Overview of Cancer Metabolism and Looking Forward

Cancer metabolism refers to the alterations in metabolism when compared cancer cells with the normal tissue cells. It usually requires the cells to go through a process called metabolic reprogramming, and this process causes numerous changes in many metabolic pathways. Most of the researches about this area focus on three topics- the alternations in aerobic glycolysis, lipid metabolism, and amino acid metabolism, which are the main biosynthesis processes that needs for tumor growth and cancer cell proliferation.

Progress in cancer metabolism- from central carbon metabolism to non-carbon metabolism

Cancer metabolism studies start with the observation of the Warburg effect, which is a phenomenon that cancer tissues in vitro use glucose to generate lactate even in the presence of enough amount of oxygen[1]. This phenomenon was once regarded as one of the prerequisites for the transformation of a differentiated cell into a proliferative cancer cell. However, the tricarboxylic acid (TCA) cycle, as the major source of energy for cells, still happen in most cancer cells to promote flux and tumor growth. In recent years, studies focusing on this topic also tried to figure out the relationship between the Warburg effect and other anabolic side pathways that support de novo synthesis of nucleotides, lipids, and amino acids that are necessary for cell proliferation[2]. From the researches published in these few years, the field has expanded, or switched, in some extent, from central carbon pathways such as glycolysis and TCA cycle to the branch metabolic pathways that are needed for tumor growth, progression, and metastasis. Due to the more profound insights to tumor microenvironment (TME) and differences in nutrient and oxygen levels between cells and host organisms, the field was driven to study more in vivo rather than in vitro as well.

As for the studies about anabolism in tumor growth, two main questions need to be answered, first, what are the rate-limiting macromolecules during all types of synthesis, and second, which are the pathways that participate in the process. Some of the results published in recent studies might partially answer the questions. It has been revealed that DNA methylation-induced downregulation of ASS1 in some cancers increases aspartate availability to sustain pyrimidine synthesis. However, aspartate, which can be produced from oxaloacetate, and its derivative asparagine can both be limiting for tumor growth. Additionally, the loss of tumor suppressor LKB1 upregulates the expression of carbamoyl phosphate synthetase 1 (CPS1), which can produce carbamoyl phosphate in the mitochondria from ammonia and bicarbonate to provide nitrogen for pyrimidine synthesis[3]. Moreover, pyruvate carboxylase (PC), which generates the TCA cycle metabolite oxaloacetate from pyruvate, has been shown to be necessary for primary and metastatic tumor growth. Signaling pathways such as ERK and AMPK also play crucial roles in the anabolism of tumor growth, since it has been proved that activation of ERK signaling pathway can promote de novo purine synthesis for tumor growth and the loss of AMPK activity has a similar function. The hyperactivation of MYC and mTORC1 could be seen as a new therapeutic intervention for the metabolic vulnerabilities of cancer cells[4].

Even though cancer research has focused on central carbon metabolism for so many years, new studies have shed light on the important roles of fatty acid and amino acid in cancer metabolism, as they serve a lot essential purposes and can never be ignored when we talk about this topic.

Fatty acid metabolism in cancer

Fatty acids (FAs) are the main building blocks of different lipid species, such as triglycerides, phospholipids, and sphingolipids, and then these can be funneled into various metabolic pathways to form more complex lipid species. Thus, they can be seen as the fuel sources, and contribute to the vast structural diversities of the cells and also serve as the secondary messengers in signaling pathways of biochemical processes.

In cancer cells, FAs are obtained mainly by two methods, exogenous uptake, and de novo synthesis. In terms of exogenous FA uptake, specialized transporters are required to facilitate efficient movement across the plasma membrane, and the most well-characterized of these include CD36, SCL27, and FABP[5]. After obtaining FAs from surroundings, cancer cells might store them in lipid droplets (LDs) and subsequently use them to produce ATP and NADPH through β-oxidation or to transduce signals[6]. Besides, the interaction between cancer cells and adipocytes is not only limited to transmission of energy, adipose cells can also function as active mediators of endocrine and paracrine signaling through secreting adipokines and cytokines that could cause the metabolism reprogramming of cancer cells. As for the de novo synthesis, the regulation mainly occurs at transcriptional level through the activation of SREBPs and induces the transcription of enzymes such as ACC, ACLY, and FASN. The activity of SCD, ELOVLs, and FADs are critical for cancer cells to generate a diverse pool of lipid species and distinct functions as they are critical enzymes for fatty acid elongation and desaturation.

Lipid metabolism in cancer cells can be regulated by different oncogenic signaling pathways, one of the most frequently dysregulated signaling pathways is PI3K-AKT signaling, which contribute to processes for de novo lipid synthesis by activating metabolic enzymes such as ACLY or by increasing NADPH production. mTOR complexes (mTORC1 and mTORC2) can also be linked with the PI3K-AKT pathway, as the mTORC1 directly phosphorylates and inactivate lipin-1 which might influence SREBP activity, and it can also lead to increase mRNA splicing of genes related to de novo lipogenesis. mTORC2 is important because of its capacity to stimulate several AKT-independent compensatory signaling pathways, including SGK and PKC. However, it also needs to be known that the enzymatic network of de novo lipogenesis can reciprocally affect the oncogenic signaling as well. For instance, the inhibition of FASN would lead to subsequently upregulation of PEA3, which is the negative regulator of HER2. As HER2-amplified tumors are particularly dependent on PI3K signaling, FASN could play a central role in modulating the initiation of growth-factor-dependent oncogenic signaling that is required for malignancy[7].

