The Metabolic Interplay between Cancer and Other Diseases

Abstract

Over the past decade, knowledge of cancer metabolism has expanded exponentially and has provided several clinically-relevant targets for cancer therapy. Although these current approaches have shown promise, there are very few studies showing how seemingly unrelated metabolic processes in other diseases can readily occur in cancer. Moreover, the striking metabolic overlap between other diseases such as diabetes, cardiovascular, neurological, obesity, and aging with cancer have provided key therapeutic strategies that have even begun to be translated into clinical trials. These promising results necessitate consideration of the interconnected metabolic network while studying the metabolism of cancer. This review will discuss how cancer metabolism is intertwined with systemic metabolism, and how knowledge from other diseases can help broaden therapeutic opportunities for cancer.

Connecting Cancer Metabolism to the Broader Context of Aberrant Metabolism

The notion of cancer as a metabolic disease predates the discovery of oncogenes, tumor suppressors, and epigenetics. As early as 1924, Otto Warburg revealed a characteristic feature of the metabolism of cancer, aerobic glycolysis [1, 2]. However, cancer metabolism is extremely heterogeneous [3–5] and how cancer connects with the whole biological system remains among the key unresolved questions today (Figure 1, Table 1).

Figure 1. Connecting Cancer Metabolism to the Broader Context of Aberrant Metabolism.

The metabolism of diseases is an interconnected network. Diseases are shown as segments of the systemic metabolic network (each disease is depicted as a piece of the same jigsaw puzzle) and cancer is shown as a part of this metabolic network (depicted as a piece of the puzzle).

Table 1.

Common Metabolic Pathways between Non-malignant Diseases and Cancer

Common Metabolic	Diseases
Pathway	Non-malignant	Cancer
Glucose metabolism through O-GlcNAcylation	Type 2 Diabetes [32]	Breast cancer, lung cancer, colon cancer, liver cancer, bladder cancer, endometrial cancer, prostate cancer, and chronic lymphocytic leukemia cells [27]
Pyruvate metabolism through OXPHOS	Hyperpyruvicemia, lactic acidosis [42], and cardiovascular diseases [45]	Breast cancer and non-small cell lung cancer [54]
Glutamine metabolism	Neurological diseases (Alzheimer’s disease [57, 58], ischemic stroke, and epilepsy [56]) and hyperammonemic diseases (hepatic encephalopathy and inborn errors of the urea cycle [63])	Pancreatic Cancer, lymphoma, prostate cancer, breast cancer, glioma, ovarian cancer, renal cell carcinomas [20]
NAAG metabolism	Neurological diseases (stroke, amyotrophic lateral sclerosis, and schizophrenia [71, 72])	Ovarian cancer, brain cancer, lymphoma, and pancreatic cancer [65]
GABA metabolism	Neurological diseases (epilepsy and schizophrenia [77])	Colon cancer, breast cancer, prostate cancer, gastric cancer, glioma [83], and pancreatic cancer [82]
Increased ROS and mitochondria dysfunction	Obesity Age-related diseases	Renal cell carcinomas, colon cancer, breast cancer, and prostate cancer [104]

Despite the many advances in cancer research, cancer is still largely studied as an isolated disease. Nonetheless some recent repurposing of therapeutic strategies across diseases is allowing for better therapeutic outcomes [6]. Metformin, for example, the commonly prescribed drug for type 2 diabetes (T2D) [7], is currently being tested in phase III clinical trials for cancer treatment [8] where it was effective in decreasing proliferation of colorectal cancer [9]. Taking advantage of metabolic overlap between diseases should not be solely applied to repurposing drugs. Researchers should take advantage of existing knowledge and pharmacological approaches for other diseases to cancer.

