Abstract
Simple SummaryIn the present review, we discuss the role of metabolic reprogramming which occurs in malignant cells. The process of metabolic reprogramming is also known as one of the “hallmarks of cancer”. Due to several reasons, including the origin of cancer, tumor microenvironment, and the tumor progression stage, metabolic reprogramming can be heterogeneous and dynamic. In this review, we provide evidence that the usage of metabolic drugs is a promising approach to treat cancer. However, because these drugs can damage not only malignant cells but also normal rapidly dividing cells, it is important to understand the exact metabolic changes which are elicited by particular drivers in concrete tissue and are specific for each stage of cancer development, including metastases. Finally, the review highlights new promising targets for the development of new metabolic drugs. The specific molecular features of cancer cells that distinguish them from the normal ones are denoted as “hallmarks of cancer”. One of the critical hallmarks of cancer is an altered metabolism which provides tumor cells with energy and structural resources necessary for rapid proliferation. The key feature of a cancer-reprogrammed metabolism is its plasticity, allowing cancer cells to better adapt to various conditions and to oppose different therapies. Furthermore, the alterations of metabolic pathways in malignant cells are heterogeneous and are defined by several factors including the tissue of origin, driving mutations, and microenvironment. In the present review, we discuss the key features of metabolic reprogramming and plasticity associated with different stages of tumor, from primary tumors to metastases. We also provide evidence of the successful usage of metabolic drugs in anticancer therapy. Finally, we highlight new promising targets for the development of new metabolic drugs.
Highlights
A high level of GLUT-1 is associated with more aggressive and less differentiated tumors. Another important glucose transporter participating in epithelial-to-mesenchymal transition (EMT) and cancer progression is GLUT-3 [115,138], whose expression is upregulated by Zeb1, TCF4/β-catenin, HMGA1, and EGFR [139,140]
Phosphorylation of eIF2α, which is an evolutionarily conserved hallmark of the starvation response [155], triggers invasiveness in melanoma [156], breast [157], pancreatic cancer [158], and CML [159]. These results indicate that EMT can serve as a mechanism for cancer cells to escape the worsening metabolic conditions and to colonize new niches to promote their growth
Seventy years of successful antimetabolite therapy in clinics has demonstrated that cancer-related metabolism can be effectively targeted
Summary
It mainly includes increased aerobic glycolysis (Warburg effect) which cooperates with oxidative phosphorylation (OXPHOS) to establish a “hybrid” metabolic state, deregulated tricarboxylic acid (TCA) cycle, lipid and glutamine metabolism, and increased one-carbon metabolism It seems that the main feature of cancer-related metabolism is not just an enhanced intensity of a particular metabolic pathway, but rather the overall plasticity of the regulation of metabolic pathways [3]. When the tumor cells reach an appropriate niche, they extravasate and undergo mesenchymal-to-epithelial transition to colonize a new milieu (Figure 1) To fit this complex and changing environment, cancer cells have evolved a high degree of plasticity in regulation of their proliferation, mobility and invasion, antioxidative responses, resistance to apoptosis, and evasion from the immune response. Deciphering the regulatory mechanisms of these reactions has identified the corresponding enzymes which are considered as promising targets for pharmacological inhibition
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