Myeloid-derived macrophages and secreted HSP90α induce pancreatic ductal adenocarcinoma development

We detected a significant elevation of serum HSP90 alpha levels in pancreatitis patients and even more in pancreatic ductal adenocarcinoma (PDAC) patients. However, there was no significant difference in the serum HSP90 alpha levels between patients with early-stage and late-stage PDAC. To study whether elevation of serum HSP90 alpha levels occurred early during PDAC development, we used LSL-KrasG12D/Pdx1-Cre transgenic mice as a studying model. Elevated serum HSP90 alpha levels were detected before PDAC formation and an extracellular HSP90 alpha (eHSP90 alpha) inhibitor effectively prevented PDAC development. Both serum HSP90 alpha level and pancreatic lesion were suppressed when the mice were administered a CD11b-antagonizing antibody, suggesting that CD11b(+)-myeloid cells were associated with eHSP90 alpha levels and pancreatic carcinogenesis. Consistently, in CD11b-DTR-EGFP transgenic mouse model with CD11b(+)-myeloid cells depletion, serum HSP90 alpha levels were suppressed and Panc-02 cell grafts failed to develop tumors. Macrophages and granulocytes are two common tissue-infiltrating CD11b(+)-myeloid cells. Duplex in situ hybridization assays suggested that macrophages were predominant HSP90 alpha-expressing CD11b(+)-myeloid cells during PDAC development. Immunohistochemical and immunohistofluorescent staining results revealed that HSP90 alpha-expressing cells included not only macrophages but also pancreatic ductal epithelial (PDE) cells. Cell culture studies also indicated that eHSP90 alpha could be produced by macrophages and macrophage-stimulated PDE cells. Macrophages not only secreted significant amount of HSP90 alpha, but also secreted interleukin-6 and interleukin-8 to induce a JAK2-STAT3 signaling axis in PDE cells, stimulating them to express and secrete HSP90 alpha. eHSP90 alpha further promoted cellular epithelial-mesenchymal transition, migration, and invasion in PDE cells. Besides myeloid cells, eHSP90 alpha can be potentially taken as a target to suppress PDAC pathogenesis.