Metformin suppresses tumor angiogenesis and enhances the chemosensitivity of gemcitabine in a genetically engineered mouse model of pancreatic cancer

Abstract Aims Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant diseases and has few effective and reliable therapeutic strategies. The anti-tumor effect of metformin is widely known, however, there is only limited evidence regarding the anti-angiogenesis effect and chemosensitization of metformin and its underlying mechanisms in PDAC. Main methods In the present study, we adopted a spontaneous PDAC mouse model named LSL‑Kras G12D/+ ; Trp53 fl/+ ; Pdx1‑Cre (KPC) mice to explore the mechanism of the modulation of tumor angiogenesis and chemosensitization of metformin by treating KPC mice with metformin, gemcitabine or a combination of the two. H&E staining, Masson staining and immunohistochemical staining were adopted to describe the histopathology and biomarkers of the KPC in different groups. Key findings Metformin plus gemcitabine reduced tumorigenic potential of PDAC. Specifically, metformin showed an anti-pancreatic stellate cells (PSCs) effect via decreasing the expression of sonic hedgehog (SHH) and then sparked some downstream effects, for example, inhibiting the production of vascular endothelial growth factor (VEGF) in the tumor microenvironment, reducing the formation of tumor neovascularization, attenuating the desmoplastic reaction and enhancing the antitumor effect of gemcitabine. Significance We concluded that metformin suppressed tumor angiogenesis and enhanced the chemosensitivity of gemcitabine via inactivating PSCs in PDAC of KPC mice.