Cancers rely heavily on adaptive metabolic shifts to afford sufficient sources of precursors for cellular bioenergy, redox homeostasis, and other metabolic building blocks in order to maintain high rates of proliferation and growth. The metabolism of glucose and the catabolism of glutamine are the two main pathways targeted with metabolic inhibitors in current clinical trials [8–10]. However, there is an ongoing debate as to which metabolic pathway(s) should be targeted for cancer therapy. Specifically, which of these pathway(s) are best suited for pharmacological targeting? Moreover, are some of these targets already established in other diseases? This poses the fundamental question for cancer metabolism: are the “hallmark” reprogrammed metabolic features of cancers unique to cancers? Here we review metabolic pathways that are shared between cancers and other diseases and discuss potential therapeutic opportunities.

From High Blood Glucose in Diabetes to Cancer—the Epidemiological Association and the Mechanistic Explanation.

Following Warburg’s discovery, research of glucose metabolism in cancers has focused extensively on the fundamental biochemical pathways of glucose-derived metabolites that sustain cancer growth [11, 12]. Could high blood glucose itself lead to cancer? Over the past decade, several epidemiological findings have linked an elevated risk of developing cancers in patients with T2D [13, 14]. According to Sacerdote et al., the risk of developing colorectal cancer is significantly elevated in patients who have T2D, with the risk being around 30% higher than people who do not have type 2 diabetes (T2D) [15]. The risk for several other types of cancers is also significantly higher in T2D patients [15]. Specifically, more than a half of pancreatic ductal adenocarcinoma patients have T2D [16]. The epidemiological association between T2D and pancreatic cancer was recently explained by a possible mechanism by which high blood glucose levels can transform normal pancreatic cells into cells carrying cancerous phenotypes [17]. This study demonstrated that high glucose in T2D can induce de novo oncogenic mutations through increased O-GlcNAcylation of ribonucleotide reductase, leading to nucleotide pool imbalance and KRAS mutations (Figure 2). O-GlcNAcylation is a post-translational modification that results from adding glucose-derived O-linked N-acetylglucosamine (O-GlcNAc) moieties to cellular proteins [18]. While other studies provide evidence that oncogenes and tumor suppressors regulate metabolic processes in cancer, for example, KRAS and MYC are known regulators of metabolism that render cancer cells addicted to glutamine [19–23] and glucose metabolism [11, 24–26], this study showed that aberrant metabolism can in turn dictate gene regulation, even in non-cancerous pancreatic cells [17].

Figure 2. Metabolic Crossroads between Cancer and Type 2 Diabetes (T2D).

Glucose from systemic circulation (green spheres) can be converted to glucose-6-phosphate and fructose-6-phosphate through the enzymes hexokinase and glucose-6-phosphate isomerase, respectively. Fructose-6-phosphate can then enter the hexosamine biosynthetic pathway or continue in glycolysis. The hexosamine biosynthetic pathway provides precursors for O-GlcNAcylation, which forms the metabolic intersection between T2D (blue circle) and cancer (yellow circle). Increased O-GlcNAcylation in T2D can lead to insulin resistance; increased O-GlcNAcylation in cancer can lead to the de novo induction of oncogenic mutations, namely KRAS. Metabolites are shown in black. Enzymes are shown in light blue. Metformin, shown in pink, is a pharmacological inhibitor used in T2D and is currently in clinical trials for cancer therapy due to its inhibition of mitochondrial complex 1, glycolysis, and glycogenesis.

Elevated levels of O-GlcNAcylation, and the glycosylating enzyme O-GlcNAc-transferase (OGT), have been observed in many cancers such as breast, lung, colon, liver, bladder, endometrial, prostate, and chronic lymphocytic leukemia cells [27]. These findings are consistent with the high uptake of extracellular glucose in cancer [28]. Targeting O-GlcNAcylation is a relatively recent addition to cancer therapy [17, 29–31]. Specifically, pharmacological inhibition of OGT results in apoptosis in breast cancer cells [29]. Genetic silencing of OGT also leads to increased sensitivity of cancer cells to other pharmacological inhibitors such as GDC-0941, a PI3K inhibitor [30]. Similar to cancer, T2D has been associated with increased O-GlcNAcylation [32]. Hence, the metabolic process overlapping T2D and cancer may provide a basis for new targeted therapeutics in cancer (Figure 2).

