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 HSP90alpha was involved, anti-HSP90alpha 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 HSP90alpha secreted by EndoMT cells could induce macrophage M2-polarization and more HSP90alpha secretion to promote PDAC tumor growth. Furthermore, anti-HSP90alpha antibody showed a potent therapeutic efficacy against the EndoMT and M2-macrophages-involved PDAC tumor growth. CONCLUSIONS: EndoMT cells can secrete HSP90alpha to harness HSP90alpha-overproducing M2-type macrophages to promote PDAC tumor growth, and such effect can be targeted and abolished by anti-HSP90alpha antibody.
Date:
2019-12-17
Relation:
Journal of Hematology and Oncology. 2019 Dec 17;12:Article number 138.
