Cellular metabolism in pancreatic cancer as a tool for prognosis and treatment (Review)

Abstract

Pancreatic cancer (PC) has one of the highest fatality rates and the currently available therapeutic options are not sufficient to improve its overall poor prognosis. In addition to insufficient effectiveness of anticancer treatments, the lack of clear early symptoms and early metastatic spread maintain the PC survival rates at a low level. Metabolic reprogramming is among the hallmarks of cancer and could be exploited for the diagnosis and treatment of PC. PC is characterized by its heterogeneity and, apart from molecular subtypes, the identification of metabolic subtypes in PC could aid in the development of more individualized therapeutic approaches and may lead to improved clinical outcomes. In addition to the deregulated utilization of glucose in aerobic glycolysis, PC cells can use a wide range of substrates, including branched-chain amino acids, glutamine and lipids to fulfil their energy requirements, as well as biosynthetic needs. The tumor microenvironment in PC supports tumor growth, metastatic spread, treatment resistance and the suppression of the host immune response. Moreover, reciprocal interactions between cancer and stromal cells enhance their metabolic reprogramming. PC stem cells (PCSCs) with an increased resistance and distinct metabolic properties are associated with disease relapses and cancer spread, and represent another significant candidate for therapeutic targeting. The present review discusses the metabolic signatures observed in PC, a disease with a multifaceted and often transient metabolic landscape. In addition, the metabolic pathways utilized by PC cells, as well as stromal cells are discussed, providing examples of how they could present novel targets for therapeutic interventions and elaborating on how interactions between the various cell types affect their metabolism. Furthermore, the importance of PCSCs is discussed, focusing specifically on their metabolic adaptations.

Evaluating Metabolite-Based Biomarkers for Early Diagnosis of Pancreatic Cancer: A Systematic Review

“…These fatty acids serve as combustible for tumor cells and important processes such as energy production or membrane biogenesis [ 41 ]. Fatty acids and other lipid-related molecules have shown alterations in PDAC patients [ 42 ]. Due to their importance in tumorigenesis and taking into account the previous studies discussed, lipids could be a promising target for biomarker discovery.…”

Effects of Ketamine, S-Ketamine and MK 801 on Integrin Beta-3-mediated Cell Migration in Pancreatic Carcinoma

“…Pancreatic ductal adenocarcinoma is one of the most aggressive malignant tumours in humans. Its oncogenic potential is primarily characterised by extremely rapid tumour growth and early-onset metastasis [ 28 ]. Novel therapeutic approaches target the effective modulation of specific signalling and transcription pathways [ 29 ].…”

The role of metabolic reprogramming in pancreatic cancer chemoresistance

“…The PI3K/AKT axis and MAPK pathway negatively modulate lipid synthesis by inhibiting SREBP1c levels and thus reducing FASN transcription. Knockout or overexpression of FASN gene significantly downregulates or upregulates the resistance of PC cells to GEM ( Yang et al, 2011 ), in which the acidic tumor microenvironment also plays a pro-drug resistance role ( Zuzčák and Trnka, 2022 ). In PC cells in vitro culture and mice transplantation models, the FASN inhibitor orlistat in combination with GEM induced endoplasmic reticulum stress, prompting apoptosis, and markedly reduced PC cell stemness.…”

“…Statins are inhibitors of cholesterol synthesis, which reduce exogenous cholesterol uptake by suppressing LDLR on the one hand and inhibit the key enzyme HMGCR on the other ( Zuzčák and Trnka, 2022 ). Lovastatin inhibits the MVA pathway to interfere with membrane structural stability and impairs the PC tumor-initiating cell (TIC) marker CD133 localized on lipid rafts.…”