We now know of one possible explanation of how high blood glucose in T2D could lead to cancer. Thus, how can we take advantage of this new knowledge for cancer therapy? Previously, many therapeutic approaches have been aimed at inhibiting key glycolytic enzymes in cancer such as lactate dehydrogenases (LDH) [12], glucose transporters (GLUT/SGLT) [28, 33], and hexokinases (HK) [34], which have shown promising results in preclinical cancer models. However, none of the studies thus far has taken into account the fact that controlling aberrant glucose levels could have a greater effect on preventing cancer initiation rather than just inhibiting cancer progression. Recent approaches have repurposed metformin, which has been used to control blood glucose in T2D for the past 25 years [35, 36], for cancer therapy. Currently, metformin is in phase III clinical trials for the treatment of a number of cancers [37]. Metformin is a mitochondrial complex 1, glycolysis, and glycogenesis inhibitor [38–40] (Figure 2). However, the mechanism of action of metformin is still being investigated [41].

Pyruvate Metabolism—Connecting Cardiovascular Diseases to Cancer

If a therapeutic approach has already been established in another disease and its metabolic overlap with cancer is clear, why shouldn’t we jump straight into clinical trials for cancer therapy? Since targeting glucose metabolism (discussed in §Section 1) seems to be a promising therapeutic avenue, investigating the metabolism of other metabolites derived from glucose closely related to cellular bioenergy appears to be the next logical step. The six-carbon backbone of glucose can be readily converted into a wide variety of different metabolites, including pyruvate, a cellular bioenergy precursor [42]. Dysregulation of pyruvate metabolism is a common metabolic feature across diseases such as hyperpyruvicemia, lactic acidosis, and cancer [42]. A major reaction of pyruvate catabolism is regulated by pyruvate dehydrogenase complex (PDC), the enzyme complex responsible for the conversion of pyruvate to acetyl-CoA, the metabolite oxidized via oxidative phosphorylation (OXPHOS) [42]. Cancers are characterized by their upregulated utilization of aerobic glycolysis in addition to OXPHOS [43]. Although aerobic glycolysis is a less efficient source of ATP than oxidation of pyruvate through the TCA cycle, it is much quicker and thereby upregulated to support the rapid rate of cancer proliferation [44]. Thus, ways to attenuate cancer’s aerobic glycolysis may provide a potential therapeutic option for cancer therapy [12].

Regulating the glycolysis-OXPHOS-axis has long been investigated in cardiovascular diseases, where the challenge is to increase metabolic efficiency by increasing OXPHOS in order to improve cardiac function [45]. Recent developments have been focused on increasing activation of PDC, the gatekeeping enzyme complex necessary for oxidative pyruvate metabolism via the TCA cycle. On the surface, this objective of inducing pyruvate oxidation in order to repress metabolism through the aerobic glycolysis pathway appears to match the problem faced in cancer.

The need for metabolic stimulation of pyruvate oxidation in the context of cardiovascular disorders led to the development of dichloroacetate (DCA), a pharmacological inhibitor of pyruvate dehydrogenase kinase (PDK), which increases cellular activity of PDC causing a shift towards OXPHOS [46–49] (Figure 3). DCA has the ability to promote metabolic shifting away from aerobic glycolysis and towards OXPHOS in preclinical models [50]. Thus, preclinical studies in the context of cardiovascular disease have shown DCA to have beneficial effects on myocardial function [51]. DCA has even reached clinical trials as a treatment for congestive heart failure although it has shown mixed results thus far [52, 53]. Due to the overlapping metabolic profiles of cardiovascular disorders and cancer, interest in DCA as a potential therapeutic approach in cancer was quickly ignited. Within a short period of time, DCA progressed to phase II clinical trials in patients with metastatic breast cancer and non-small cell lung cancer (NSCLC) [54]. However, two patients died during the treatment period [54]. These negative clinical outcomes could be due to the late stage of cancer or could be explained by the fact that cancer cells utilize both aerobic glycolysis and OXPHOS [43] to support their growth. Therefore, pharmacologically promoted metabolism through OXPHOS, a feature still present in cancer cell metabolism, may not be a good approach (Figure 3). Thus, while the approach of using DCA as a possible cancer therapy initially appeared promising, researchers must remain extremely cautious when translating pharmacological approaches from one disease to another.

