Abstract
Simple SummaryAlong with cancer cells, tumor mass also contains numerous types of non-malignant cell populations, all together contributing to an organ-like multicellular organization. This review underlines the importance of taking into consideration the effects metabolic drugs used for cancer therapy may exert on the cells of the tumor microenvironment.Metabolic reprogramming is a well-known hallmark of cancer, whereby the development of drugs that target cancer cell metabolism is gaining momentum. However, when establishing preclinical studies and clinical trials, it is often neglected that a tumor mass is a complex system in which cancer cells coexist and interact with several types of microenvironment populations, including endothelial cells, fibroblasts and immune cells. We are just starting to understand how such populations are affected by the metabolic changes occurring in a transformed cell and little is known about the impact of metabolism-targeting drugs on the non-malignant tumor components. Here we provide a general overview of the links between cancer cell metabolism and tumor microenvironment (TME), particularly focusing on the emerging literature reporting TME-specific effects of metabolic therapies.
Highlights
Interdepartmental Center of Industrial Research (CIRI) Life Science and Health Technologies, University of Bologna, 40064 Ozzano dell’Emilia, Italy
PI3K/AKT cascades, which are often activated in cancer as a consequence of oncogene and tumor suppressor mutations. mTORC1 signaling increases glycolysis via upregulation of Hypoxia-Inducible Factor 1 alpha (HIF-1α) and c-Myc; supports glutamine metabolism and anaplerosis by repressing sirtuin 4, and promotes lipid biosynthesis and the pentose phosphate pathway by activating Sterol Regulatory Element-Binding Protein 1 (SREBP-1) [12,13]
The additional level of complexity given by the tumor microenvironment (TME) populations and by their alteration in response to metabolic therapy, calls attention to the fact that even the most general approach may require a personalized fine-tuning in terms of drug delivery and dosage, and possibly implementation of adjuvant therapies targeting TME
Summary
The concept that tumors have specific metabolic requirements has been known since the seminal Warburg’s observation of the aerobic glycolysis in cancer tissue [1]. The signaling pathways regulating cellular metabolism are mainly orchestrated by mammalian Target Of Rapamycin Complex I (mTORC1), under control of MAPK or PI3K/AKT cascades, which are often activated in cancer as a consequence of oncogene and tumor suppressor mutations. Isoforms acquire neomorphic function by which α-ketoglutarate (α-KG) is reduced to D-2hydroxyglutarate (D-2HG), an oncometabolite whose accumulation eventually triggers a series of epigenetic modifications promoting tumor growth [16]. These are only some of the most emblematic examples of cancer metabolic reprogramming and the complexity of cancer metabolism has extensively been reviewed elsewhere [17,18,19]
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