cancer metabolism thesis

A Glance at the Effects of Secondary Metabolites in Fighting Cancer

• First Online: 29 August 2024

Cite this chapter

• Ala’ M. Abuh-Odeh   ORCID: orcid.org/0000-0002-0011-2921 1 ,
• Leedia Abuelshayeb 1 ,
• Rajaa Daghash 2 ,
• Kamel Jaber 3 ,
• Areej M. Jaber 4 ,
• Manal Ayyash 5 ,
• Ayah Daghash 6 ,
• Layan Awad 7 &
• Wamidh H. Talib 8  

Part of the book series: Interdisciplinary Cancer Research

Cancer is one of the top causes of morbidity and mortality globally. Cancer is a disease of unregulated cell growth that invades and spreads to other cells and tissues. Chemotherapy of cancer has many challenges due to the low selectivity, poor water solubility, instability of molecules, and development of resistance against them. Plant-derived natural products exhibit numerous biological activities with unique mechanisms of action, making them attractive for drug development for the management of chronic human diseases, including cancer. Natural products are considered potential cancer therapies either alone or in combination with conventional anticancer medications. Most natural products exhibit own pleiotropic effects when affecting cancer cells and modulating several signal transduction and modulators, in addition to their unique structures. The goal of our study was to elucidate the mechanisms of action of several secondary metabolites’ classes on different aspects of the carcinogenesis process. We reviewed the pharmacological actions and molecular targets of the secondary metabolites. Furthermore, we emphasized the influence of secondary metabolites and conventional anticancer drug combinations on several cancer types to understand the mechanisms and advantages underlying these combinations.

Plant-derived natural products fight cancer through different strategies, including apoptosis induction strategy through DNA damage and caspase activation. The antiproliferative strategy inhibits the mitogen-activated protein kinase (MAPK) pathway, immunomodulation, and anti-inflammatory activities. The other strategies target altered metabolism and tumor microenvironment, as well as inhibition of angiogenesis and metastasis. Recently, a novel practice, so-called combinatorial therapy, has been investigated by engaging plant-derived natural substances with conventional chemotherapeutics. It has been reported that plant metabolites may fortify the drug’s effective concentration, pile on the collective effect of both administered therapeutics, or increase the selectivity to tumor cells. Moreover, by steering numerous signaling pathways, combinatorial therapy uses several mechanisms to diminish the development of resistance to antitumor drugs. The interaction between plant-derived natural compounds and conventional chemotherapeutics initiates a new aspect in the research and therapy of cancer. It could be a gifted approach to treat cancer and gain fruitful improvements while diminishing adverse effects associated with conventional anticancer medications. The most studied phytochemicals include curcumin, epigallocatechin gallate, and resveratrol. Among the most investigated chemotherapeutics were 5-fluorouracil, doxorubicin, and cisplatin.

A better understanding of the multifaceted mechanisms of action of phytochemical metabolites is anticipated to open new approaches in the coming years for managing all types of cancers. In the present chapter, we report on our efforts to determine the major strategies used to treat cancer by phytochemicals in cancer cells.

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Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmacy, Applied Science Private University, Amman, Jordan

Ala’ M. Abuh-Odeh & Leedia Abuelshayeb

Department of Clinical Pharmacy and Therapeutics, Amman, Jordan

Rajaa Daghash

School of Medicine, The University of Jordan, Amman, Jordan

Kamel Jaber

Faculty of Pharmacy, Pharmacologic and Diagnostic Research Center, Al-Ahliyya Amman University, Amman, Jordan

Areej M. Jaber

Department of Pharmaceutical Sciences and Pharmaceutics, Applied Science Private University, Amman, Jordan

Manal Ayyash

Department of Applied Pharmaceutical Science, Faculty of Pharmacy, Isra University, Amman, Jordan

Ayah Daghash

MEU Research Unit, Middle East University, Amman, Jordan

Faculty of Allied Medical Sciences, Applied Science Private University, Amman, Jordan

Wamidh H. Talib

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Abuh-Odeh, A.M. et al. (2024). A Glance at the Effects of Secondary Metabolites in Fighting Cancer. In: Interdisciplinary Cancer Research. Springer, Cham. https://doi.org/10.1007/16833_2024_328

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Targeting cancer cell metabolism as a therapeutic strategy

Chaneton, Barbara Julieta (2014) Targeting cancer cell metabolism as a therapeutic strategy. PhD thesis, University of Glasgow.

In the past 15 years the field of cancer metabolism has burst providing vast quantities of information regarding the metabolic adaptations found in cancer cells and offering promising hints for the development of therapies that target metabolic features of cancer cells. By making use of the powerful combination of metabolomics and 13C-labelled metabolite tracing we have contributed to the field by identifying a mitochondrial enzymatic cascade crucial for oncogene-induced senescence (OIS), which is a tumour suppressive mechanism important in melanoma, linking in this way OIS to the regulation of metabolism. Furthermore, we have identified the dependency on glutamine metabolism as an important adaptation occurring concomitantly with the acquisition of resistance to vemurafenib (BRAF inhibitor) in melanoma, which opens the possibility to combine therapies targeting glutamine metabolism with BRAF inhibitors, in order to overcome or avoid the onset of resistance in melanoma. Using the same strategy we have discovered an important mechanism of interregulation between glycolysis and amino acid metabolism, identifying the glucose-derived amino acid serine as an activator of the main isoform of pyruvate kinase present in cancer cells, PKM2. In addition, we provide new insights into the mechanism of allosteric regulation of this complex protein and a better understanding of the way it regulates central carbon metabolism. In summary, our results open new possibilities for the development of cancer therapies that manipulate metabolic adaptations found in cancer cells in order to kill them specifically or halt their growth.

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Metabolite Predictors of Breast and Colorectal Cancer Risk in the Women's Health Initiative

Affiliations.

• 1 Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
• 2 Biostatistics Division, Kaiser Permanente Washington Health Research Institute, Seattle, WA 98101, USA.
• 3 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
• 4 Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
• 5 Biostatistics Program, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
• 6 Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98195, USA.
• 7 Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE 68198, USA.
• 8 Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
• 9 Center for Metabolic and Vascular Biology, College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA.
• 10 Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
• 11 Department of Internal Medicine, Division of Medical Oncology, College of Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
• PMID: 39195559
• DOI: 10.3390/metabo14080463

Metabolomics has been used extensively to capture the exposome. We investigated whether prospectively measured metabolites provided predictive power beyond well-established risk factors among 758 women with adjudicated cancers [ n = 577 breast (BC) and n = 181 colorectal (CRC)] and n = 758 controls with available specimens (collected mean 7.2 years prior to diagnosis) in the Women's Health Initiative Bone Mineral Density subcohort. Fasting samples were analyzed by LC-MS/MS and lipidomics in serum, plus GC-MS and NMR in 24 h urine. For feature selection, we applied LASSO regression and Super Learner algorithms. Prediction models were subsequently derived using logistic regression and Super Learner procedures, with performance assessed using cross-validation (CV). For BC, metabolites did not increase predictive performance over established risk factors (CV-AUCs~0.57). For CRC, prediction increased with the addition of metabolites (median CV-AUC across platforms increased from ~0.54 to ~0.60). Metabolites related to energy metabolism: adenosine, 2-hydroxyglutarate, N -acetyl-glycine, taurine, threonine, LPC (FA20:3), acetate, and glycerate; protein metabolism: histidine, leucic acid, isoleucine, N -acetyl-glutamate, allantoin, N -acetyl-neuraminate, hydroxyproline, and uracil; and dietary/microbial metabolites: myo-inositol, trimethylamine- N -oxide, and 7-methylguanine, consistently contributed to CRC prediction. Energy metabolism may play a key role in the development of CRC and may be evident prior to disease development.

Keywords: breast cancer; colorectal cancer; dietary biomarkers; metabolite predictors; metabolomics.

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Matthew Vander Heiden seeks new cancer treatments that exploit tumor cells’ abnormal metabolism.

Anne trafton | mit news office, august 28, 2018.

Nearly 100 years ago, the German chemist Otto Warburg discovered that cancer cells metabolize nutrients differently than most normal cells. His discovery launched the field of cancer metabolism research, but interest in this area waned; by the 1970s most cancer scientists had shifted their focus to the genetic mutations that drive cancer development.

In the past decade or so, interest in cancer metabolism has resurged, and the first drugs that target cancer cells’ abnormal metabolism were approved to treat leukemia in 2017.

“Cancer metabolism is a very sophisticated field at this point,” says Matthew Vander Heiden, an associate professor of biology at MIT. “We have a lot better understanding of what nutrients cancer cells use and what determines how those nutrients are used. This has led to different ways to think about drugs.”

Vander Heiden, who is also a member of MIT’s Koch Institute for Integrative Cancer Research, is one of the people responsible for the recent surge in cancer metabolism research. As a graduate student and postdoc, he published some of the first studies of how cancer cells alter their metabolism, and now his lab at MIT is devoted to the topic.

“All of the time that I was in grad school and working as a postdoc, I was never working in a lab that was dedicated to studying metabolism. So my vision, if someone gave me a job, was to set up a lab that could really be built in a way that would allow us to ask questions about metabolism,” he says.

Metabolism and cancer

Vander Heiden grew up in a small town in Wisconsin, and unlike most of his high school classmates, he headed out of state for college, to the University of Chicago. He was interested in science, so decided on a pre-med track. A work-study job in a plant biology lab led him to discover that he also enjoyed doing research.

“At that point I already had this idea I was going to go to medical school, but then the idea of MD/PhD came up, and I ended up going down that path,” Vander Heiden says.

While in the MD/PhD program at the University of Chicago Medical School, he worked in the lab of Craig Thompson, now president of Memorial Sloan Kettering Cancer Center. At that time, Thompson was studying the biochemical regulation of apoptosis, the programmed cell death pathway. For his PhD thesis, Vander Heiden investigated the function of a protein called Bcl-x, which is a regulator of apoptosis found in the membranes of mitochondria — cell organelles responsible for generating energy.

“That project really got me thinking about how the mitochondria work and how metabolism works,” Vander Heiden recalls. “At the time, I came to the realization that we don’t understand cell metabolism anywhere near as well as we thought we did, and someone should really study this.”

After finishing his degrees, he spent five years doing clinical training, then decided to pursue research in cancer metabolism.

“Altered metabolism has been known about in cancer for 100 years, but few people were studying it,” Vander Heiden says. “The challenge was finding a lab that would allow me to study metabolism and cancer, which in 2004-2005 was not such an obvious thing to do.”

He ended up going to Harvard Medical School to work with Lewis Cantley, who studies signaling pathways in cells and was receptive to the idea of exploring cancer metabolism. There, Vander Heiden began studying an enzyme called pyruvate kinase M2 (PKM2), which is involved in regulation of glycolysis, a biochemical process that cells use to break down sugar for energy.

In 2008, Vander Heiden, Cantley, and others at Harvard Medical School reported that when cells shift between normal and Warburg (cancer-associated) metabolism, they start using PKM2 instead of PKM1, the enzyme that adult cells normally use for glycolysis. Cantley and Craig Thompson have since founded a company, Agios Pharmaceuticals, that is developing potential drugs that target PKM2, as well as other molecules involved in cancer metabolism.