Figure 3. Metabolic Crossroads between Cancer and Cardiovascular Diseases.

Pharmacological inhibition of pyruvate dehydrogenase kinase (PDK) via dichloroacetate (DCA) causes an increase in the activity of the pyruvate dehydrogenase complex (PDC), which catalyzes the reaction of pyruvate to acetyl-CoA, which then enters the TCA cycle. Subsequently, NADH generated from the TCA cycle leads to increased oxidative phosphorylation (OXPHOS). Cancers (pink circle) also exhibit aerobic glycolysis in addition to OXPHOS. Metabolites are shown in purple.

Glutamine Metabolism – The Driving Engine of Neurological Diseases Also Provides the Building Blocks of Cancer

While glutamine catabolism provides cancers with a source of nitrogen for protein and nucleotide synthesis as well as the carbon skeleton for TCA cycle components [55], elevated levels of glutamate, the immediate catabolic product of glutamine, have been shown to have neurodegenerative properties in the human brain [56]. The dependency of cancer cells on glutamine (also called glutamine addiction [20]) has become one of the most promising therapeutic targets in recent years [10]. One of the explanations for the vital role of glutamine metabolism in cancer is to provide an important fuel for the TCA cycle in cancers when glucose is sparse [43]. Similarly, neurological diseases have shown a strong association with the upregulation of glutamine metabolism, with glutamate having a neurodegenerative effect contributing to the onset and progression of Alzheimer’s disease (AD) [57, 58]. Glutamate-induced neuronal excitotoxicity has also been demonstrated to contribute to the pathogenesis of a number of other neurological diseases including ischemic stroke and epilepsy [56].

The pathogenic overlap of neurological diseases and cancers not only offers new insights into the shared aspects of glutamine metabolism underpinning these diseases, but also provides novel opportunities for the future of cancer therapy (Figure 4). Specifically, the action of glutamate through N-methyl-D-aspartate receptor (NMDAR), which is identified as an important contributor in the pathogenesis of AD [59] has now garnered great interest for cancer therapy due to its role in promoting cancer growth [60–62]. Inhibition of this receptor has led to decreased tumor growth in in vivo models [61], suggesting NMDAR as a new target of glutamine metabolism for cancer therapy.

Figure 4. Glutamate is a Metabolic Axis Connecting Several Diseases.

Glutamate metabolism is a common feature of cancers, neurological diseases, and hyperammonemic diseases. Glutamate can be produced from γ-aminobutyric acid (GABA, green semicircle) through coupled transamination of α-ketoglutarate (α-KG) via GABA transaminase. This reaction also produces succinate semialdehyde (green arrow). Succinate semialdehyde can then be converted to succinate by succinic semialdehyde dehydrogenase (SSADH), which can produce glutamate via the TCA cycle coupled with an α-KG-linked aminotransferase such as aspartate aminotransferase (AAT/GOT) or through glutamate dehydrogenase (GDH). Glutamate can also be produced through the hydrolysis of N-acetyl-aspartyl-glutamate (NAAG, yellow semicircle) catalyzed by glutamate carboxypeptidase II (GCPII) (brown arrow). NAAG can be produced from glutamate and NAA via N-acetylaspartylglutamate synthetases A and B. NAA can be produced from aspartate and acetyl-CoA through aspartate N-acetyltransferase. Glutamine (red full circle) also acts as an important source of glutamate via direct conversion through glutaminase (GLS), or through the glutaminase II pathway intermediates - α-ketoglutaramate (KGM) and α-KG - initially catalyzed by glutamine transaminases (such as GTK) (red arrows). N-methyl-D-aspartate receptor (NMDAR), shown in purple, is a receptor connected to cancer and neurological diseases. Metabolites are shown in black. Diseases are shown in blue. Enzymes are shown in red.

