Hyperglycemic tumor microenvironment induces perineural invasion in pancreatic cancer

Glucose intolerance and frank diabetes mellitus (DM) can increase the risk of cancer death for pancreatic cancer (PanCa). However, the mechanism by which these factors influence cancer deaths is not clear. In this study, we established a model system to mimic the pancreatic tumor microenvironment in patients with DM to examine the biological behavior of PanCa cells and nerves in cell culture and in animals. Our in vitro studies demonstrated that hyperglycemia promoted the proliferation and invasion of PanCa cell lines and upregulated the expression of nerve growth factor in these cells. Also, the migration of Schwann cells (SCs) was inhibited by hyperglycemia and neurites exerted pathological regeneration. Furthermore, the interaction between the PanCa cells and nerves was enhanced in the tumor microenvironment. We further showed that hyperglycemia promoted the perineural invasion (PNI) of PanCa in vivo. These data suggest that DM worsens the prognosis of PanCa because of aggravated PNI. Thus, our study illustrates a novel mechanism by which hyperglycemia decreases survival in patients with PanCa.