While at Harvard, Vander Heiden also worked on a paper that contributed to the eventual development of drugs that target cancer cells with a mutation in the IDH gene. These drugs, the first modern FDA-approved cancer drugs that target metabolism, shut off an alternative pathway used by cancer cells with the IDH mutation.

New drug targets

In 2010, Vander Heiden became one of the first new faculty members hired after the creation of MIT’s Koch Institute, where he set up a lab focused on metabolism, particularly cancer metabolism.

His research has yielded many insights into the abnormal metabolism of cancer cells. In one study, together with other MIT researchers, he found that tumor cells turn on an alternative pathway that allows them to build lipids from the amino acid glutamine instead of the glucose that healthy cells normally use. He also found that altering the behavior of PKM2 to make it act more like PKM1 could stop tumor cell growth.

Studies such as these can offer insights that may help researchers to develop drugs that starve tumor cells of the nutrients they need, offering a new way to fight cancer, Vander Heiden says.

“If one wants to develop drugs that target metabolism, one really needs to focus on the context in which it’s happening, which is the environment of the cell plus the genetics of the cell,” he says. “That is what defines the sensitivity to drugs.”

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Oxford researchers are studying metabolic changes in cancer and their relation to the tumour microenvironment to understand the impact on cancer cell growth and help develop new therapies.

Researchers are investigating a number of areas including metabolic reprogramming of cancer cells in response to environmental stress, cellular mechanisms involved in amino acid update and the effect of nutrient starvation on tumour growth and invasion. They are also exploring how drugs that target metabolic pathways, such as metformin, might be used therapeutically. Researchers use a range of experimental approaches and also clinical trials for these studies. In some cases, they are applying computational approaches to exploring global changes in metabolic pathways across tumour samples.

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Rare, deadly liver cancer rewires cell metabolism to grow

By krishna ramanujan, cornell chronicle.

A deadly liver cancer that mainly affects children and young adults rewires its cellular metabolism in order to thrive, according to a new study that opens the door to exploring new targets for therapies.

Fibrolamellar carcinoma, which does not respond to conventional treatments,  accounts for only 1-2% of all liver cancers, but is without standard of care and has often metastasized by the time it is detected, leaving patients with approximately a year to live on average.

While many cancers prefer glucose to promote their survival, some show dependence on other nutrients. Fibrolamellar carcinoma depends on glutamine for energy production, and also seems to place a strong emphasis on serine utilization for this purpose as well, according to the study. 

“There appears to be with this cancer an impairment in metabolizing sugar and it actually seems to be very keen on amino acids, which is something that deviates from the norm in terms of what the general public typically think about cancer,” said Donald Long Jr., the study’s lead author, Howard Hughes Medical Institute Gilliam Fellow, and a doctoral candidate in the lab of senior author Praveen Sethupathy ’03, professor of physiological genomics and chair of the Department of Biomedical Sciences in the College of Veterinary Medicine.

The paper, “ Proteo-metabolomics and Patient Tumor Slice Experiments Point to Amino Acid Centrality for Rewired Mitochondria in Fibrolamellar Carcinoma ,” published Aug. 28 in the journal Cell Reports Medicine.  

“Our findings point to specific features of the cancer that represent therapeutic vulnerabilities, and could be very useful for testing specific drug combinations,” Sethupathy said. 

In the study, the researchers used proteomics (to determine the spectrum of proteins in the cancer cells) and metabolomics (the spectrum of metabolites) and identified more than 8,000 proteins and 135 metabolites. They obtained frozen patient tissue samples from the Fibrolamellar Cancer Foundation Biobank and developed a predictive model based on the omics data that was generated in collaboration with co-author Lukas Orre, an associate professor at the Karolinska Institute in Sweden. Several key aspects of the model were experimentally validated via functional studies using fresh tumor tissue slices directly from patients, in collaboration with co-author Taranjit Gujral, an associate professor at the Fred Hutchinson Cancer Center. 

Under normal circumstances, the glycolytic pathway breaks down glucose to form a metabolite called pyruvate, which then enters the mitochondria (the cell’s powerhouse) and is used to produce ATP, a small molecule that stores chemical energy used to power the cell’s biochemical reactions.

“We saw from our analysis of the proteomic and metabolomic data, and additional experiments in a cell model of fibrolamellar carcinoma, that this pathway was impaired,” Long said.

The researchers then identified a liver-specific protein, called serine dehydratase, as the 10th-most upregulated protein in the proteomics dataset. This enzyme can convert the amino acid serine into pyruvate. The pyruvate then follows the usual path into the mitochondria to produce ATP. In tests using the fresh patient cancer tissue slices, the researchers inhibited serine dehydratase and found the cancer tissues became much less viable. A drug that blocks pyruvate entry into the mitochondria also dramatically affected the survival of the fibrolamellar cancer tissues.

The researchers also predict another use of pyruvate, where the metabolite is also employed in the production of proline. Proline is a non-essential amino acid that is integral to making collagen, the primary building block of connective tissue.

One of the hallmarks of fibrolamellar carcinoma is that its tumors have fibrous bands of collagen running through them.

“It looks like, potentially, the mitochondria is being rewired to produce copious amounts of proline, presumably to integrate into this collagen matrix that promotes the tumor’s growth,” Long said.

Co-authors also included Rosanna Ma and Adam Francisco in the Sethupathy lab; Nathaniel Vacanti , assistant professor, Joeva Barrow , assistant professor, and Pei-Yin Tsai, a doctoral student, all in the Division of Nutritional Sciences in the College of Human Ecology; and researchers from UCLA, the Johns Hopkins University School of Medicine and Rutgers University.

The study was funded by the National Science Foundation, the Howard Hughes Medical Institute and the Fibrolamellar Cancer Foundation.

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Cancer as a Metabolic Disorder

Jones gyamfi.

1 Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Veritas Hall D 306, 85 Songdogwahak-ro, Incheon 21983, Korea; [email protected] (J.G.); moc.liamg@33606lalw (J.K.)

2 Department of Medical Laboratory Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana

Jinyoung Kim

Junjeong choi.

Cancer has long been considered a genetic disease characterized by a myriad of mutations that drive cancer progression. Recent accumulating evidence indicates that the dysregulated metabolism in cancer cells is more than a hallmark of cancer but may be the underlying cause of the tumor. Most of the well-characterized oncogenes or tumor suppressor genes function to sustain the altered metabolic state in cancer. Here, we review evidence supporting the altered metabolic state in cancer including key alterations in glucose, glutamine, and fatty acid metabolism. Unlike genetic alterations that do not occur in all cancer types, metabolic alterations are more common among cancer subtypes and across cancers. Recognizing cancer as a metabolic disorder could unravel key diagnostic and treatments markers that can impact approaches used in cancer management.

1. Introduction

Despite the progress made in our understanding of cancer, cancer burden has continuously increased. Data from the World Health Organization (WHO) in 2018 indicated that globally, 18.1 million new cases were recorded with 9.6 million cancer deaths [ 1 , 2 ]. In several high-income countries (HICs), cancers have overtaken cardiovascular diseases as the leading cause of death, accounting for twice as many deaths as cardiovascular diseases [ 1 , 2 ]. Our deepening understanding of cancer only seems to reveal the complexity of the disease. The development of cancer involves a multi-step process, evolving from an in situ state and ultimately resulting in a malignant tumor [ 3 ]. The invasion and metastasis of cancer cells to nearby or distant organs accounts mostly for all cancer-related morbidity and mortality [ 4 ]. Advances in molecular and cell biology techniques have helped unravel key aspects of how neoplastic cells progress through carcinogenesis and acquire their metastatic ability. However, several questions pertaining to carcinogenesis, and metastasis remain unanswered. These insights into the biology of cancer have not translated into effective treatments or even effective long-term management. To date, management of metastatic cancers remain a major challenge as it was 40 years ago [ 4 ]. Statistics from the American Cancer Society indicate that 569,490 people died of cancer in the United States in 2010; similarly, in 2002 cancer deaths were estimated to be 555,500 and in 2020 606,520 deaths [ 5 ]. These statistics are alarming and indicate the slow pace of progress in cancer management.

The emergence of immunotherapy has opened a new avenue of treatment and offered an opportunity to reduce cancer deaths. However, the long-standing challenges that faced targeted therapy (i.e., resistance and disease relapse) similarly pose a challenge to immunotherapy [ 6 , 7 ]. The explosion in whole genome or exome sequencing of cancer has enhanced our knowledge of genomic changes that occur in cancer but has not translated into the identification of effective targets for therapy. If anything, the advancement of cancer sequencing has compounded the complexity of cancer. Several mutations and genomic alterations are highlighted daily and touted as potential targets for therapy, but targets highlighted from these studies as breakthroughs have not led to transformative therapeutic options. The slow rate of progress in cancer treatment raises great concerns particularly with the significant investment made into research. The major success in several cancers is attributed to improved diagnosis at an early stage, occasioned by enhanced awareness of contributing factors and avoidance of major risk factors [ 4 , 8 ]. These factors are in no way linked to advances in systemic metastasis management [ 4 ].

Our progress and approach to cancer management over the years is based strongly on the theory that cancer is a genetic disease, characterized by a sequence of mutations and genomic alterations in cells leading to the acquisition of the cancer phenotype. This theory serves as the basis for the cancer genomic sequencing era. With the promise that the identification of mutations and genetic alterations common to cancers will result in the development of new drugs. However, it is fair to say that this promise has not fully materialized. The recent success of immunotherapy was not steered by the genetic theory of cancer. Thus, it is time that other theories about the origin and basis of cancer development be given much attention. The theory that cancer may be a metabolic disease has lingered for years, and recent evidence provides strong support for this theory. In this review, we seek to provide information on scientific evidence supporting the metabolic theory of cancer, challenges of the theory, and opportunities associated with this theory even in an era of cancer immunotherapy.

2. Cancer as a Genetic Disease

Over the years various models have been suggested to explain the complexity of cancer. In the landmark paper by Hanahan and Weinberg, the authors highlighted key features characterizing cancers that have widely been accepted [ 9 , 10 ]. Their model offered strong support for the genetic basis of cancer—the idea that cancer is a disease caused by the accumulation of mutations, epigenetic changes, and genetic alterations in key genes that regulate cell replication, cell division, cell metabolism, and cell growth. These genes are classified as oncogenes and tumor suppressors based on their effect following mutation. The genetic model for cancer development, although not complete, has offered key insights into the genetic events governing cancer initiation, progression, metastasis, response to therapy, and the development of drug resistance [ 9 , 10 , 11 ]. Support for this theory is widespread, with mutation in certain genes identified in a wide range of tumor types. The era of sequencing has resulted in a catalogue of the various genes mutated in cancers. Presently, over 1000 genes have been linked to cancer and are classified as cancer-associated genes (~250 oncogenes, ~700 tumor suppressors) [ 12 ]. The Knudson’s “two-hit” hypothesis postulates that both alleles of a tumor suppressor gene require genetic silencing to cause phenotypic change. Thus, applying the Knudson’s hypothesis to the identified cancer-associated genes translate to over a million potential cancer genotypes [ 12 , 13 ]. How does one disease possibly translate to a million genotypes? How do we successfully manage or treat a million different diseases? This has been a major drawback for the genomic theory of cancer.