It is well known that the conversion of glutamine to glutamate and ammonia is upregulated in cancers [20]. In other fields unrelated to cancer, α-ketoglutaramate (KGM), a direct product of glutamine catabolized by glutamine transaminases [63] via the glutaminase II pathway, is a biomarker for primary and secondary hyperammonemic diseases, such as hepatic encephalopathy and inborn errors of the urea cycle [63]. While the pathogenic role for the glutaminase II pathway through KGM in the context of hyperammonemic diseases had been developed over the past half-century, the relevancy of this biochemical pathway was largely overlooked in the field of cancer metabolism. The study of these two diseases has remained separated over the past few decades. Only one recent study has identified the role of the glutaminase II pathway as a source of glutamate in cancer [64] (Figure 4). Importantly, blocking the first step of the glutaminase II pathway, glutamine conversion to KGM, led to complete inhibition of pancreatic tumorigenesis in vivo [64]. It turns out that the metabolic mechanisms underlying hyperammonemic diseases and cancers share some common metabolic characteristics. Thus, the intersection between cancers and other diseases provides great potential opportunities to enrich our understanding of the metabolism of cancer as well-known metabolic reactions in one disease could occur in the other.

NAAG Metabolism – From Neuropeptide in Neurological Diseases to a Glutamate Reservoir for Cancer

Previous studies of glutamine metabolism were confined to glutaminolysis, resulting in a somewhat limited view of the vast metabolic network of tumors. Recent work has breached this boundary in search of new sources of glutamate production beyond glutaminolysis [65]. Preliminary work had detected N-acetyl-aspartyl-glutamate (NAAG), a peptide-based neurotransmitter found in the mammalian central nervous system [66], as an active metabolite in cancers. However, the specific mechanism of action of NAAG in cancer remained unresolved [67]. On the other hand, there is abundant literature documenting the role of NAAG in the neurological system [66]. The most recent study revealed a strong, inverse association between tumor or plasma NAAG concentrations versus survival time for patients with brain tumors [65]. Since NAAG is a neurotransmitter/neuromodulator, there is the possibility that the source of this neurotransmitter could be released by nerves in the tumor microenvironment [68, 69]. To test whether NAAG was actually produced by cancer cells, they used stable isotope-resolved metabolomics [70] and observed an abundant production of NAAG from ¹³C ¹⁵₅N₂-labeled glutamine especially in MYC-ON as compared to MYC-OFF lymphoma cancer cells grown in vitro, indicating the endogenous formation of NAAG in cancer cells [65]. They further found significantly increased production of glutamine-derived NAAG in higher-grade ovarian in vivo. These findings indicated that the neurotransmitter NAAG can be found in non-glial tumors. These findings led to the further investigation into the specific role of NAAG in cancer [65]. Specifically, NAAG hydrolysis through glutamate carboxypeptidase II (GCPII), a known enzymatic target in neurological diseases [71], was demonstrated to play a crucial role in glutamate production for cancer [65]. This glutamate can then be catabolized to provide cancers with the carbon and nitrogen necessary to support elevated nucleotide and protein synthesis [55]. Hence, the role of NAAG, the most abundant peptide-based neurotransmitter in the mammalian central nervous system (CNS) [66], to promote cancer growth was discovered for the first time [65] (Figure 4). The glutamine addiction phenomenon in cancer was established several years ago [20]. The hydrolysis of NAAG to glutamate through GCPII, which was already well-known in neurological diseases, might have been discovered in cancer much earlier had metabolic overlap between cancers and other diseases been more avidly pursued as a strategic approach. Hence, the GCPII inhibitor 2-PMPA (2-phosphonomethyl pentanedioic acid), which was extensively investigated as a pharmaco-therapeutic approach for a number of neurological diseases including stroke, amyotrophic lateral sclerosis, and schizophrenia [71, 72], is now being investigated for cancer therapy [65, 73]. Preclinical study of GCPII inhibition through the pharmacological inhibitor 2-PMPA has shown success in decreasing tumor growth in mice bearing patient-derived recurrent ovarian and pancreatic tumors [65]. Furthermore, combination therapy with GCPII and the current clinical trial glutaminase inhibitor, CB-839 (2-(pyridin-2-yl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acetamide), accentuated tumor reduction more than either treatment alone [65]. Of note, the oral form of the GCPII inhibitor, 2-MPPA (2-(3-mercaptopropyl)pentanedioic acid), has passed a Phase I clinical trial for other diseases [74]. Thus, 2-MPPA can move into clinical trials for cancer therapy quickly. The metabolic interplay between cancers and other diseases is an invaluable key to unlocking new therapeutic opportunities for one disease from existing knowledge of another.