Amino acid metabolism in cancer

Amino acids, nutrient vital for the survival of all cell types, are also critical for the tumor growth and proliferation of cancer cells. They can be used as alternative energy fuels and biosynthesis materials, and needed in regulations of metabolic enzymes and transporters, function as regulators for epigenetic and posttranscriptional processes. The interconnection between amino acids and other metabolic pathways makes the networks complex and extremely extensive, so it becomes popular to be studied as potential therapeutic strategies for cancers.

Most studies regarding amino acid metabolism in cancer focus on the regulatory mechanisms, considering the roles it plays, as intermediates, in connecting glucose, lipid, and nucleotide metabolism. For instance, glutamine, when it works as the metabolic intermediates, can enter the TCA cycle, thus supplementing and renewing the TCA cycle under the condition of glucose deficiency[8], and oncogenic alterations in cancer cells might change glutamine metabolism and then induce the promotion in tumorigenesis[9]. Serine, one of the one-carbon sources in nucleotide synthesis and DNA methylation, is critical for cancer progression. Serine starvation can inhibit the proliferation of specific types of cancer in vitro[10]. Glutamine and branched-chain amino acids also have function in DNA and histone demethylation. Amino acids such as arginine participate in T-cell survival, proliferation, and activation, now becomes effective tumor therapeutic targets. As for signaling transduction, most amino acids can activate mTOR signaling somehow, and since many amino acid transporters participate in the signaling transduction, it becomes very complex and can regulate extensive processes in cancer amino acid metabolism[11].

Redox balance in cancer

Reactive oxygen species (ROS) are chemically active radicals including the superoxide anion (O2−), hydrogen peroxide (H2O2), and the hydroxyl radical (OH·), which produced by biochemical reactions that occur during the processes of respiration in organelles such as mitochondria and can activate diverse signaling pathways and disrupt redox homeostasis depending on their concentration. Historically, ROS have been thought as lethal byproducts of biochemical reactions, since the accumulation of excessive amount of ROS can initiate toxicity, DNA damages, and then reduce tumorigenesis. However, after several decades studying on this topic, the important roles of how it regulates cellular signaling and homeostasis have been unveiled.

During tumorigenesis and metastasis, the metabolic activity increases significantly in cancer cells, which induces highly increased ROS production and result in subsequently activate of signaling pathways such as AMPK and mTOR that related to cancer cells survival and proliferation. High concentration of ROS is toxic to cancer cells, so the antioxidant capacity is needed to prevent the toxic levels of ROS and allow for the cancer progression. Because of the highly demanding of oxygen, the tumor microenvironment (TME) is always under hypoxia, which is the main cause of ROS overproduction. And the low glucose levels limit the flux through the oxidative pentose phosphate pathway (PPP), thus decrease the production of NADPH. Cancer cells under this circumstance would diminish the activation of NADPH consuming anabolic pathways such as de novo lipid synthesis that requires high levels of NADPH, and active AMPK signaling pathway to stimulate NADPH production. ROS-dependent signaling transduction is also necessary for the tumor metastasis, since the cancer cells might encounter high levels of ROS in TME after they detach from the matrix. So the ability of up-regulate the antioxidant proteins is critical to enable the cancer cells to achieve distant metastasis. It suggests a good perspective to prevent metastasis in cancer therapy, by inhibiting the production of antioxidant proteins and disabling the antioxidant capacity might be able to prevent the tumor metastasis.

What to expect from the future?

Given the extensive role of fatty acids and amino acids in tumor growth, progression, and metastasis, clinical therapeutic strategies targeting the related metabolic enzymes and signaling transducers have been studied a lot as well. According to the clinical results to date, this area of research holds great promise for the future implementation of combinatorial strategies with other cancer-related research fields and the dynamic interaction with the overall tumor microenvironment can offer us more comprehensive perspectives in different types of cancer therapies.

References:

1. Koppenol, W.H., P.L. Bounds, and C.V. Dang, Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer, 2011. 11(5): p. 325-37.
2. Ghergurovich, J.M., et al., Local production of lactate, ribose phosphate, and amino acids within human triple-negative breast cancer. Med (N Y), 2021. 2(6): p. 736-754.
3. Kim, J., et al., CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. Nature, 2017. 546(7656): p. 168-172.
4. Martinez-Reyes, I. and N.S. Chandel, Cancer metabolism: looking forward. Nat Rev Cancer, 2021. 21(10): p. 669-680.
5. Su, X. and N.A. Abumrad, Cellular fatty acid uptake: a pathway under construction. Trends Endocrinol Metab, 2009. 20(2): p. 72-7.
6. Carracedo, A., L.C. Cantley, and P.P. Pandolfi, Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer, 2013. 13(4): p. 227-32.
7. Koundouros, N. and G. Poulogiannis, Reprogramming of fatty acid metabolism in cancer. Br J Cancer, 2020. 122(1): p. 4-22.
8. Yang, L., S. Venneti, and D. Nagrath, Glutaminolysis: A Hallmark of Cancer Metabolism. Annu Rev Biomed Eng, 2017. 19: p. 163-194.
9. Perez-Escuredo, J., et al., Lactate promotes glutamine uptake and metabolism in oxidative cancer cells. Cell Cycle, 2016. 15(1): p. 72-83.
10. Maddocks, O.D., et al., Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells. Mol Cell, 2016. 61(2): p. 210-21.
11. Wei, Z., et al., Metabolism of Amino Acids in Cancer. Front Cell Dev Biol, 2020. 8: p. 603837.