The advancement of genomic sequencing has generated enormous genetic data that have further compounded this dilemma. These comprehensive genomic sequence studies in approximately 1 million tumor samples have identified more than 2 million coding point mutations, >6 million noncoding mutations, >10,000 gene fusions, ~61,000 genome rearrangements, ~700,000 abnormal copy number segments, and over 60 million abnormal expression variants [ 12 , 14 ]. In a recent study, whole genome sequencing of tumor samples compared to adjacent normal tissues contained 10,000–50,000 unique single nucleotide variants [ 12 , 15 ]. These studies basically reveal that tumor cells are characterized by millions of genetic alterations. With advancement in sequencing technologies and with the application of single cell sequencing to cancers, our knowledge of the genetic alterations characterizing tumor cells is bound for an explosion. Using these genetic characterizations of tumors to identify targets and develop tumor-specific drugs appears to be a daunting task. Our interest in cancer cannot just be about elucidating the genetic alterations characterizing tumors but should also focus on how these can be translated into effective therapies for cancer management.

The stepwise mutational events governing cancer development are strongly supported in some cancer types than others. Childhood cancers are usually devoid of mutations that characterize adult tumors [ 16 ]. While certain mutations are common across several cancers, others appear exclusive to specific cancer types. These discrepancies in the genetic theory of cancer are yet to be resolved. In colon cancer, the sequential mutational events that characterize its development have been extensively studied. This was demonstrated experimentally using sequential CRISPR/Cas guided knockout of the adenomatous polyposis coli (APC) gene, tumor protein p53 (TP53) gene, Kirsten rat sarcoma virus (KRAS) gene, and SMAD family member 4 (SMAD4) gene in intestinal stem cells resulting in mutant tumors with invasive carcinoma when xeno-transplanted into mice [ 17 ]. Studies like this provide strong evidence that genetic alterations in genes are key drivers of cancer development. However, unlike colon cancer, such sequential genetic events in genes resulting in cancer cannot be shown for other cancer types. Studies looking to characterize the mutational events in cancers usually show a continual increase in the mutational burden of tumors as they progress into advanced form but do not usually identify genes that are exclusively responsible for each step-in tumor progression. How cells with hundreds of mutations and genomic rearrangements survive and obtain an advantage over healthy normal cells is quite unthinkable. In all our understanding of genetics, this concept appears contrary to the expected, as accumulating mutations should disadvantage cancer cells. Unless the resulting mutations are the outcome of an underlying defect.

Another strong piece of evidence of cancer as a genetic disease comes from the presence of mutations in the genome of cancer cells that do not occur in nearby normal tissues. Despite the hallmarks of cancer being shared by all cancers, not a single gene mutation is linked to all cancers. The gene commonly mutated in most types of cancers is the TP53 gene [ 18 , 19 ]. Despite its high frequency, TP53 mutations are not found in every cancer. In several cancers (i.e., ovarian, esophageal, colorectal, head and neck, larynx, and lung cancer) with high rates of p53 mutations, the rate is about 38–50% [ 18 , 19 ]. The mutational rate of p53 is even lower in other cancers (i.e., primary leukemia, sarcoma, testicular cancer, malignant melanoma, and cervical cancer) occurring at a rate of ~5% [ 18 , 19 ]. This demonstrates that no single gene mutation is a feature in all cancers. The genetic theory postulates that alterations in different sets of genes ultimately result in the cancer phenotype. This explanation is not entirely supported by our current understanding of most genetic disorders where mutations in very different set of genes yield the same phenotypic outcome. Could the mutations that occur in cancers be an outcome of a deeper cause and not the main cause of the tumor. Subsequently, targeting and treating these mutations are just a surface approach. If this theory is true, then there would be a need to find the originating events and target that for therapy. This concept is not farfetched, as a recent study detailing the functions of commonly identified tumor suppressors and oncogenes linked their function to key roles in cellular metabolism [ 20 ]. The unlimited mutations in cancer-associated genes affect three main metabolic pathways: the aerobic glycolytic pathway, the glutamine catabolic pathway, and one-carbon metabolism [ 21 ]. These genetic alterations create an altered metabolic state allowing cancer cells to generate the large quantities of macromolecules (amino acids, nucleotides, and fatty acids) and metabolic intermediates required to fuel rapid cell growth and division [ 21 ]. Thus, could cancer be essentially a metabolic disease?

3. Cancer as a Metabolic Disorder

In 1927, Otto Warburg reported that cancer cells manifest a unique metabolic phenotype, characterized by enhanced consumption of glucose compared to normal cells. This phenomenon has become known as the “Warburg effect” [ 21 ]. Warburg’s observations led to the notion that cancer was a metabolic disease, an idea that was widely supported until the 1970s when the concept of cancer as a genetic disorder emerged [ 22 ]. Recently, the idea of cancer as a metabolic disorder has re-emerged and drawn much attention. Ironically, this growth is supported by enhanced sequencing technologies coupled with increased genetic data and an increased accessibility to metabolomics. The progress in these areas have led to the discovery of oncometabolites; endogenous cellular metabolites that accumulate in tumors sustaining tumor growth and metastasis. The discovery of 2-hydroxyglutarate as an oncometabolite in high concentrations in gliomas led to the discoveries of many other oncometabolites in different cancers [ 23 , 24 ]. The oncometabolite 2-hydroxyglutarate functionally modifies histone methylation patterns, alters differential gene expression, and results in carcinogenesis [ 25 ]. Among the recently characterized oncometabolites are fumarate in renal cell carcinoma; sarcosine in prostate cancer; glycine in breast cancer; asparagine in leukemia; choline in prostate, brain, and breast cancer; lactate, glucose, glutamine, and serine in several cancers [ 26 , 27 ]. The increase and accumulation of oncometabolites in cancer is linked to its need to sustain aerobic glycolysis, glutaminolysis, or one-carbon metabolism [ 26 , 27 ]. The discovery of oncometabolites provides evidence for the metabolic state in cancer, linking the emergence of cancer to disturbances in energy production.

Earlier, support for cancer as a metabolic disorder, proposed that cancer arose from defects in energy production through oxidative phosphorylation (OxPhos) in the mitochondria [ 3 ]. OxPhos generates most of the energy needed by cells; hence, any defect in the number, structure, and function of mitochondria will alter the energy production in cells [ 3 ]. Gradually, this defective energy production results in the replacement of insufficient respiration with fermentation for energy production, resulting in the activation of pathways that results in neoplasia [ 3 , 4 ], hence, aerobic fermentation of lactic acid (Warburg effect) being the most common pathological phenotype of cancers. Recent evidence also indicates that tumor cells can use mitochondrial substrate-level phosphorylation as another fermentation pathway to compensate for defective respiration [ 3 , 4 ]. Mitochondrial substrate-level phosphorylation provides evidence previously missing in Warburg’s theory [ 3 , 4 ]. Defective OxPhos with a compensatory reliance on fermentation for energy produces reactive oxygen species (ROS) that are both mutagenic and carcinogenic [ 3 , 4 ]. Thus, according to the metabolic theory of cancer, the somatic mutations and all other hallmarks of cancer are downstream epiphenomenon occurring from the initial disturbances of cellular energy metabolism [ 3 , 4 ].

A well-known feature of almost all cancers is their high uptake of 2-deoxy-2(18F)-fluoro-D-glucose [ 28 , 29 ]. A feature that is exploited for diagnosis of cancer by positron emission tomography (PET) scans and clearly a metabolic feature. This technique relies on the enhanced dependence of cancer cells on glucose and glutamine for diagnosis, and clearly indicates that both early- and late-stage cancers are characterized by this metabolic feature. This feature is not limited to only a subset of cancer but occurs in almost all cancer types irrespective of the accompanying genetic changes. This feature offers a key insight into cancers: that looking for distinct metabolic events could be useful in cancer diagnosis. Several key metabolites identified in cancers (e.g., acetate, lactate, serine, sarcosine, asparagine, or choline) can be screened in blood, saliva, breath, or urine [ 12 ]. Recent studies of metabolites in colonic polyps and early-stage pancreatic cancer demonstrate the potential role of metabolites as biomarkers [ 30 , 31 ]. Ironically, although cancer has been deemed a genetic disease for decades and genetic alterations have continuously been highlighted in cancers, no definitive genetic screening is available for cancer. It is astonishing that not a single gene is known that has mutated across all cancers, yet cancer is considered a genetic disease; however, a metabolic feature observed in >90% of cancers is still overlooked. Metabolite screening holds great potential for future early diagnosis and pre-cancer screening and would be fast and cost-efficient. This clearly reveals the metabolic nature of cancers and provides credence for the metabolic basis of cancer. As indicated earlier, much of the success in cancer management comes from early cancer detection and cancer metabolite screening would be valuable in this aspect.

More evidence of cancer as a metabolic disorder comes from nuclear-cytoplasm transfer studies ( Figure 1 ). These experiments involve the replacement of damaged mitochondria with normal mitochondrion or the replacement of the nucleus of a cancerous cell with a normal nucleus with the aim of determining if a damaged mitochondria or damaged nuclear serves as the origin of cancer. If cancer originates from a damaged nucleus, its replacement with a healthy nucleus should suppress tumor growth. However, if cancer originates from dysregulated metabolism originating from mitochondria dysfunction, its substitution with a normal mitochondrion should prevent cancer ( Figure 1 ) [ 3 , 4 ]. These experiments involve the use of cybrids, cells generated when cytoplasm from enucleated normal cells is fused with nucleated tumor cells. The generated cybrids thus have a single nucleus but a blended cytoplasm from different cells. Cybrid studies conducted by Koura et al. involved the fusion of whole cancerous B16 mouse melanoma cells and enucleated non-cancerous rat myoblasts [ 3 , 4 ]. The generated cybrids contain healthy mitochondrion from normal cells but damaged nucleus from cancer cells. Interestingly, the reconstituted cybrids evolved distinct morphology and cellular arrangements [ 3 , 4 ]. In the isolated reconstituted clones, tumorigenicity was repressed ( Figure 1 ). After prolonged cultivation of these reconstituted clones, tumorigenicity remerged in some clones [ 3 , 4 ]. These studies provide concrete evidence to support the potential role of normal mitochondria in repressing the malignant phenotype of cancer cells. Other evidence in support of cybrid experiments were provided by Israel and Schaeffer. They demonstrated that nuclear/cytoplasmic hybrids generated from cytoplasts (nucleus absent) malignant cells with nucleus present normal cells produced tumors in 97% of the animals injected [ 3 , 4 ]. Several nuclear–cytoplasmic transfer studies like these provide evidence for the metabolic basis of cancer. These experiments performed in various model systems from studies in rho (ρ) cells (cells depleted of mitochondrial DNA), Lucke frog renal cell tumors, mouse medulloblastoma, and early mouse embryo show that respiratory competent normal mitochondria could suppress tumorigenicity but normal nucleus is incapable of tumor suppression ( Figure 1 ) [ 3 , 4 ].

