Molecular aspects of pancreatic cancer: focus on reprogrammed metabolism in a nutrient-deficient environment and potential therapeutic targets.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is still burdened with high mortality (5-year survival rate < 9%) due to late diagnosis, aggressiveness, and a lack of more effective treatment methods. Early diagnosis and new therapeutic approaches based on the reprogrammed metabolism of the tumor in a nutrient-deficient environment are expected to improve the future treatment of PDAC patients. Research results suggest that genetic and metabolic disorders may precede the onset of neoplastic changes, which should allow for earlier appropriate treatment. Glycolysis and glutaminolysis are the most investigated pathways associated with the highest aggressiveness of pancreatic tumors. Blocking of selected metabolic pathways related to the local adaptive metabolic activity of pancreatic cancer cells improving nutrient acquisition and metabolic crosstalk within the microenvironment to sustain proliferation may inhibit cancer development, increase cancer cells death, and increase sensitivity to other forms of treatment (e.g., chemotherapy). Depriving cancer cells of important nutrients (glucose, glutamine) revealed tumor "checkpoints" for the mechanisms that drive cell proliferation and metastasis formation in order to determine its accuracy for individualization of the therapeutic approach. The present review highlights selected metabolic signaling pathways and their regulators aimed at inhibiting the neoplastic process. Particular attention has been paid to the adaptive metabolism of pancreatic cancer, which promotes its development in an oxygen-deficient and nutrient-poor environment.