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Is metabolism the magic bullet for targeted cancer therapy?

Is metabolism the magic bullet for targeted cancer therapy? Altered cellular metabolism has long been recognized as a hallmark of cancer. Oncogenic signaling cascades induce metabolic rewiring that further supports tumorigenesis, therapy resistance and metastasis. In view of this, the Collection on ‘Cancer Metabolism’ highlights the current views and focus of research on personalized medicine approach to target metabolism for cancer therapy. Background and anabolic processes that enable cancer cells to use The last years of research have taught us that cancer is a substitute resources and improvise as needed. very complex, multifaceted disease. Despite being “body- The history of cancer metabolism started nearly a hun - own”, cancer cells build up an aggressive, self-sustaining dred years ago when Otto Warburg discovered aerobic ecosystem with the aim of surviving, expanding and ulti- glycolysis and lactate production in cultured tumor slices mately defeating the host. No matter how different the despite the availability of sufficient oxygen [ 1]. Warburg cancer from a normal cell, they rely on the same funda- assumed that mitochondrial respiration is deficient in mental needs for nutrients and energy. While there are a cancers for unknown reasons. Nowadays, we know that few metabolic signatures that are unique to cancer cells mitochondria are rarely damaged in cancers and genes and not found in normal cells, the metabolic processes coding for mitochondrial enzymes are highly preserved are overall similar. The advantage of a cancer cell lies in and rarely mutated, suggesting how essential and con- its ability to rewire and adapt its metabolism to whatever served respiration in cancers is. The activation of glycoly - source of food and energy is available. Activated onco- sis as a process is nothing else but satisfying the need of genes and signaling networks trigger alternative catabolic a proliferating cancer cell for glycolytic inter-metabolites, ribose and hexose sugars that support nucleotide syn- thesis and protein glycosylation [2, 3]. Beyond glucose, cancer cells utilize alternative fuels to meet their energy demand which warrants further investigation for a com- *Correspondence: Marija Trajkovic-Arsic plete characterization of cancer metabolism. Recent marija.trajkovic-arsic@uk-essen.de works emphasize that glycolysis is necessary for the Elavarasan Subramani regeneration of high NAD + levels needed for increased esubramani@mdanderson.org Division of Solid Tumor Translational Oncology, German Cancer proliferation [4, 5]. Furthermore, cancer cells can scav- Consortium (DKTK, Partner Site Essen) and German Cancer Research enge the necessary nutrients from the microenvironment Center, DKFZ, Heidelberg, Germany 2 to promote the different steps of metastasis [ 6]. West German Cancer Center, Bridge Institute of Experimental Tumor Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, There are many factors to consider when performing Germany and interpreting metabolic experiments. The broad vari - Department of Cancer Systems Imaging, The University of Texas MD ety of models ranging from in vitro 2D-, 3D-, co-culture Anderson Cancer Center, Houston, TX, USA © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Trajkovic-Arsic and Subramani BMC Cancer (2023) 23:484 Page 2 of 3 cell systems to mouse models and even “in patient” in in translating these imaging approaches into effective vivo approaches offer platforms for addressing many methods for predicting and monitoring the response to metabolic questions. Cell culture has been instrumen- cancer-targeted therapies. In the current era of preci- tal in addressing groundbreaking questions about which sion medicine, such approaches would be invaluable in metabolic processes and nutrients are essential to main- providing better information on treatment response and tain cancer growth. However, there are at least two sig- ultimately improving patient outcomes. nificant drawbacks to cell culture systems which are Finally, we would like to draw attention to the emerg- especially discussed in metabolic terms. First, they lack ing subject of sexual dimorphism in cancer incidence and microenvironmental support that is, as we now know, mortality, which highlights the genetic, epigenetic, hor- an indispensable part of the cancer ecosystem. Second, monal, immune and metabolic differences between can - they rely on “non-physiological” concentrations of nutri- cers in males and females [15]. Not surprisingly, the same ents in the cell culture media. The standard cell culture cancer occurring in males or females may use different media used world-wide were originally not designed to metabolic strategies and resources to survive. Thus, we address metabolic questions but to support cell growth. need to acknowledge that the first step towards person - Thinking in metabolic terms, feeding the cells with dra - alized oncology is to appreciate the patients’ sex and the matically supraphysiological concentrations of glucose, metabolic specificities that it may bring. glutamine and other essential nutrients may bias the In recognition of this important field, we are now wel - metabolic findings and induce different responses to drug coming submissions to our new Collection of articles treatments. Performing metabolic experiments