Nuclear–cytoplasmic studies (modified from the nucleus and mitochondria in the origin of tumors as previously described by Seyfried, 2012d; Seyfried et al., 2014). These studies involved the replacement of damaged mitochondria with normal mitochondria or the replacement of the nucleus of a cancerous cell with a normal cell nucleus. If cancer originates from a damaged nucleus, replacement with a healthy nucleus should suppress tumor growth. However, if cancer originates from dysregulated metabolism originating from mitochondria dysfunction, its substitution with a normal mitochondrion should suppress cancer. Exchange of the nucleus of a cancerous cell (shown in blue) with a normal cell nucleus (shown in red) generates a cybrid that generates cancerous cells despite the absence of tumor-associated genomic abnormalities. The exchange of the nucleus of a normal cell (shown in red) with a cancerous cell nucleus (shown in blue) generates normal cells with distinct morphology despite the presence of tumor-associated genomic abnormalities. Figure created using BioRender.

Probably, the most compelling evidence from cybrids comes from experiments by Jonasson and Harris conducted in human–mouse hybrids [ 30 , 31 ]. Using hybrid clones generated from fusions of diploid human fibroblasts and lymphocytes with the cells of a malignant mouse melanoma, they demonstrated that human diploid cells were as effective as mouse diploid cells in suppressing the malignancy in vivo, indicating clearly that human nuclear genetic materials are not liable for cancer repression [ 3 , 30 , 31 ]. To validate their findings, human fibroblast cells were irradiated before fusion with melanoma cells [ 3 , 30 , 31 ]. The generated hybrids led to substantially higher tumor incidence, indicating that repression of tumor formation likely depended on the function of a radiosensitive extrachromosomal element ( Figure 1 ) [ 3 , 30 , 31 ]. Their findings are remarkable for several reasons, firstly, it indicated that something in normal cytoplasm was responsible for tumor suppression in malignant cells. Secondly, the suppression of tumors was not dependent on human chromosome or nuclear genetic material. Finally, the cytoplasm factor was sensitive to radiation, capable of being destroyed by irradiation leading to the loss of tumor suppression. The ability of radiation to destroy this cytoplasmic factor is consistent with earlier findings by Warburg that radiation destroys mitochondrial respiration. These studies remarkably indicate that the differentiated state of cells is maintained by normal mitochondrial function thereby repressing carcinogenesis. However, damaged/dysfunctional mitochondria enhance dedifferentiation and promote carcinogenesis. Hence, the origin of carcinogenesis depended on the mitochondria health and not on the genetic material in the cell’s nucleus [ 3 , 4 ]. Which begs the question: why is the genetic theory of cancer the predominant theory? These studies highlight the role of the mitochondria and cellular metabolism in carcinogenesis and the need to explore the role of dysregulated metabolism in carcinogenesis. The metabolic theory of cancer is fast gaining roots in the field of cancer studies and generating much excitement. It is evidently clear that the genetic theory generates more complexity for our understanding of cancer, while the metabolic theory of cancer is incredibly simple and holds great promise for cancer diagnosis and treatment.

4. Glucose Metabolism in Cancer

Cancer cells have a heightened macromolecule demand to sustain their enhanced proliferation state; thus, there is an increased demand for macromolecule synthesis or importation. In this heightened energy state, cancer cells rely on enhanced glycolysis to generate ATP with the production of lactate irrespective of oxygen availability [ 32 , 33 ]. The Warburg effect is established as a prominent feature of rapidly growing tumor cells and observed in various cancer types irrespective of their tissue of origin [ 32 , 33 ]. This feature has driven much of the conflict in the origin of cancer, i.e., as to whether cancer is a genetic or metabolic disorder. It raises the question of whether the increased reliance on glycolysis is due to the fact of mitochondria dysfunction or occurs following genetic alterations to sustain the proliferative state of cancer cells with healthy mitochondria.

The reliance on glycolysis to meet ATP needs is a highly inefficient process generating only two molecules of ATP compared to OxPhos, which generates 34 molecules of ATP per complete oxidation of glucose [ 33 ]. Rapidly proliferating cells demand lots of ATP molecules, hence why the use of glycolysis in cancer for energy production seems highly inefficient and raises the question of why it is a basic feature of cancer cells. To explain this observation in cancer cells, Warburg hypothesized that the increased dependence on glycolysis stems from a dysfunctional mitochondrion in cancer cells [ 3 , 4 ]. Recent research provides evidence of enhanced glycolysis in cancer cells with functional mitochondria [ 34 , 35 ]. These findings indicate that the enhanced reliance on glycolysis may serve other functions, for example, generating glycolytic intermediates that are essential precursors for various anabolic pathways, ribose-6-phosphate, and biomolecules required by cancer cells [ 36 ]. For cancer to be considered a metabolic disease, dysregulated metabolism occurring from damaged or insufficient respiration should be present. Without even completely resolving this puzzle, what is evidently clear is that dysregulated metabolism is a key characteristic of all cancer types. Hence, what remains to be answered is whether genetic alternation results in the altered metabolism in cancer or a dysregulated metabolism gives rise to the genetic alteration seen in cancer [ 37 ]. The cancer as a metabolic disease supports the later; thus, cancer occurs from dysregulated metabolism. The theory postulates that the metabolic dysregulation of cancer cells leads to upregulation or suppression of genes regulating metabolism in order to remain viable and proliferate [ 37 ].

5. Glucose Metabolic Reprogramming in Cancer Cells

The most dysregulated metabolic pathway in cancer is the glucose metabolism pathway ( Figure 2 ). Glucose metabolic reprogramming occurs across cancer types; however, the specific mechanisms involved in glucose metabolic reprogramming differ among cancer types and even within cancers of the same origin. Central to glucose metabolic reprogramming are changes in the expression of enzymes involved in glucose metabolism ( Figure 2 ) [ 38 ]. For a growing tumor, oxygen and nutrient supply is a challenge owing to the tortuous nature of the blood vessels formed in the tumor; the limited supply of oxygen creates a hypoxic environment. Cancer cells subsequently induce the expression of hypoxia-inducible factor 1 and 2 (HIF-1 and HIF-2), transcription factors that regulate the expression of genes during hypoxic conditions [ 39 , 40 ]. Under normoxia, HIF-1α is degraded following oxygen-dependent hydroxylation by prolyl hydroxylase 2 (PHD2) and their recognition by von Hippel–Lindau tumor suppressor (VHL) [ 39 , 40 ]. In hypoxia, VHL-mediated degradation of HIF-1α does not occur, allowing them to accumulate and dimerize with HIF-1β and localize in the nucleus. In the nucleus, HIF-1 dimers regulate the expression of target genes by binding to the hypoxia response element (HRE) sequence of target genes [ 39 , 40 ]. The chronic hypoxic environment in many cancers means HIF-1 becomes constitutively activated to regulate the expression of glycolytic enzymes. Increased HIF-1 expression increases the expression of glucose transporters GLUT1 and GLUT3, enhancing glucose uptake, hexokinase 2 (HK2) to phosphorylate, and commits glucose to the glycolytic pathway ( Figure 2 ) [ 39 , 40 ]. This enhanced glycolytic phenotype of cancers enhances cancer cell migration and invasion, induces angiogenesis, and influences therapeutic response.

Mechanisms of glucose metabolic reprogramming in cancer. Hypoxia drives metabolic reprogramming in cancer cells. Increased expression of HIF transcription factors activates oncogenes (i.e., Ras, PI3K-Akt, and c-Myc) or inactivates tumor suppressors (p53 and PTEN) to sustain the glycolytic phenotype of cancer cells. Inactivation of the tumor suppressor gene TP53 is a common feature in cancers and contributes to the enhanced dependence on glycolysis. Inactivation of p53 releases repression of glucose transporters (e.g., GLUT1 and GLUT4) and decreases the expression of TIGAR, a glycolytic inhibitor. Activation of growth factor receptors activate the oncogenic PI3K/Akt pathway and activates downstream targets (FOXOs, HIF1a, c-Myc, and SREBP) that contribute to glucose metabolic reprogramming in cancer cells. Figure created using BioRender.

Oncoproteins that commonly mutate or genetically alter in cancer cells, including the oncogenic KRAS, oncogenic BRAF, and activated PI3K/AKT, have been shown to result in glucose metabolic reprogramming in cancer cells ( Figure 2 ) [ 41 ]. The PI3K/Akt signaling pathway is a convergence point for several tyrosine kinase receptors activated in cancer. The PI3K/Akt pathway is a master regulator of glucose uptake. Activated PI3K/Akt increases the expression of GLUT1 and its translocation to the cell surface [ 41 , 42 ]. Akt also potentiates the activity of the hexokinase which phosphorylate glucose and prevent their efflux from cells. Downstream of the PI3K/Akt pathway is the transcription factor c-Myc. The c-Myc transcription factor (the master transcriptional regulator of metabolism) is overexpressed in ~70% of human tumors. C-Myc dimerizes with c-Myc-associated protein X (Max) to form a heterodimer that transcriptionally regulates the activity of genes that regulate apoptosis, cell growth, and metabolism [ 33 , 43 ]. In contrast to normal cells, where c-Myc expression is induced by growth factor stimulation, c-Myc expression is constitutively activated in cancer cells [ 33 , 43 ]. This increased c-Myc expression promotes energy production and biomolecule synthesis (key requirements in rapidly proliferating cells) by activating target genes involved in glucose transport (GLUT1) and lactate efflux (MCT1) ( Figure 2 ) [ 33 ]. Enhanced glycolytic pathways and MYC expression generate glycolytic intermediates that are utilized in other metabolic pathways. Interestingly, HIF proteins can also collaborate with c-Myc to enhance the metabolic advantages of cancer cells. Specifically, HIF-2α stabilizes the c-Myc–Max complex and potentiates their transcriptional regulation of target genes [ 33 ]. Alternatively, in normal cells, HIF-1α acts opposite to HIF-2α by binding to Max, and HIF-1α renders c-Myc inactive. In cancers where c-Myc is overexpressed, its activity is not affected by HIF-1α. The increased expression of c-Myc stabilizes the c-Myc–Max heterodimers and reprograms cancer cell metabolism, protein synthesis, and cell cycle progression [ 33 ].

