblasts which contribute to desmoplasia of many malignancies including pancreatic ductal adenocarcinoma (PDAC). We investigated the clinical relevance of EndoMT in PDAC, and explored its underlying mechanism and therapeutic implication. METHODS Expression levels of 29 long non-coding RNAs were analyzed from the cells undergoing EndoMT, and an EndoMT index was proposed to survey its clinical associations in the PDAC patients of The Cancer Genome Atlas database. The observed clinical correlation was further confirmed by a mouse model inoculated with EndoMT cells-involved PDAC cell grafts. In vitro co-culture with EndoMT cells or treatment with the conditioned medium were performed to explore the underlying mechanism. Because secreted HSP90α was involved, anti-HSP90α antibody was evaluated for its inhibitory efficacy against the EndoMT-involved PDAC tumor. RESULTS A combination of low expressions of LOC340340, LOC101927256, and MNX1-AS1 was used as an EndoMT index. The clinical PDAC tissues with positive EndoMT index were significantly correlated with T4-staging and showed positive for M2-macrophage index. Our mouse model and in vitro cell-culture experiments revealed that HSP90α secreted by EndoMT cells could induce macrophage M2-polarization and more HSP90α secretion to promote PDAC tumor growth. Furthermore, anti-HSP90α antibody showed a potent therapeutic efficacy against the EndoMT and M2-macrophages-involved PDAC tumor growth. CONCLUSIONS EndoMT cells can secrete HSP90α to harness HSP90α-overproducing M2-type macrophages to promote PDAC tumor growth, and such effect can be targeted and abolished by anti-HSP90α antibody.

中文翻译：

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内皮间质转化利用分泌HSP90α的M2巨噬细胞加重胰腺导管腺癌。

背景技术内皮向间充质转变（EndoMT）可提供与癌症相关的成纤维细胞的来源，所述成纤维细胞促成包括胰腺导管腺癌（PDAC）在内的许多恶性肿瘤的异型增生。我们调查了EndoMT在PDAC中的临床相关性，并探讨了其潜在的机制和治疗意义。方法从接受EndoMT的细胞中分析29种长非编码RNA的表达水平，并提出EndoMT指数以调查其在癌症基因组图谱数据库中的PDAC患者中的临床关联。接种EndoMT细胞的PDAC细胞移植物的小鼠模型进一步证实了观察到的临床相关性。进行与EndoMT细胞的体外共培养或用条件培养基处理以探索潜在的机制。由于涉及分泌的HSP90α，因此评估了抗HSP90α抗体对涉及EndoMT的PDAC肿瘤的抑制作用。结果LOC340340，LOC101927256和MNX1-AS1的低表达组合被用作EndoMT索引。EndoMT指数阳性的临床PDAC组织与T4分期显着相关，并且M2巨噬细胞指数呈阳性。我们的小鼠模型和体外细胞培养实验表明，EndoMT细胞分泌的HSP90α可以诱导巨噬细胞M2极化，并且更多的HSP90α分泌可以促进PDAC肿瘤的生长。此外，抗HSP90α抗体显示出对EndoMT和M2巨噬细胞相关的PDAC肿瘤生长的有效治疗功效。结论EndoMT细胞可以分泌HSP90α来利用过量生产HSP90α的M2型巨噬细胞来促进PDAC肿瘤的生长，