In diabetic indivi duals, hyperglycemia in susceptible cells results in the overproduction of superoxide through the mitochondrial elec tron transport chain, and this procedure would be the vital to initiat ing all damaging pathways associated to diabetes. Hyperglycemia also specifically activates polyol metabol ism which has a consequent lower in Na, K ATPase ac tivity in pancreatic duct epithelial cells. Additionally, hyperglycemia enhances the invasive and migratory exercise of pancreatic cancer cells through hydrogen peroxide as well as improved expression of urokinase plasminogen activator. Hyperglycemia can attenuate antioxidant enzyme activ ity and in turn generate a state of oxidative stress.
The PanCa lines BxPC 3, MiaPaCa 2, and AsPC one have decreased manganese superoxide dismutase immunoreactive protein expression and exercise, and selelck kinase inhibitor decreases in MnSOD correlate very well with enhanced rates of tumor cell proliferation as determined by cell doubling time. Cullen et al. discovered the cytoplasmic values of MnSOD, catalase, and glutathione peroxidase had been decreased in pancreatic cells from continual pancreatitis specimens when compared with standard pancreas. Also, elevated fructose may perhaps directly contribute to oxidative pressure in pancreatic cancer. Suzuki et al. showed that fructose increases H2O2 amounts and lipid peroxidation of hamster islet tumor cells, which originated from ham ster pancreatic beta cells. In addition, glutathione perox idase is inactivated by fructose, and also the mRNA expression of GPx is suppressed by fructose.
Glial cell line derived neurotrophic component is really a chemoattractant for pancreatic cancer cells within the professional cesses of tumor progression, migration and invasion. In in vitro research, Jemal et XL147 al. have confirmed the stimulat ing result of GDNF about the proliferation and invasion of pancreatic cancer cells by way of the activation of the RET tyrosine kinase receptor. Glucose alters the expression of GDNF and RET within a concentration dependent method, corresponding with all the alterations in cell proliferation. Upregulation of the GDNF and RET ligand receptor interaction could possibly participate in the glucose induced cancer progression. Substantial glucose also promotes PanCa cell proliferation by way of the induction of epidermal growth factor expression and trans activation of EGFR. The function of hyperglycemia in perineural invasion in pan creatic cancer is just not clear.
We have now hypothesized that hyperglycemia promotes perineural invasion in PanCa by effects on nerve and cancer cells, respectively. Our clinical study also showed that nerve damage and regener ation arise concurrently within the tumor microenviron ment of PanCa patients with hyperglycemia, therefore aggravating the procedure of perineural invasion. The abnor mal expression of nerve growth element and p75 might also be involved with this process and subsequently lead to a lower rate of curative surgical procedure.