In the year 1993, the transcription factor p53 was touted as the molecule of the year by Science Magazine . It was regarded as a key molecule in cancer, and scientists hoped this discovery would open an avenue for cancer cure [ 44 , 45 ]. However, this hope has not directly translated into a treatment option. Regarded as a tumor suppressor, p53 is best known for its function in DNA damage response and apoptosis. Recently, important roles of p53 in regulating glycolysis and oxidative phosphorylation have been reported. Functional p53 decreases the glycolytic rate by inhibiting the expression of glucose transporters (i.e., GLUT1 and GLUT4) and decreasing the levels of phosphoglycerate mutase, the enzyme responsible for converting 3-phosphoglycerate to 2-phophoglycerate in glycolysis ( Figure 2 ) [ 33 ]. Wild-type p53 regulates the expression of the tumor suppressor, phosphate and tensin homolog (PTEN), that inhibits the PI3K pathway [ 33 ]. Inhibition of PI3K leads to decreased activation of Akt1 and HIF proteins, which are essential drivers of glycolysis ( Figure 2 ) [ 33 ]. The high frequency of p53 mutation in cancers means it controls metabolic regulation and glycolysis is lost. Cancer cells with mutant p53 have increased expression of glucose transporters, glycolytic enzymes, and activation of AKT and HIF.

Taken together, these findings reveal that multiple growth signaling nodes and key oncogenes identified through genetic studies of cancers remotely facilitate cancer cells’ cellular responses to regulating glucose metabolism. The glucose metabolic reprogramming occurring in cancer cells includes increased expression and translocation to the plasma membrane of GLUT1 and other glucose transporters and increased expression of enzymes involved in glycolysis [ 41 ]. This metabolic reprogramming is orchestrated by multiple mechanisms involving oncoproteins and oncogenic transcription factors.

6. Glutamine Metabolic Reprogramming in Cancer

Along with glucose metabolic reprogramming, cancer cells exhibit a substantial metabolic flexibility including an altered amino acid metabolism. A common metabolic feature in cancer cells is the increased levels of glutamine metabolism commonly referred to as “glutamine addiction” [ 32 , 46 ]. Glutamine addiction refers to the enhanced dependence on glutamine as a catabolic and anaplerotic substrate. The increased demand for glutamine is utilized in cancer cell metabolism. Its precursor, glutamic acid or its salt glutamate, regulate signaling pathways, proliferation, and metastasis in cancer cells [ 47 ]. Glutamine is an important nutrient in oxidative metabolism, ATP generation, biosynthesis of biomolecules, redox homeostasis, and the regulation of signal transduction. Glutamine is an anaplerotic substrate for the TCA cycle, generating metabolic intermediates [ 47 , 48 ]. Glutamine is utilized for energy generation and generates carbon and nitrogen for biomass accumulation in rapidly proliferating cells such as cancer cells, lymphocytes, and enterocytes of the small intestine [ 33 , 46 ].

In cancer cells, the increased demand for glutamine is achieved through membrane transporters. Glutamine is imported into cells by membrane glutamine transporters, including SLC1A5 (also known as ASCT2), SLC7A5, SLC38A1, and SLC38A217, with SLC1A5 being the most studied [ 46 , 49 , 50 ]. Imported glutamine can be utilized for biosynthesis of nucleotides, NADPH, and antioxidant. The first step of glutamine utilization is its conversion to ammonium ion and glutamate by cytoplasmic/mitochondrial glutaminases (GLS) [ 51 ]. The mitochondrial enzyme glutamate dehydrogenase (GLDH; encoded by the highly conserved and more broadly expressed GLUD1 or the hominoid-specific GLUD2, collectively termed GLUD) convert glutamate to α-ketoglutarate. Alternatively, glutamate conversion to α-ketoglutarate can be achieved through several non-ammonia-producing aminotransferases [ 46 ]. The α-ketoglutarate produced from this process enters the TCA cycle to generate ATP through the production of reduced molecules NADH and FADH 2 [ 48 ]. In glucose scarce periods, cells utilize glutamate dehydrogenase (GDH) to produce α-KG without requiring an amino acceptor. This means in periods of glucose abundance, glutamate dehydrogenase is dispensable; however, in periods of glucose deprivation glutamate dehydrogenase is required for cell survival [ 48 , 52 ]. The reliance of cancer cells on glucose and glutamine allows them to meet their metabolic needs and maintain a steady supply of carbon-skeleton molecules or metabolic intermediates that can be utilized for anaplerosis to generate macromolecules to meet their cellular demands.

7. Mechanisms of Glutamine Metabolic Reprogramming

The high demand for amino acids by tumor cells requires a steady upregulation of selective amino acid transporters. Different tumor types rely on different amino acid transporters to support their growth. Compared to normal tissues, the expression of amino acid transporters is elevated in various tumors. SLC7A5 is an obligatory exchanger that couples the influx of one amino acid substrate into cells with the mandatory efflux of another amino acid substrate ( Figure 3 ) [ 38 , 53 ]. Increased SLC7A5 expression has been reported in many cancer types including triple-negative breast cancer, colon cancer, lung cancer, glioblastoma, and prostate cancer. The main function is to maintain amino acid supply to cancer cells [ 38 , 53 ]. Clearly, the regulation of SLC1A5 expression is an essential activity in cancer cells. Much of this regulation is reported to occur at the transcriptional level. The elevation of HIF transcription factors in the tumor hypoxic environment does not only alter the cellular glucose metabolism. Hypoxia-induced expression of HIF-2α upregulates SLC7A5 expression, allowing for increased importation of glutamine to support the tumor metabolic needs [ 52 , 54 , 55 ]. In addition, under hypoxic conditions, GLS1 expression is transcriptionally upregulated in an HIF-1α-dependent manner. Hypoxic cancer cells reprogram glutamine metabolism from glutamine oxidative metabolism towards reductive carboxylation utilizing glutamine to generate citrate to sustain proliferation [ 55 , 56 ].

Glutamine import occurs through glutamine transporters and is utilized in various anabolic pathways such as nucleotides, lipid synthesis, and amino acid synthesis. Cancer cells exhibit a dependence on glutamine (i.e., glutamine addiction), and glutamine catabolism in the mitochondria generates metabolic intermediates to sustain cancer cell biomass. The dependence of cancer cells on glutamine is sustained by alterations in oncogenes and tumor suppressors. Expression of the glutamine transporter SLC1A5 is increased in various cancers to enhance their dependence on glutamine. Activation of the oncogenes KRAS and c-Myc further enhances SLC1A5 expression. The oncogene c-Myc indirectly regulates glutaminolysis through inhibition of miR23a/b, a microRNA involved in regulating GLS1/2 expression. The tumor suppressor p53 upregulates GLS2 expression and enhances glutaminolysis. Glutamine activates the mammalian target of rapamycin complex 1 (mTORC1), which functions to support cancer cell growth. Figure created using BioRender.

The promoter region of SLC7A5 also contains the canonical binding sites for c-Myc, hence the increased expression of c-Myc in cancer that allows for constitutive expression of SLC7A5. C-Myc and n-Myc control of SLC7A5 expression has been demonstrated in glioblastoma and neuroblastoma, respectively. C-Myc and n-Myc activation induces SLC1A5 expression enhancing glutamine uptake and metabolism. Consensus sequences for c-Myc are found upstream of promoters for different amino acid transporter genes (i.e., ASCT2 (SLC1A5)), allowing c-Myc to directly bind and increase SLC1A5 expression. The increased SLC1A5 expression results in elevated uptake of glutamine and increased catabolic usage. C-Myc is also reported to regulate glutaminase activity. Mitochondrial glutaminase (GLS1) expression is regulated by c-Myc and has gained significant interest in cancer. C-Myc was shown to increase expression of GLS1, enhancing cancer cell proliferation and survival ( Figure 3 ) [ 57 ].

Glutaminases involved in glutamine metabolism have altered expression in cancer. While GLS1 expression is usually upregulated in cancers, GLS2 expression is generally repressed [ 56 ]. Like SLC7A5, the oncogene c-Myc regulates the expression of key enzymes involved in the glutamine catabolic pathway i.e., GLS1, glutamine synthetase (GLUL), GLUD, and aminotransferases ( Figure 3 ) [ 52 , 56 , 58 ]. Unlike the direct regulation of SLC1A5 by c-Myc, c-Myc regulation of GLS1 occurs indirectly through transcriptional repression of miR-23a and miR-23b [ 52 , 56 , 58 ]. MiR-23a and miR-23b are microRNAs known to target the 3’ untranslated regions (UTRs) of GLS1, decreasing expression ( Figure 3 ). Several oncogenic pathways have been implicated in the regulation of GLS activity in a c-Myc dependent manner. The oncogenic transcriptional factor c-JUN is also reported to regulate GLS1 expression [ 52 , 56 , 58 ]. GLS1 is regulated indirectly through the GSK3α/β pathway modulating the protein stability of c-Myc and c-Jun. The mTORC1/S6K1 pathway positively regulates GLS1 through the eIF4B-dependent control of c-Myc translation [ 46 , 56 , 59 ]. Post-transcriptional modification of glutaminase is another common regulatory mechanism. Mutations in oncoprotein genes also affect glutamine dependence in cancers. KRAS mutations are frequent events in cancers and are shown to influence cancer cell metabolism. KRAS diverge glucose from the TCA, enhancing glycolysis and glutamine addiction [ 54 , 58 ]. In KRAS-mutated cells, the NRF2 (nuclear factor erythroid 2-related factor 2) pathway reprograms metabolism toward glutamine dependence ( Figure 3 ) [ 54 , 58 ].

These examples indicate the myriad of ways cancer cell metabolism can be altered to depend on glutamine. These examples are only a fraction of the available data highlighting the enhanced dependence on glutamine in cancer cells. This compounding evidence provides support for the metabolic nature of cancer and that commonly identified mutations alter pathways to sustain the metabolic demand of cancer cells.

8. Fatty Acid Metabolic Reprogramming in Cancer

A less studied aspect of cancer metabolic reprogramming is lipid metabolism. Recently, attention is being drawn to the roles altered lipid metabolism play in cancer growth [ 60 ]. Lipids, also referred to as fats, are building blocks for various classes of lipids comprising triglycerides (TGs), phospholipids, sphingolipids, cholesterol, and cholesterol esters [ 60 ]. Regulation of lipid metabolism is key in cellular function and health, and dysregulated lipid metabolism contributes to metabolic disorders, i.e., cardiovascular diseases, obesity, diabetes and, recently, cancer [ 61 , 62 ]. In cancer cells, the requirements for metabolic intermediates for macromolecule synthesis are high, and lipid metabolism serves as an essential pathway for the supply of metabolites [ 61 , 62 ]. Cancer cells strike a balance between lipid anabolism and catabolism, utilizing corresponding signaling networks to generate molecules for membrane formation, energy storage, signaling molecule production, and ATP generation via fatty acid oxidation (FAO) [ 63 ]. Extensive research into the role of FA in cancer cell metabolism and tumorigenesis has revealed the dependence of cancer cells on de novo biosynthesis and exogenous FA uptake to support their enhanced proliferative state, particularly in periods of metabolic stress. Recent studies are shedding light on their role in cancer cell metastasis and response to therapy.