GABA Metabolism – From the Master Inhibitory Neurotransmitter to a Succinate Precursor for Cancer

γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the mammalian brain [75] and is formed by decarboxylation of glutamate catalyzed by glutamate decarboxylase (GAD) (Figure 4). GABA is metabolized by transamination to form succinic semialdehyde. Succinic semialdehyde, in turn, is converted to succinate, an intermediate metabolite of the TCA cycle [76]. Due to the prominent role of GABA as an inhibitory neurotransmitter, dysregulation of GABA metabolism has been implicated in a large number of neurological diseases including epilepsy and schizophrenia [77]. The role of GABA metabolism in neurological diseases, coupled with the biochemical role of GABA as a precursor to succinate, prompted exploration into the potential role of GABA in cancers. The rapid rates of proliferation and reprogrammed metabolisms of cancers readily necessitate the additional source of carbon from the incorporation of succinate (derived from GABA) into the TCA cycle [78] (Figure 4). Although GABA is only present at nano- or micro- molar concentrations either in blood [79] or cerebrospinal fluid [80], it is surprising to see that GABA supplementation at low micro-molar concentrations was sufficient to increase cellular proliferation in HER2+ breast-to-brain metastatic cancer cells [81]. Takehara et al. also demonstrated that GABA increases cancer cell proliferation [82]. These findings are consistent with the notion that cancer cells may utilize these alternative sources of metabolic precursors when access to the primary metabolic pathways (such as glycolysis, glycogen breakdown or glutaminolysis) are limited. Furthermore, several studies found elevated GABA and GAD levels in colon, breast, prostate, gastric cancers, and glioma [83]. The metabolic role of GABA in cancers was demonstrated, as cancers to have the ability to break down GABA into succinate as a TCA intermediate for bioenergy metabolism [78, 81, 84]. The increased GABA uptake in progressing neurological disease and cancers have stimulated the uncovering of a new, unexpected source of metabolic precursors in cancers and have provided a potential metabolic target for the next generation of pharmaco-therapeutic inhibitors.

From Obesity to Cancer – The Unexpected Ways Obesity Can Contribute to Carcinogenesis

While the causative link between obesity and T2D or cardiovascular diseases is known, only recently have epidemiological studies provided ample evidence to demonstrate an association between obesity and the risk of getting a number of cancers, including colorectal, breast, endometrial, kidney, esophageal, liver, bladder, pancreatic, thyroid, and liver cancers [85, 86]. Specifically, a study by Calle et al. revealed that 14.2% of cancer deaths in men and 19.8% in women can be attributed directly to obesity [86].

One of the main characteristics of obesity is the presence of high levels of adipose tissue [87]. Interestingly, studies have demonstrated the collaborative role of adipocytes in helping cancer cell growth [88, 89]. Excess lipogenesis and decreased fatty oxidation could lead to hepatic steatosis as a consequence of surpassing the normal storage capacity of the liver. Steatosis eventually leads to liver damage and often to hepatocellular carcinoma at later stages. Moreover, a growing number of studies have demonstrated obesity to directly contribute to insulin resistance [90, 91] through the harmful secretion of triglycerides, leptin, resistin, cytokines and free fatty acids from adipose tissues. Chronic insulin resistance, and consequently prolonged exposure to a high-glucose environment, can lead to oncogenic alterations as discussed in §T2D Section. In addition, a study by Yu et al. demonstrated hyperglycemia to induce mitochondrial dysfunction and promote reactive oxygen species (ROS) accumulation [92]. ROS accumulation, in turn, can directly promote cellular damage and thereby drive the formation of malignant phenotypes through redox-sensitive transcription factors, DNA mutations, and epigenetic changes [93]. Changes in redox homeostasis result in not only the activation of a number of known oncogenes such as Ras, Bcr-Abl, and c-MYC but also the promotion of PI3K/Akt and MAPK/ERK pathways involved in cell proliferation [94]. Hence, the ability for metabolic perturbation to induce genetic and epigenetic changes is an underlying mechanistic link between obesity and cancer (Figure 5). The metabolic mechanisms of obesity and cancer are fundamentally intertwined and developing a better understanding of this association may provide new insights into the etiology of cancer.

