Endothelial-mesenchymal transition harnesses HSP90α-secreting M2-macrophages to exacerbate pancreatic ductal adenocarcinoma
Endothelial-mesenchymal transition harnesses HSP90α-secreting M2-macrophages to exacerbate pancreatic ductal adenocarcinoma
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DOI：
10.1186/s13045-019-0826-2
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发表时间：
2019-12-17
影响因子：
28.5
通讯作者：
Huang, Tze-Sing
中科院分区：
文献类型：
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作者：
Fan, Chi-Shuan;Chen, Li-Li;Huang, Tze-Sing
背景：内皮到间充质转化（EndoMT）可以提供癌症相关成纤维细胞的来源，这些成纤维细胞有助于包括胰腺导管腺癌（PDAC）在内的许多恶性肿瘤的结缔组织增生。我们研究了EndoMT在PDAC中的临床意义，并探讨了其潜在的机制和治疗意义。方法：分析29种长链非编码rna的表达水平，并提出EndoMT指数，调查其在癌症基因组图谱数据库PDAC患者中的临床相关性。通过接种EndoMT细胞相关的PDAC细胞移植物的小鼠模型进一步证实了所观察到的临床相关性。通过体外与EndoMT细胞共培养或条件培养基处理来探索其潜在机制。由于参与了分泌的HSP90 α，我们评估了抗HSP90 α抗体对endomt累及的PDAC肿瘤的抑制作用。结果：以低表达的LOC340340、LOC101927256和MNX1-AS1组合作为EndoMT指数。EndoMT指数阳性的临床PDAC组织与t4分期显著相关，m2 -巨噬细胞指数阳性。我们的小鼠模型和体外细胞培养实验表明，EndoMT细胞分泌HSP90 α可诱导巨噬细胞m2极化，分泌更多HSP90 α促进PDAC肿瘤生长。此外，抗hsp90 α抗体对EndoMT和m2 -巨噬细胞相关的PDAC肿瘤生长显示出强有力的治疗效果。结论：EndoMT细胞可分泌HSP90 α，利用过量产生HSP90 α的m2型巨噬细胞促进PDAC肿瘤生长，这种作用可通过抗HSP90 α抗体靶向和消除。
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 HSP90 alpha was involved, anti-HSP90 alpha 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 HSP90 alpha secreted by EndoMT cells could induce macrophage M2-polarization and more HSP90 alpha secretion to promote PDAC tumor growth. Furthermore, anti-HSP90 alpha antibody showed a potent therapeutic efficacy against the EndoMT and M2-macrophages-involved PDAC tumor growth.Conclusions: EndoMT cells can secrete HSP90 alpha to harness HSP90 alpha-overproducing M2-type macrophages to promote PDAC tumor growth, and such effect can be targeted and abolished by anti-HSP90 alpha antibody.