The initial step in fatty acid metabolism involves the import of fatty acids into cells. Several membrane-associated fatty acid transporters have been identified and characterized: these included CD36/FAT, FABPpm, and FATPs [ 62 , 64 ]. FATPs are integral membrane proteins with six identified isoforms (FATP1–6). The membrane protein CD36/FAT (88 kDa) is another well-characterized fatty acid transporter that play key roles in fatty acid uptake and β-oxidation. The functions of CD36/FAT have also been linked to angiogenesis, inflammation, and lipid metabolism [ 65 , 66 ]. Functionally, CD36 differs from FATPs in that CD36 is shuttled intermittently between intracellular endosomes and the plasma membrane of cells, allowing it to function in fatty acid uptake and β-oxidation regulation [ 65 , 66 ].

Imported fatty acids in the cytosol are activated to fatty acyl-CoA and shuttled to the mitochondria for oxidation. In the mitochondria, β-oxidation catabolizes fatty acids that produce acetyl-CoA, which fuels ketogenesis and the TCA cycle. The generated reduced FADH and NADH are fed into the electron transport chain [ 67 , 68 ].

9. Mechanisms of Fatty Acid Metabolic Reprogramming

A less studied aspect of metabolic reprogramming in cancer cells is their lipid metabolic abnormalities. However, recently, the potential role of altered lipid metabolism in cancer is increasingly being recognized. Deciphering the genetic alterations that characterize fatty acid metabolism has been a daunting task. The number of ways by which fatty acid metabolism can be altered are vast, ranging from upregulation of enzymes that are involved in lipogenesis and upregulation of transporters involved in fatty acid import and enzymes involved in FAO [ 68 , 69 ].

The first level of alteration pertaining to fatty acid metabolism in cancer relates to de novo lipogenesis. In various cancers, key regulators of lipogenesis are significantly upregulated including transcription factors. The sterol regulatory element-binding proteins (SREBPs), acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and stearoyl-CoA desaturase 1 (SCD1), are among the most reported alterations linked to fatty acid lipogenesis ( Figure 4 ) [ 68 , 69 ]. The increased de novo lipogenesis in cancer cells were demonstrated several years ago when Medes and colleagues demonstrated that cancer tissues relied on de novo lipogenesis to generate fatty acids and phospholipids at levels similar to liver tissues [ 70 , 71 ]. They also noted that exogenous import of lipids occurred in tumor tissues; however, de novo lipogenesis supplied the bulk of lipids required for tumor growth [ 70 , 71 ].

Mechanisms of fatty acid metabolic reprogramming. De novo lipogenesis and exogenous uptake of fatty acid both occur to sustain the altered lipid metabolism in cancer cells. The transporters CD36, FATPs, and FABPpm regulate exogenous fatty acid import. Increased CD36 and FATP expression is reported in various cancers. The oncogenic PI3K/Akt pathway is activated to regulate fatty acid metabolism. Activation of SREBPs is key in de novo lipogenesis and catabolism of imported fatty acids. MCT, monocarboxylate transporter; CD36, cluster of differentiation 36; FAs, fatty acids; FATPs, fatty acid transport proteins; FABPpm, fatty acid-binding protein; ACLY, ATP–citrate lyase; ACSS2, acyl-CoA synthetase short-chain family member 2; ACC, acetyl-CoA carboxylase; FASN, fatty acid synthase; SREBPs, sterol regulatory element-binding proteins. Figure created using BioRender.

SREBP expression is regulated by intracellular sterol concentrations. In periods of low sterol concentrations, SREBP/SCAP complex translocate to the Golgi complex, and it is cleaved by the membrane-bound proteases (i.e., MBTPS1 and MBTPS2) releasing the transcriptionally active fragment [ 72 , 73 ]. The active fragment containing the DNA-binding and transcriptional activation domains translocate into the nucleus and binds to the sterol-regulatory elements within the promoter of target genes to regulate their activity [ 72 , 73 ]. SREBPs are downstream targets of growth factor signaling pathways that sense and respond to nutrient and cellular energy status [ 74 ]. In several cancers, including breast, ovarian, and prostate, dysregulated SREBP activation and expression of target genes have been reported. Activation of the PI3K/Akt pathway in response to growth factor signaling activates SREBPs and its target genes responsible for cholesterol and FA biosynthesis ( Figure 4 ) [ 74 ]. SREBP activity is also regulated by AMP-regulated protein kinase (AMPK) regarded as the central sensor of cellular energy. Phosphorylation of SREBP by AMPK inhibits its proteolytic cleavage and activation [ 74 ].

Changes in SREBP expression during cancer progression occur with changes in the expression of SREBP-regulated target genes [ 75 , 76 , 77 , 78 ]. SREBP1 promotes cancer cell proliferation, migration, and invasion through transcriptional regulation of androgen receptor (AR) gene expression [ 75 , 76 , 77 , 78 ]. SREBP1 is linked to fatty acid and phospholipid synthesis, whiles SREBP2 is linked to cholesterol synthesis through its regulation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (the rate-limiting enzyme in cholesterol synthesis), mevalonate kinase (MVK), and other key enzymes [ 74 ]. Several key pathways implicated in tumorigenesis, such as the p53 and PI3K/Akt pathways, activate SREBP2 to promote tumorigenesis. SREBP2-mediated tumorigenesis is reported to occur, in part, by SREBP2-mediated mevalonate metabolism activating the EMT program in cancer cells [ 77 , 79 ]. Significant upregulation of SREBP2 has been reported in prostate cancer, breast cancer, and hepatocellular carcinoma and has been touted as a potential target for therapy [ 77 , 78 , 80 ]. Oncogenic PI3K or K-Ras activation of mTORC1 is mediated, in part, through SREBPs, inducing de novo lipogenesis to promote tumor growth and proliferation with increased SREBP-2 expression correlating with poor prognosis in cancer patients ( Figure 4 ) [ 62 , 78 ].

The multifunctional polypeptide, fatty-acid synthase (FASN), catalyzes the last step in de novo biogenesis of fatty acids [ 81 ]. FASN produces saturated fatty acids sequentially by adding seven malonyl-CoA molecules to one acetyl-CoA to form the 16-carbon palmitate [ 82 , 83 ]. FASN has been studied in various cancers, these studies report FASN overexpression correlates with tumor progression [ 81 , 84 , 85 , 86 , 87 ].

A second level of altered lipid metabolism occurring in cancers is related to lipid uptake from exogenous environments. As our understanding of how the tumor microenvironment influences cancer progression deepens, it is becoming clear that cancer cells acquire and accumulate lipids from their microenvironment and utilize them in various processes to drive their progression. Aside from its role in transporting fatty acids into cells, CD36 has been implicated in a myriad of roles that enhance cancer cell growth, metastasis, and EMT ( Figure 4 ) [ 88 , 89 ]. Importantly, CD36 is linked to metabolic crosstalk between cancer cells and their microenvironment and drives the tumor cell’s dependence on exogenous lipids [ 89 , 90 ]. High CD36 expression has been reported in various cancer types and is correlated with poor prognosis in cancers [ 88 , 90 ]. Mechanistically, CD36-dependent lipid uptake is linked to allowing metastatic-initiating cells to acquire lipids from the extracellular environment and utilize them through FAO to generate ATPs and meet their high energy need [ 90 , 91 ].

A second class of exogenous fatty acid importers are the FATPs. FATP transporters are unusual in that they also express intrinsic very long acyl-CoA synthase (ACSs) enzyme activity that allows fatty acids to be activated for α/β-oxidation in the mitochondrial or peroxisomes ( Figure 4 ) [ 92 ]. FATPs are basically involved in the uptake of free fatty acids and esterification of imported fatty acids with CoA to generate acyl-CoA [ 92 ]. Studies into the role of FATPs in cancer are limited with few studies highlighting the role of specific FATPs in cancer [ 93 ]. Overall, FATPs seem to play an important role in lipid uptake and metabolism. The role of FATPs in cancer, particularly in relation to the import of exogenous fatty acid to enhance tumorigenesis, are just beginning to emerge and further research is required.

Intracellular trafficking of fatty acids is another aspect of altered lipid metabolism commonly highlighted in cancer cells. Fatty acid binding proteins (FABPs) are a class of proteins involved in intracellular shuttling of fatty acids chains, bile acids, and retinoids [ 94 ]. The role of FABPs in facilitating intracellular fatty acid transport is known; however, their physiological functions are not fully elucidated [ 94 , 95 ]. FABP5 is the most characterized FABP isoform in cancers. Increased FABP5 expression has been reported in hepatocellular carcinoma, cholangiocarcinoma, and liver, pancreatic, cervical, and breast cancers [ 96 , 97 , 98 , 99 , 100 ]. FABPs are rapidly emerging as essential proteins in fatty acid transport and metabolism in cancer cells. More research is required to understand and fully elucidate the diverse functions of FABPs in tumor cells.

A final step in altered lipid metabolism in cancer relates to alterations that influence lipid catabolism to meet their enhanced energy needs and sustain growth and proliferation. Reprogramming of FA oxidation is a critical feature of cancer cells, and it is the culminating step following the increased de novo lipogenesis and enhanced lipid import from exogenous sources. Lipid metabolism through β-oxidation generates ATP and metabolic intermediates to supplement the metabolic demands of cancer cells. Aside from fatty acid oxidation generating twice as many ATPs compared to carbohydrates, FAO also generates cytosolic NADPH to support biosynthesis ( Figure 4 ). At present, our understanding of the role of β-oxidation in cancer is limited with only a handful of studies reporting increased expression of FAO enzymes in tumors, highlighting the relevance of the pathway to cancer. Current advances in FAO studies are rapidly changing our understanding of the relevance of FAO to cancer. Accumulating evidence indicates the altered FAO activity contributes in several ways to sustaining cancer cell proliferation, survival, stemness, drug resistance, and metastasis [ 101 ]. Regulators of the FAO and enzymes catalyzing the various reactions have emerged as potential targets for cancer therapy.

10. Conclusions

For a long time, the theory that cancer is a genetic disorder has driven cancer research. Despite all the progress and understanding gained through cancer sequencing, this knowledge has not always translated into relevant treatment options. A prominent characteristic of cancer cells is an altered metabolic state, with alteration in metabolism affecting the glucose, glutamine, and fatty acid metabolic pathways. These alterations generate ATP and metabolic intermediates that sustain the proliferative state of cancerous cells. Metabolic alterations are achieved through several mechanisms, and characterizing these alterations holds promise for identifying targets for diagnosis and therapy. Our understanding of the metabolic reprogramming of cancers continues to grow, particularly with the emergence of oncometabolites and their roles in carcinogenesis, diagnosis, and treatment. Considering cancer as a metabolic disease will open new avenues for research, and more insight will be gained into the metabolic basis of cancer and how we can effectively target these alterations for efficient cancer management.

Author Contributions

Conceptualization, J.G. and J.C.; writing—original draft preparation, J.G. and J.K.; writing—review and editing, all authors; Figures design, J.G., J.K. and J.C.; supervision, J.C. All authors have read and agreed to the published version of the manuscript.

This work was part of research projects funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (NRF-2018R1A6A1A03023718, NRF-2020R1A2C1003378, NRF-2017R1D1AB03033362, and NRF-2020M3F7A1094094).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Conflicts of interest.

The authors declare no conflict of interest.