Figure 5. Alterations in Metabolism Associated with Obesity and Aging Could Lead to Cancer.

Metabolism is depicted directionally from young and healthy (upper) to obese (lower left) and aged (lower right). Metabolism decrease in older adults is commonly accompanied by an increase in reactive oxygen species (ROS). Accumulation of ROS, a common feature of aging and obesity, can lead to oncogenic mutations and epigenetic changes over time, subsequently increasing the risk of cancer. ROS related metabolites, such as superoxide, hydrogen peroxide, and hydroxyl radical, are shown in red. Enzymes are shown in blue.

From Aging to Cancer – Why does the Risk of Getting Cancer Increase with Age?

Is it because our genes change over time, or due to changes in our lifestyle, diet and metabolism? In order to distinguish between the environmentally-driven and genetically-driven effects observed with aging, Vinuela et al. assessed the RNA-sequence of several types of samples from 855 human adult female twins [95]. They identified over a hundred genes with age-related changes in variance and around forty genes with age-related discordance between co-twins, implying that the latter were driven by environmental effects [95]. The way we live our lives over time can affect metabolic pathways and ROS production, which in turn can regulate immune responses, epigenetic control, and DNA repair (Figure 5).

Metabolism slowing down with age is arguably the most universal contributor to metabolic changes, including T2D, which in turn increases risk factors for cancer [96] (Figure 5). However, the discoveries of gene mutations causing cancer should not overshadow other consequences of metabolic disturbances. The formation of cancer involves not only alterations in genetics (oncogene, tumor suppressor activation or deactivation) but also epigenetics (such as alterations in DNA methylation and histone modifications) accompanied with chromosomal instability and DNA repair deficiency. Age can also lead to dysregulated hepatic gluconeogenesis, adipose lipogenesis, and defective glycogen synthesis and glucose uptake in muscle. The accumulation of co-factors, byproducts, and proteins plays a crucial role in post-translational modifications [97]. These factors can lead to changes in epigenetic regulation, which form the basis for a potential causational link between aging and cancer. In addition to the increase in the acquisition of somatic nuclear mutations as age progresses [98], metabolism also changes dramatically with age. Key metabolic proteins such as mTOR (mechanistic target of rapamycin) [99] and IGFs (insulin-like growth factors, IGF-I and IGF-II) were found to be upregulated in cancer [100], while AMPK (AMP-activated protein kinase) was found to be downregulated in cancer [101]. Since AMPK activation is a negative regulator of cell proliferation and lipid synthesis, its lack of activation facilitates tumor growth and enables lipid production [97]. Specifically, AMPK activation leads to phosphorylation and inhibition of the essential enzymes Acetyl-CoA carboxylase and HMG-CoA reductase involved in lipid production [102, 103]. Therefore, metabolism is believed to be a main link between aging and cancer risk.

