Hyperglycemia promotes the perineural invasion in pancreatic cancer.

The role of hyperglycemia in perineural invasion in pancreatic cancer is not clear. Pancreatic cancer is characterized by extremely high frequency of perineural invasion (can be as high as 90%, even 100%), which has been associated with poorer survival. In previous epidemiologic, the prevalence of diabetes mellitus in pancreatic cancer is 34-40% and more than half of them are new-onset, which means the course of disease of diabetes mellitus is less than 24 months before cancer diagnosis. The association between diabetes mellitus and pancreatic cancer has long been recognized as that long-standing diabetes mellitus is thought to be an etiologic factor for pancreatic cancer and new-onset diabetes mellitus may be a manifestation of the cancer. Long-standing diabetes mellitus can cause peripheral neuropathy. The main morphological features of established neuropathy include a combination of demyelinization and axonal degeneration of myelinated fibers, degeneration with regeneration of unmyelinated fibers and endoneurial microangiopathy, with nerve fiber loss in its final stage. Diabetes mellitus can also induce the high expression of cytokines such as nerve growth factor to repair the damaged nerves. We present the hypothesis that hyperglycemia promotes the perineural invasion in pancreatic cancer through two mechanisms. One is that hyperglycemia enhances the proliferation of cancer cells, which subsequently increase the expression of cytokines such as nerve growth factor. The overexpression of nerve growth factor can enhance the interaction between nerve and cancer cell and neurotropism. The other is that hyperglycemia causes demyelinization and axonal degeneration of nerves, which can form defections to make cancer cells enter nerves with deeply invasion. The above two mechanisms can promote the perineural invasion in pancreatic cancer. Controlling hyperglycemia might reduce the perineural invasion in pancreatic cancer.