High-glucose microenvironment promotes perineural invasion of pancreatic cancer via activation of hypoxia inducible factor 1 alpha

Pancreatic cancer (PC) is one of the most lethal diseases, with a 5-year survival rate of <9%. Perineural invasion (PNI) is a common pathological hallmark of PC and is correlated with a poor prognosis in this disease. Hyperglycemia has been shown to promote the invasion and migration of PC cells; however, the effect of hyperglycemia on the PNI of PC and its underlying mechanism remains unclear. In the present study, Western blotting was utilized to detect the expression of hypoxia inducible factor 1 alpha (HIF1 alpha) and nerve growth factor (NGF). Transwell and wound-healing assays were performed to detect the influence of hyperglycemia on the invasion and migration ability of PC cells. An in vitro PC-dorsal root ganglion (DRG) co-culture system and an in vivo PNI sciatic nerve-infiltrating tumor model were used to evaluate the severity of PNI in hyperglycemic conditions. In the results, hyperglycemia promoted the invasion/migration ability and elevated the expression of NGF in PC by upregulating HIF1 alpha. Moreover, in vitro short-term hyperglycemia caused little damage on the DRG axons and accelerated both the PNI of the PC and the outgrowth of the DRGs by increasing the expression of NGF via activation of HIF1 alpha. Indeed, in vivo long-term hyperglycemia promoted the infiltration and growth of PC, and then disrupted the function of the sciatic nerve in a HIF1 alpha-dependent manner. In conclusion, a high-glucose microenvironment promotes PNI of PC via activation of HIF1 alpha.