In 2005, Douglas Wallace hypothesized that mitochondrial dysfunction plays a central role in various forms of cancer [104] which echoed Otto Warburg’s suggestion from 50 years prior that mitochondrial dysfunction is the origin of cancer [1, 2]. Wallace proposed that the accumulation of somatic mutations in the mitochondrial DNA (mtDNA) with age would lead to the dysfunction of energy homeostasis and consequently to an increase in ROS. Increased ROS, in turn oxidizes the ferrous ion and consequently inactivates prolyl hydroxylases (PHDs) as oxidation of ferrous iron is essential for this catalytic mechanism. Inactivation of PHDs leads to HIF-1a stabilization, thereby upregulating glycolysis and decreasing mitochondrial respiration [105]. Stemming from this viscous cycle of increased ROS and mitochondrial dysfunction, several researchers have proposed the free radical theory of aging and cancer [106, 107]. Is the increased risk of cancer with increased age, which is accompanied by evidence of increased oxidative stress, a causative or correlative relationship? While ROS are endogenous products of normal metabolic processes (predominantly occurring in the mitochondria), excess accumulation over time can lead to protein and DNA damage which is a precondition for the development of cancer and other age-related diseases. While cancer cells have demonstrated mechanisms to deal with ROS accumulation [19, 108, 109], most experts accept that the free radicals produced during aging still remain one of the causes, or at least a facilitator, of cancer [107]. Metabolite intermediates and ROS can act as second messengers regulating signaling pathways, genetic and epigenetic mechanisms, and form the foundation for cancer development. For example, compounds directly essential to the function of epigenetic enzymes are produced during metabolism, such as S-adenosylmethionine (SAM) for methylation. Researchers have established that there is an epigenetic drift to indicate the methylation changes in aging [110]. Another link between metabolism and epigenetics is through acetyl-CoA. Acetyl-CoA regulates histone acetylation and demethylation. Acetyl-CoA itself is regulated by glucose availability. Glucose availability also affects O-GlcNAcylation, which requires UDP-GlcNAc as a donor substrate, a product of the hexosamine biosynthesis pathway that uses 2–5% of imported glucose. O-GlcNAcylation is found to be upregulated in cancer [111] and is often used as a tumor grade and prognostic marker [112].

Another aspect to consider in the metabolism of aging is provided by Goodrick et al., and others, who have uncovered that calorie restriction together with steady sleep and circadian cycle resulted in health benefits, lifespan extension, reduced inflammation and reduced cancer in rodent models [113, 114]. Excess or lack of metabolites and substrate from nutrient uptake can disrupt the energy balance as reflected by the ATP/AMP, or NAD+/NADH ratios, and compromise cellular function and biological systems as a whole [115]. Mitochondria, the factory for respiratory energy production, is also the major source of ROS production and the common place for multiple metabolic pathway intersections. Thus, the continued uncovering of new metabolic pathways in a wide range of different diseases yields new opportunities for sharing knowledge between cancer and other fields.

Concluding Remarks

Although recent studies in cancer metabolism have shown that metabolic aspects from other diseases can readily take place in tumors, there still remain a number of unresolved questions (See Outstanding Questions). The converging metabolic profiles of other diseases and cancer may therefore be a key to unlocking new therapeutic insights for the treatment of cancer. Metabolite intermediates, and other products of metabolic processes, such as ROS, hold the ability to directly influence cancer initiation and progression by damaging cellular genetic and epigenetic processes. Thus, aberrant metabolism itself can trigger carcinogenesis and maintain cancer growth. This can thereby form a vicious cycle in which metabolic perturbations can promote the acquisition of one disease which in turn can increase the risk for generation of another disease. Despite these challenges, given the new interest and knowledge into the study of cancer metabolism, the opportunity to utilize existing knowledge to combine with recent findings provides a bright future for cancer therapy.

Outstanding Questions.

• What strategy should we use to screen the possible metabolic overlaps between cancer and other diseases more effectively for therapeutic potential?

• Would applying the knowledge from other diseases to cancer sooner have resulted in more effective therapeutic approaches for cancer?

• Why are there very few studies thus far examining the metabolic overlap between cancer and other diseases?

• Why have well-established biochemical pathways in other diseases been largely overlooked in the field of cancer metabolism?

Highlights.

• The metabolic features of many diseases have a striking overlap with cancer.

• The metabolism of diseases is an interconnected network.

• Connecting cancer metabolism to the broader context of aberrant metabolism is necessary and may reveal new therapeutic strategies.

• It is important to know whether a potential cancer therapeutic target has been already established in other diseases.