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Detecting pancreatic cancer through changes in body composition and metabolism

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By Marla Broadfoot, Ph.D.

Pancreatic cancer is a formidable disease, often diagnosed too late for effective treatment. However, new research from Mayo Clinic represents a promising step toward identifying biological signals or biomarkers that may aid in early detection.

By tracking changes in body composition and metabolism, researchers are working to identify high-risk patients who could benefit from selective screening for the disease, which kills more than 50,000 Americans a year.

"When most patients come to us with pancreatic cancer, their cancer has already spread and their survival over a five-year period is only three percent. But if we catch them early, at stage 1A, their five-year survival rate can be as high as 80%," says  Yan Bi, M.D., Ph.D. , a gastroenterologist at Mayo Clinic Comprehensive Cancer Center in Florida. "Detecting the cancer earlier is the best way to improve survival."

Early detection is tricky because the first symptoms of pancreatic cancer — digestive issues, belly pain and weight loss — are not specific. "Weight loss occurs even before the diagnosis," says Dr. Bi. "A majority of pancreatic cancer patients will lose weight before they discover they have cancer."

Studies have shown that as the disease progresses, cancer cells promote a wide range of metabolic and physiologic changes. Dr. Bi and her colleagues wondered if these changes could serve as biomarkers, to enable healthcare professionals to detect pancreatic cancer earlier than ever before.

Dr. Bi teamed up with Derk Klatte, M.D., and  Michael Wallace, M.D. , to examine medical records of patients with a common type of pancreatic cancer known as pancreatic ductal adenocarcinoma (PDAC) who had been diagnosed at Mayo Clinic between 2002 and 2021. They analyzed abdominal CT scans and blood tests taken up to three years before the patients were diagnosed. Using advanced algorithms developed by data scientist Alex Weston, Ph.D., the researchers measured changes in body fat, muscle and bone, as well as shifts in blood-based biomarkers like cholesterol and glucose levels.

The findings, published in the journal  Clinical Gastroenterology and Hepatology , revealed changes in a variety of physiological and metabolic measurements. The researchers observed significant reductions in both fat surrounding the organs (visceral fat) and the fat under the skin (subcutaneous fat) as patients approached their diagnosis date. In addition, patients exhibited a notable drop in serum lipids — fats found in the blood — such as low-density lipoprotein (LDL), total cholesterol and triglycerides.

Conversely, the study found that blood glucose levels increased up to three years before patients were diagnosed with pancreatic cancer, confirming a  link previously described  by gastroenterologist Suresh Chari, M.D. Additional findings revealed that patients also experienced a loss of muscle mass and bone volume, which became more pronounced in the last six months before their cancer was detected.

"It is a bizarre condition," says Dr. Bi. "Patients' bodies are changing — they are losing weight and their total cholesterol levels are going down…many things you think would be healthy, but in this case, they're not. Nobody knows exactly what is going on, but we aim to find out."

Dr. Bi recently received two grants, one from the National Institutes of Health and another from the Department of Defense, to investigate how the growth of pancreatic tumors could drive such widespread metabolic changes.

She is also expanding her work on pancreatic cancer biomarkers, searching for the best combination of factors to make an early diagnosis. "We are using many different layers of information — medical records, labs and data gathered from wearable devices," she says.

Dr. Bi is part of the  Kern Health Care Delivery Scholars Program  in the Mayo Clinic  Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery . The program supports the next generation of clinically trained, doctoral-level fellows and junior faculty in health services research.

As a Kern Health Care Delivery Scholar, Dr. Bi has been working on a project that uses wearables like Apple Watches or Fitbits to track changes in body composition as well as the power of artificial intelligence (AI).

"My goal is to combine that information with all the other data we have on a patient and use AI to calculate their risk of developing pancreatic cancer in three years," she says. "If they are at increased risk, we could start doing surveillance with abdominal imaging."

The team's early findings suggest that capturing the subtle yet significant body changes that occur as pancreatic cancer develops could be a key strategy in the fight against the disease. Recognizing these changes early could lead to timely diagnosis and treatment, potentially saving lives.

Dr. Bi and her colleagues at Mayo Clinic are active in the  Pancreatic Cancer Early Detection (PRECEDE) consortium , a global effort to improve early detection and prevention of pancreatic cancer. The consortium's goal is to increase the five-year survival rate to 50% after 10 years.

"It is very ambitious," she says, "but I hope we can reach that goal by pushing for early detection."

Review the  study  for a complete list of authors, disclosures and funding.

Learn more about pancreatic cancer and find a clinical trial at Mayo Clinic.

Join the Pancreatic Cancer Support Group on Mayo Clinic Connect , an online community moderated by Mayo Clinic for patients and caregivers.

Also, read these articles:

• Teamwork and a new nickname inspire patient through pancreatic cancer treatment
• Researchers make unexpected discovery in how pancreatic cancer spreads
• Mayo Clinic’s AI innovation inspires hope in early detection of pancreatic cancer

A version of this article was originally published on the Mayo Clinic News Network .

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August 27, 2024

Keto diet enhances experimental cancer therapy in mice

At a glance.

• Researchers showed how a ketogenic diet can enhance the effects of an experimental anti-cancer drug and starve pancreatic tumors in mice.
• The findings suggest that diet might be paired with drugs to block the growth of certain types of cancerous tumors.

Cancer cells need fuel to survive and thrive. The energy they need usually comes from glucose in the blood. Some studies have shown that intermittent fasting or a ketogenic diet—high in fat and low in carbohydrates—can help to protect against cancer. These cause the body to break down fat to form molecules called ketones, which can serve as the body’s main energy source while glucose is scarce. Fasting and ketogenic diets likely work by limiting the amount of glucose available to feed cancer cells. But some cancers, such as pancreatic cancer, can also use ketones as an energy source.

A research team led by Dr. Davide Ruggero of the University of California, San Francisco, set out to better understand the underlying gene activities and metabolic pathways affected by diet and fasting. They hope to use this knowledge to enhance cancer therapies. The team focused on a protein called eIF4E (eukaryotic translation initiation factor), which is often hijacked by cancer cells. Results appeared in Nature on August 14, 2024.

The researchers found that chemical tags called phosphates are added to eIF4E as mice transition from fed to fasting. Further analyses showed that this phosphorylated eIF4E (P-eIF4E) plays an important role in coordinating the activity of genes involved in processing fats for energy during fasting. When mice were placed on a ketogenic diet instead of fasting, the P-eIF4E protein similarly triggered a shift to using fat for energy.

The scientists next asked how fasting activated eIF4E. They found that free fatty acids, the small molecules released by fat shortly after fasting begins, activated a chain of events leading to eIF4E phosphorylation. This suggests that free fatty acids have a dual role, serving both as an energy source and as signaling molecules that boost fat-based energy production during fasting.

To assess the relevance of these findings to cancers that can thrive on fat, the researchers combined a ketogenic diet with an experimental anti-cancer drug that blocks P-eIF4E. The drug is called eFT508 (or tomivosertib). They found that giving eFT508 alone did not slow the growth of pancreatic tumors in mice, likely because the tumors could survive with energy from carbohydrates. But when mice were given the drug while on a ketogenic diet, the cancer cells no longer had ready access to glucose or fat for energy. The cells then starved, and growth declined.

"Our findings open a point of vulnerability that we can treat with a clinical inhibitor that we already know is safe in humans,” Ruggero says. “We now have firm evidence of one way in which diet might be used alongside pre-existing cancer therapies to precisely eliminate a cancer.”

—by Vicki Contie

Related Links

• Research in Context: Obesity and Metabolic Health
• An mRNA Vaccine To Treat Pancreatic Cancer
• Keto Molecule Offers Clue for Preventing Colorectal Cancer
• Low-Fat Diet Compared to Low-Carb Diet
• Nutrition in Cancer Care
• Pancreatic Cancer

References:  Remodelling of the translatome controls diet and its impact on tumorigenesis. Yang H, Zingaro VA, Lincoff J, Tom H, Oikawa S, Oses-Prieto JA, Edmondson Q, Seiple I, Shah H, Kajimura S, Burlingame AL, Grabe M, Ruggero D. Nature . 2024 Aug 14. doi: 10.1038/s41586-024-07781-7. Online ahead of print. PMID: 39143206.

Funding:  NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Cancer Institute (NCI), and National Institute of General Medical Sciences (NIGMS); American Heart Association; American Cancer Society; Howard Hughes Medical Institute.

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• Published: 10 December 2019

Cancer Metabolism

Metabolism and cancer: the future is now

• Christian Frezza 1  

British Journal of Cancer volume  122 ,  pages 133–135 ( 2020 ) Cite this article

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In the last decade, the field of cancer metabolism transformed itself from being a description of the metabolic features of cancer cells to become a key component of cellular transformation. Now, the potential role of this field in cancer biology is ready to be unravelled.

If we look back 10 years ago, the main questions in the field of cancer metabolism were whether and why cancer cells exhibited the so-called “Warburg effect”, a metabolic switch from oxidative to glycolytic metabolism. For years it was unclear why fast proliferating cancer cells would undergo this metabolic switch considered by many an inefficient use of nutrients (reviewed in 1 ). This fervid discussion was epitomised by a landmark review from Vander Heiden and colleagues, 2 who proposed that the “Warburg effect” should not be viewed solely from the point of view of energy generation, but, instead, should be considered as a mean to synthesise anabolic molecules. This change in perspective, almost a new Weltanschauung for the field, fostered new lines of enquiries to determine how cancer cells fulfil their biosynthetic needs, and connected the “Warburg effect” to nucleotide, lipids, and protein metabolism. Nowadays, we are facing another revolution. After years spent charting the many metabolic pathways explored by cancer cells to retrieve nutrients for growth and proliferation, the community has realised that the metabolic layer is at the interface between many other cellular processes in the cells and that it is more heterogeneous and subject to external cues than anticipated. In this second instalment of the special issue on Cancer Metabolism in the British Journal of Cancer , which has been co-edited by me and Professor Adrian Harris, we present primary research papers and reviews that investigate poorly explored areas of cancer metabolism and the many processes to which dysregulated metabolism contributes.

Mapping cancer metabolism

Despite the many recent efforts, the metabolic reprogramming of cancer cells is far from being fully characterised because of technical and experimental limitations. In this special issue, several contributions added essential pieces to this puzzle. For instance, Berndt et al. 3 capitalise on a unique in silico modelling approach using proteomics data not only to predict metabolic changes in liver cancer, but also to identify metabolic pathways whose inhibition selectively affects cancer cells. In addition, Becker 4 provides an extensive review of the regulation of pH in cancer cells and proposes the concept of a ‘transport metabolon’, whereby multiple transporters act together to regulate acid/base homoeostasis in cancer cells, a key regulator of cellular metabolism.

