12th World Cancer Conference
First Affiliated Hospital, Xi'an Jiaotong University, China
Title: Desmoplasia Suppression by Metformin-mediated AMPK Activation Inhibits Pancreatic Cancer Progression
Biography: Qingyong Ma
The desmoplastic reaction is one of the most prominent histological features of pancreatic ductal adenocarcinoma (PDAC), and it contributes to the aggressive nature of PDAC cells. Persistent activation of pancreatic stellate cells (PSCs) induced by cancer cells is responsible for the desmoplastic reaction in PDAC. AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine protein kinase that is involved in regulating pathological fibrosis processes. Recently, emerging evidence has suggested that metformin may be useful in preventing and treating cancer; however, the underlying mechanism remains relatively unknown. In this study, using histological analysis, we found that low P-AMPK staining correlated with a dense stroma reaction and a poorer prognosis in PDAC. Furthermore, metformin-induced AMPK activation in cancer cells inhibited the desmoplastic reaction and prevented tumor growth in mice with subcutaneous pancreatic cancer. In vitro experiments demonstrated that metformin inhibited pancreatic cancer cell migration and invasion; more interestingly, metformin suppressed PSC activation during direct and indirect PC-PSC co-culture conditions by inducing AMPK phosphorylation only in PCs and downregulating fibrogenic-related cytokine production in PCs. More importantly, the combination of metformin with gemcitabine enhanced the antitumor effect of gemcitabine without affecting the blood glucose levels of mice. In conclusion, our findings uncover the mechanism underlying the antitumor effect of metformin. Additionally, inducing AMPK activation in PCs can reduce the desmoplastic reaction by targeting the interaction between PSCs and PDAC cells and may represent a novel therapeutic approach for treating advanced PDAC.