Cancer metabolism and intervention therapy

Abstract

Metabolic reprogramming with heterogeneity is a hallmark of cancer and is at the basis of malignant behaviors. It supports the proliferation and metastasis of tumor cells according to the low nutrition and hypoxic microenvironment. Tumor cells frantically grab energy sources (such as glucose, fatty acids, and glutamine) from different pathways to produce a variety of biomass to meet their material needs via enhanced synthetic pathways, including aerobic glycolysis, glutaminolysis, fatty acid synthesis (FAS), and pentose phosphate pathway (PPP). To survive from stress conditions (e.g., metastasis, irradiation, or chemotherapy), tumor cells have to reprogram their metabolism from biomass production towards the generation of abundant adenosine triphosphate (ATP) and antioxidants. In addition, cancer cells remodel the microenvironment through metabolites, promoting an immunosuppressive microenvironment. Herein, we discuss how the metabolism is reprogrammed in cancer cells and how the tumor microenvironment is educated via the metabolic products. We also highlight potential metabolic targets for cancer therapies.

Keywords: Cancer; Heterogeneity; Metabolic reprogramming; Targeted therapy; Tumor microenvironment.

Fig. 1

The primarily anabolic pathways of cancer cells. Tumor mobilize various nutrients uptake and intracellular anabolic pathways to provide abundant cellular building blocks such as nucleic acid, protein and lipid for rapid proliferation. Cancer cells obtain glucose, glutamine and fatty acids via transport proteins, respectively; certain cancers acquire mutations that can capture extracellular macromolecules through macropinocytosis. Then, the nutrients obtained from extracellular enter multiple anabolic pathways including rapid aerobic glycolysis, glutaminolysis, de novo FAS and nucleotide synthesis to fulfill the biosynthetic and energetic demands of rapid proliferation

Fig. 2

The major catabolic pathways in cancer cells under stress. To survive from stress, such as glucose deprivation, loss of attachment, irradiation or chemotherapy, tumor cells have to reprogram their metabolism from biomass production towards more ATP generation. AMPK, a critical sensor of cellular energy, activated by low ATP level via LKB1, or calcium-dependent CaMKII. Once activated, AMPK inhibits mTOR activity, thereby inhibiting synthesis of proteins, nucleotides and lipids, leading to growth arrest. Additionally, AMPK also promotes autophagy by a variety of signal, and autophagy generates many metabolic substrates by breaking down damaged organelles and misfolded proteins, providing small-molecule substrates to TCA cycle and PXPHOS. On the other hand, AMPK inhibits ACC2 activity and reduces the production of molonyl-CoA, which removing the inhibition of molonyl-CoA on CPT1. Furthermore, PML mediates the activation of PGC1-α/PPARs, subsequently, transcriptionally activates the expressions of HSL, ATGL, ACADVL, ACOX2, UCP1 and other genes, promoting lipolysis, FAO, and OXPHOS etc. Moreover, AMPK and PGC1-α/PPARs signaling synergistically facilitate ATP production, maintain the survival and resistance to stress

Fig. 3

ROS scavenging system in cancer cells. a Intracellular redox levels are determined by ROS production and antioxidant activity, and ROS levels of tumor cells were higher than that in normal cells. After treatment, ROS level in cancer cells is further increased. Once the antioxidant capacity of cells fails to eliminate intracellular ROS, high levels of ROS will trigger apoptosis, even cell death. b Intracellular ROS generated from both endogenous and exogenous sources. If cancer cells fail to adapt to high level of ROS, intracellular DNA, RNA and proteins will be damaged, even leading to cell death. On the other hand, ROS can activate the antioxidant system of Keap/Nrf2, which activates the expression of a series of downstream antioxidant genes and scavenging ROS. In addition, NADPH generated by the PPP and exogenous antioxidants can also participate in ROS scavenging. Redox adaption promotes cell survival under oxidative stress, and thus facilitating cancer progression and therapeutic resistance

Fig. 4

Metabolic interactions in the TME. a Metabolic coupling between cancer cells and CAFs, adipocytes, MSCs in tumor environment. b Nutrition competition for FAs, glucose, tryptophan and arginine occurring between cancer cells and immunocytes (including Teff, Treg, TAM and MDSC). c Cancer cells secrete metabolites as signaling molecules, such as lactate, kynurenine, FAs, cholesterol, PGE₂, LTB₄ as well as LXA₄ to remodel an immunosuppressive TME