The dysregulation of mitochondrial function remains one the main components of the metabolic reprogramming of cancer. Here, Raimondi and colleagues 5 provide a comprehensive review of the connection between dysregulation of electron transport chain and cancer, focusing on the formation of reactive oxygen species (ROS), whose role in cancer biology has never been more debated. They propose that if, on one hand, multiple oncogenic cascades can cause aberrant ROS production, ROS production itself can trigger oncogenic processes, making it very difficult to disentangle the cancer-causing role of oxidative stress. Ciccarone and colleagues 6 demonstrate that the mitochondrial enzyme aconitase 2 (ACO2) is reduced in breast cancer and, when overexpressed, it can dysregulate pyruvate metabolism, revealing a potential metabolic vulnerability in cancers associated with ACO2 loss. Zhang et al. 7 show that the modulation of mitofusin 1, a protein involved in mitochondrial fusion, can also affect cellular metabolism with implications for cancer biology. Indeed, they found that in hepatocellular carcinoma, MFN1 is suppressed and its loss leads to defects in mitochondrial metabolism and promotes metastasis.

Cancer metabolism is heterogeneous and subject to environmental cues

The metabolic reprogramming of cancer is by and large transcriptionally regulated by oncogenes and mutated tumour suppressors. Yet, it is now clear that the metabolic composition of the tumour microenvironment can affect the metabolic phenotype of the cells. Therefore, cancer cells in a tumour, exposed to different levels of oxygen and nutrients, might be metabolically heterogeneous and their metabolic phenotype could further change during tumour progression, when nutrients become limiting. In this special issue, Nanda et al. 8 provide a comprehensive description of the genetic and environmental cues that drive cancer metabolism, with a specific focus on the cell-intrinsic and cell-extrinsic factors that contribute to metabolic heterogeneity. Importantly, as highlighted by Vettore and colleagues, 9 cancer cells and other components of the tumour microenvironment, including fibroblasts and immune cells, form a metabolic community and exchange metabolites regulating each other’s functions. Intriguingly, metabolites within the tumour microenvironment can affect cancer cell behaviour beyond providing energy substrates. For instance, Sola-Penna and colleagues 10 have identified the neurotransmitter serotonin as an important player in cell-to-cell communication mediated by the serotonin receptor. They then show that serotonin signalling offers a proliferative advantage to breast cancer cells by both increasing cell proliferation and decreasing cell death.

Technical limitations of metabolomic analyses, which often require the destruction of the tumour tissue, do not allow a full characterisation of tumour heterogeneity. To overcome these issues, new technologies are becoming available to analyse metabolite levels in intact tissues. Björkblom and colleagues 11 describe the use of microdialysis to investigate the metabolic changes in brain tumours upon treatment with the anticancer drug cisplatin, highlighting distinct metabolic patterns associated with the treatment. In another paper, Kawashima and colleagues 12 describe the use of matrix-assisted laser desorption and ionisation imaging mass spectrometry to investigate the distribution of phosphatidylinositols in human tumours. They found a correlation between the accumulation of these metabolites and invasion and nodal metastasis in breast cancer.

Targeting metabolism

A vital outcome of the work in cancer metabolism is our ability to translate these findings into actionable anticancer targets. In this special issue, several primary research papers provide important examples to support that targeting metabolism can be used in the clinic. For instance, James et al. 13 show that the inhibition of the cancer-specific pyruvate kinase 2 in pancreatic cancer cells using shikonin reduces their growth and invasion. Intriguingly, though, they demonstrate that this toxicity is due to the inhibition of a pool of PKM2 localised at the plasma membrane, where it provides a privileged ATP supply to the ATP-dependent plasma membrane calcium pump. Therefore, the inhibition of PKM2 causes calcium overload and cell death, rather than the expected metabolic catastrophe. In a different context, breast cancer, Lord and colleagues 14 elegantly showed that metformin, a drug commonly used in Type 2 diabetes but with promising yet unclear anticancer effects, acts as an inhibitor of fatty acid oxidation at clinical doses. This work, together with their previous finding that the mitochondrial response to metformin in primary breast cancer defines antitumour effect, 15 suggests that metabolic profiling can be used to predict the response to metformin, and more in general to anticancer drugs. Finally, Liu and colleagues 16 describe the role of cystine metabolism in cancer cells and report that the activation of the trans-sulphuration pathway to which cysteine contributes plays a key role in the resistance to a specific iron-dependent form of cell death defined ferroptosis.

Conclusions

In summary, many discoveries were made in this last decade in the field of cancer metabolism. Never before have we achieved such a comprehensive understanding of the metabolic needs of cancer cells. We have learned that this metabolic rewiring is not only needed to fuel energy needs or to support biomass generation, but it has essential roles in other cancer features such as migration, invasion, and metastasis. We have also evidence that targeting some of these metabolic pathways can reduce cancer growth if not as a single agent, probably in combination with other anticancer drugs. Yet, we should not be complacent. Indeed, emerging evidence indicates that cancer metabolism is highly dynamic and heterogenous, and the current analytical platforms do not enable us to grasp this complexity in full. Better technologies to investigate metabolism at the single-cell level without disrupting the tumour tissue are needed. If the progress is as steady as the one we experience in the last decade, I have no doubts we can break this barrier and achieve an even deeper understanding of the role of metabolism in cancer.

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Berndt, N., Egners, A., Mastrobuoni, G., Vvedenskaya, O., Fragoulis, A., Dugourd, A. et al. Kinetic modelling of quantitative proteome data predicts metabolic reprogramming of liver cancer. Br. J. Cancer  https://doi.org/10.1038/s41416-019-0659-3 (2019).

Becker, H. M. Carbonic anhydrase IX and acid transport in cancer. Br. J. Cancer  https://doi.org/10.1038/s41416-019-0642-z (2019).

Raimondi, V., Ciccarese, F. & Ciminale, V. Oncogenic pathways and the electron transport chain: a dangeROS liaison. Br. J. Cancer   https://doi.org/10.1038/s41416-019-0651-y (2019).

Ciccarone, F., Di Leo, L., Lazzarino, G., Maulucci, G., Di Giacinto, F., Tavazzi, B. & Ciriolo, M. R. Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response. Br. J. Cancer   https://doi.org/10.1038/s41416-019-0641-0 (2019).

Zhang, Z., Li, T.-E., Chen, M., Xu, D., Zhu, Y., Hu, B.-Y. et al. MFN1-dependent alteration of mitochondrial dynamics drives hepatocellular carcinoma metastasis by glucose metabolic reprogramming. Br. J. Cancer   https://doi.org/10.1038/s41416-019-0658-4 (2019).

Nanda, C. S., Venkateswaran, S. V., Patani, N. & Yuneva, M. Defining a metabolic landscape of tumours: genome meets metabolism. Br. J. Cancer   https://doi.org/10.1038/s41416-019-0663-7 (2019).

Vettore, L., Westbrook, R. L., & Tennant, D. A. New aspects of amino acid metabolism in cancer. Br. J. Cancer  https://doi.org/10.1038/s41416-019-0620-5 (2019).

Sola-Penna, M., Paixão, L. P., Branco, J. R., Ochioni, A. C., Albanese, J. M., Mundim, D. M. et al. Serotonin activates glycolysis and mitochondria biogenesis in human breast cancer cells through activation of Jak1/STAT3/ERK1/2 and adenylate cyclase/PKA, respectively. Br. J. Cancer   https://doi.org/10.1038/s41416-019-0640-1 (2019).

Björkblom, B., Jonsson, P., Tabatabaei, P., Bergström, P., Johansson, M. & Asklund, T. Metabolic response patterns in brain microdialysis fluids and serum during interstitial cisplatin treatment of high-grade glioma. Br. J. Cancer   https://doi.org/10.1038/s41416-019-0652-x (2019).

Kawashima, M., Tokiwa, M., Nishimura, T., Kawata, Y., Sugimoto, M., Kataoka, T. R. et al. High resolution imaging mass spectrometry combined with transcriptomic analysis identified a link between fatty acid composition of phosphatidylinositols and the immune checkpoint pathway at the primary tumour site of breast cancer. Br. J. Cancer  https://doi.org/10.1038/s41416-019-0662-8 (2019)

James, A. D., Richardson, D. A., Oh, I.-W., Sritangos, P., Attard, T., Barrett, L. & Bruce, J. I. E. Cutting off the fuel supply to calcium pumps in pancreatic cancer cells: role of pyruvate kinase-M2 (PKM2). Br. J. Cancer   https://doi.org/10.1038/s41416-019-0675-3 (2019).

Lord, S. R., Collins, J. M., Cheng, W.-C., Haider, S., Wigfield, S., Gaude, E. et al. Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin. Br. J. Cancer   https://doi.org/10.1038/s41416-019-0665-5 (2019).

Lord, S. R., Cheng, W. C., Liu, D., Gaude, E., Haider, S., Metcalf, T. et al. Integrated pharmacodynamic analysis identifies two metabolic adaption pathways to metformin in breast cancer. Cell Metab. 28 , 679–688.e4 (2018).

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Scientists find way to starve breast cancer cells

by Jennifer Michalowski, Cold Spring Harbor Laboratory

Cancer cells have voracious appetites. And there are certain nutrients they can't live without. Scientists have long hoped they might stop tumors in their tracks by cutting off an essential part of cancer cells' diet. But these cells are crafty and often find a new way to get what they need. How? By reprogramming their metabolism and switching to backup food supplies.

Now, Cold Spring Harbor Laboratory (CSHL) Assistant Professor Michael Lukey has found a way to deprive cancer cells of both a vital nutrient and their backup supply. In lab experiments with breast cancer cells, patient-derived tissue models, and mice, this strategy killed breast cancer cells and shrank tumors.

The study is published in the journal Nature Metabolism .

How does this work? Let's go back to cancer metabolism. Aggressive cancer cells avidly consume an amino acid called glutamine. They use this vital nutrient to generate the energy and materials needed to grow and replicate.

Previous studies have shown that starving cancer cells of glutamine or preventing its conversion into metabolites can stop the cells' growth in the lab. However, in recent clinical trials, breast cancer patients didn't benefit from a drug taking this approach. This suggests that breast cancer cells can adapt and find a way to live without glutamine.

Lukey and postdoc Yijian Qiu saw the same thing in their lab. They noticed that breast cancer cells adapt to glutamine starvation by switching on a pathway that generates a critical metabolite called alpha-ketoglutarate, normally derived from glutamine. This enables cancer cells to continue producing the energy and building materials they would otherwise get from glutamine. It was a lightbulb moment for Lukey's lab.

"That made us think, could we exploit this for cancer therapy ?" Lukey recalls. "Could we target glutamine metabolism? We know the cells adapt to that. So, could we simultaneously target their adaptive response by inhibiting the pathway?"

The approach was successful, killing breast cancer cells in lab dishes and effectively treating tumors in mice. Lukey's team saw tumors stop growing and even shrink with the combination treatment. The animals remained healthy.

Inhibitors of both metabolic pathways are now under further investigation. Lukey notes that these pathways might be especially important for breast cancer metastasis to different tissues, including some that are very difficult to treat. "Brain metastases in particular lack any effective therapies," Lukey explains.

Lukey hopes his lab's combination therapy could ultimately improve the efficacy of glutamine metabolism inhibitors in the clinic. This could mean effective new treatments that target cancer's metabolic addictions.

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