Linking Metabolic Reprogramming, Plasticity and Tumor Progression

Abstract

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.

Keywords: aerobic glycolysis; cancer metabolism; cancer therapy; lipid metabolism; metabolic reprograming; one-carbon metabolism.

Figure 1

Different stages of tumor are associated with specific metabolic features. During the cancer development, neoplastic cells pass through several stages: tumor initiation, growth, intravasation into blood or lymph vessels, and dissemination across the body, extravasation, and Mesenchymal–Epithelial Transition (MET) to colonize appropriate niches. These events are associated with various challenges and require metabolic plasticity. GSH—glutathione; NADPH—Nicotinamide adenine dinucleotide phosphate; Arrows mean increasing the amount of GSH or NADPH; E/M—“hybrid” epithelial/mesenchymal state. Explanations are given in the text.

Figure 2

Several examples of the oncogene-mediated regulation of metabolic reprogramming. AKT upregulates oncogenic c-Myc and HIF1 and concomitantly downregulates the tumor suppressor FoxO. In turn, transcription factors HIF1, c-Myc, and FoxO (marked by specific geometric figures) regulate expression levels of enzymes indicated. ENO—enolase; PFK—phosphofructokinase; PK—pyruvate kinase; ASCT2—Solute Carrier Family 1 Member 5; PSAT—phosphoserine aminotransferase; PSPH—phosphoserine phosphatase; SHMT2—Serine Hydroxymethyltransferase 2; CAD—Carbamoyl-Phosphate Synthetase 2; Aspartate Transcarbamylase, And Dihydroorotase.

Figure 3

Epithelial-to-mesenchymal transition (EMT), its molecular drivers, and metabolic features. The process of EMT is triggered by various autocrine and paracrine factors, including TGF-β, PI3K, and AKT. In addition, certain metabolic factors (alterations of glucose level, deregulation of lipid metabolism, loss of function mutations in several TCA genes can also trigger EMT. The metabolic changes alter homeostasis of epigenetics through the accumulation of particular metabolites. EMT master-regulators (Zeb, Snail, and Twist families) as well as other inducers and coregulators of EMT (TGF-β, AKT, K-RASmut, HIF1α, c-Myc) are able to directly regulate glycolysis and lipid metabolism. All arrows mean “increase”, whereas “bars” mean inhibition. Red color—names of proteins, black color—processes and description. More explanations are given in the text.

Figure 4

The scheme of metabolic pathways which are targeted in clinical oncology. The scheme shows metabolic pathways and the key enzymes (shown in red) involved in these processes. Inhibitors that are used as anticancer therapeutics (shown in pink) are also shown. Malignant cells consume energy mainly through utilizing glucose, fatty acids, and glutamine. The process of glycolysis begins with glycose phosphorylation and culminates with pyruvate, which then enters the TCA cycle in mitochondria. Pyruvate is also converted to lactate to maintain high levels of glycolysis. Lactate is exported from the cells mainly by Monocarboxylate carrier 1 (MCT-1) (which is inhibited by AZD3965 and lonidamide) to prevent intracellular acidosis. Fatty acids are transported inside mitochondria by Carnitine Palmitoyltransferase (CPT-1) (which is inhibited by Etomoxir). This step limits their beta-oxidation. The latter is the source of energy consumed by cancer cells via acetyl-CoA entering the TCA cycle. Additionally, cancer cells, unlike nonmalignant ones, are able to synthesize fatty acids. Fatty acid synthase (FASN) (which is inhibited by TVB-2640) mediates the limiting repeating step in this process. Mutated enzymes of the TCA cycle, isocitrate dehydrogenase 1 (IDH1) and IDH2, can be targeted by ivosedinib and edasidenib, respectively. Glutamine is converted to glutamate by Glutaminase (GLS) enzyme (which is inhibited by CB-839) and then to alpha-ketoglutarate in the next step reaction. Alpha-ketoglutarate, in turn, enters the TCA cycle and may be used for either energy production or anabolic metabolism (anaplerosis). The pivotal part of the one-carbon metabolism is the folate cycle, which can be inhibited by methotrexate and pemetrexed via inhibition of DHFR. The one-carbon metabolism provides one-carbon donor groups for biosynthesis of different compounds including nucleotides that are the rate-limiting factor for DNA synthesis and hence, proliferation of cancer cells. Fluouracil (5-FU), raltitrexed, and pemetrexed all inhibit Thymidylate Synthase (TS), whereas gemcitabine inhibits Ribonucleotide reductase (RNR). Detailed explanations are given in the text.