Glucose and Lactate Transport in Pancreatic Cancer: Glycolytic Metabolism Revisited

Abstract

Membrane transporters fulfill essential roles in maintaining normal cellular function in health. In cancer, transporters likewise facilitate the aberrant characteristics typical of proliferating tumor cells. Pancreatic ductal adenocarcinoma is remarkable in its aggressiveness, and its metabolism is supported by a variety of membrane transporters. Glucose transporter 1 is upregulated in pancreatic cancer, enables rapid cellular uptake of glucose, and contributes to the invasiveness and metastatic ability of the disease. Likewise, the machinery of glycolysis, enzymes such as pyruvate kinase type M2 and hexokinase 2, is particularly active and ultimately leads to both lactate and tumor formation. Lactic acid channels and transporters include monocarboxylate transporters 1 and 4, connexin43, and CD147. In conjunction with glucose transporters and glycolytic metabolism, lactic acid transport helps perpetuate tumor cell metabolism and contributes to the formation of the unique tumor microenvironment in pancreatic cancer. These transporters may serve as potential therapeutic targets.

Genomic stratification and liquid biopsy in a rare adrenocortical carcinoma (ACC) case, with dual lung metastases

“…Indeed, the majority of cancers do rely upon glycolysis to promote proliferation over differentiation (Fernandez-de-Cossio-Diaz and Vazquez 2017; Yu et al 2017), as compared to OXPHOS, it is quicker and generates more metabolites that are used as building blocks downstream for nucleic acids, proteins, and lipids (Zheng 2012; Yu et al 2017). Further, glycolysis appears to be essential for cancer survival, as too much ATP generated by OXPHOS inhibits glycolysis and may result in more reactive oxygen species (ROS), which are dangerous to cancer cells (Zheng 2012; Anderson et al 2018; Cameron et al 2018). However, increasing data show that some cancers rely upon functioning OXPHOS and that this pathway is not entirely dependent upon glucose-derived pyruvate to function, and can, in fact, decouple itself from glycolysis.…”

Molecular and Metabolic Subtypes Correspondence for Pancreatic Ductal Adenocarcinoma Classification

“…Overall, the glycolytic state is characterised by an increased expression of glycolytic enzymes and glucose and lactate transporters, such as Glucose Transporter 1 (GLUT1), and Monocarboxylate Transporters 1 and 4 (MCT1, MCT4) [ 54 , 55 ]. Specifically, the overexpression of these membrane transporters leads to an enhanced glucose scavenging from the hypovascularised tumour microenvironment, which results in increased glucose availability in the cancer cell as well as a better balance of the glucose pathway in order to keep glycolysis at high rate.…”

“…On the one hand, GLUT1 is an ATP-independent glucose transporter that enables glucose transference from a high-gradient extracellular compartment to low-gradient cytoplasmic compartment. Its expression dosage has been reported to be associated with PDAC progression from low- to high-grade pancreatic preneoplastic lesions when compared to normal pancreas [ 54 ]. On the other hand, MCT1 and MCT4 are proton-coupled symport transporters with higher affinity for lactate efflux.…”

Dietary Polyphenols in Cancer Chemoprevention: Implications in Pancreatic Cancer

“…Malignant cells require nutrients such as glucose and amino acids to support their sustained growth, and in their absence, tumor cells scavenge extracellular proteins such as albumin for their survival [115,116]. To transport the specific nutrients, cancer cells acquire transport mechanisms, such as glucose transporters for the transport of glucose, etc., [117,118]. Therefore, agents that can inhibit such transporters or their metabolism are being explored as promising therapeutic agents for cancer intervention.…”