in media titled ‘Cancer metabolism’. More details can be found with nutrient concentrations that resemble more what is here: https://www.biomedcentral.com/collections/CM. found in the tumor microenvironment may improve our Overall, a deeper understanding of metabolic changes views and understanding of what is metabolically really that support cellular growth and function will open new happening in the cancer cells. The recent introduction of horizons on how to utilize metabolism to fight against “physiological” media [7, 8], is certainly a step forward in cancer. optimizing cell culture for metabolic research needs. Acknowledgements The cancer’s ability to rewire the metabolic pathways, We are deeply grateful to the Editor, Dr. Chiara Cilibrasi, and the editorial board adapt to the availability of nutrients and activate the non- for the opportunity to be the guest editors of this Collection. canonical catabolic metabolism is its best adaptive fitness Authors’ contributions feature [9]. While metabolic rewiring is potentially the M.T. and E.S. have been involved in writing, editing, and submitting the best support to uncontrolled proliferation, the different manuscript. All authors read and approved the final manuscript. use of specific nutrients creates therapeutic vulnerabili - Funding ties that can be targeted. Currently, there is a discussion Not applicable. on how a specific diet can influence the cancer metabo - Data Availability lism and induce a metabolic dependency that can be tar- Not applicable. geted by keeping the cancer on a defined nutrient source. The most famous examples of dietary interventions in Declarations cancer are caloric restriction and the ketogenic diet, both showing varying levels of success and opposing effects in Ethics approval and consent to participate Not applicable. different cancer types [ 10, 11]. Recently, there has been a lot of attention focused on limiting dietary amino acids Consent for publication such as serine, glycine, methionine or glutamine, as their Not applicable. dietary removal has been shown to retard tumor growth Competing interests in different mouse models [ 12, 13]. Additionally, there is M.T. and E.S. serve as guest editors of the Collection “Cancer metabolism”. E.S. recent evidence suggesting that gut microbiota-derived is also serving as an editorial board member of BMC Cancer. metabolites, such as indole-3-acetic acid, influence the Received: 15 May 2023 / Accepted: 23 May 2023 response to chemotherapy in pancreatic ductal adeno- carcinoma patients, further supporting the rationale for nutritional interventions during cancer treatment [14]. Due to the important role of metabolism in malig- nancy, metabolic imaging is now emerging as a power- References ful tool with the development of new radiotracers and 1. Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309–14. MRI-based imaging agents that can provide real time 2. Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, Locasale JW, Son J, Zhang H, Coloff JL, et al. Oncogenic Kras maintains signatures of cancer metabolism in both basic research and clinical settings. However, there has been a delay Trajkovic-Arsic and Subramani BMC Cancer (2023) 23:484 Page 3 of 3 pancreatic tumors through regulation of anabolic glucose metabolism. Cell. 10. Lien EC, Westermark AM, Zhang Y, Yuan C, Li Z, Lau AN, Sapp KM, Wolpin BM. 2012;149(3):656–70. Vander Heiden MG: low glycaemic diets alter lipid metabolism to influence 3. Sharma NS, Gupta VK, Garrido VT, Hadad R, Durden BC, Kesh K, Giri B, Fer- tumour growth. Nature. 2021;599(7884):302–7. rantella A, Dudeja V, Saluja A, et al. Targeting tumor-intrinsic hexosamine 11. Lien EC, Vander Heiden MG. A framework for examining how diet impacts biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy. J Clin Invest. tumour metabolism. Nat Rev Cancer. 2019;19(11):651–61. 2020;130(1):451–65. 12. Maddocks ODK, Athineos D, Cheung EC, Lee P, Zhang T, van den Broek NJF, 4. Wang Y, Stancliffe E, Fowle-Grider R, Wang R, Wang C, Schwaiger-Haber M, Mackay GM, Labuschagne CF, Gay D, Kruiswijk F, et al. Modulating the thera- Shriver LP, Patti GJ. Saturation of the mitochondrial NADH shuttles drives peutic response of tumours to dietary serine and glycine starvation. Nature. aerobic glycolysis in proliferating cells. Mol Cell. 2022;82(17):3270–3283e3279. 2017;544(7650):372–6. 5. Luengo A, Li Z, Gui DY, Sullivan LB, Zagorulya M, Do BT, Ferreira R, Naamati 13. Maddocks OD, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E, Vousden A, Ali A, Lewis CA, et al. Increased demand for NAD(+) relative to ATP drives KH. Serine starvation induces stress and p53-dependent metabolic remodel- aerobic glycolysis. Mol Cell. 2021;81(4):691–707e696. ling in cancer cells. Nature. 2013;493(7433):542–6. 6. Faubert B, Solmonson A, DeBerardinis RJ. Metabolic reprogramming and 14. Tintelnot J, Xu Y, Lesker TR, Schonlein M, Konczalla L, Giannou AD, Pelczar P, cancer progression. Science 2020, 368(6487). Kylies D, Puelles VG, Bielecka AA, et al. Microbiota-derived 3-IAA influences 7. Vande Voorde J, Ackermann T, Pfetzer N, Sumpton D, Mackay G, Kalna G, chemotherapy efficacy in pancreatic cancer. Nature. 2023;615(7950):168–74. Nixon C, Blyth K, Gottlieb E, Tardito S. Improving the metabolic fidel - 15. Clocchiatti A, Cora E, Zhang Y, Dotto GP. Sexual dimorphism in cancer. Nat ity of cancer models with a physiological cell culture medium. Sci Adv. Rev Cancer. 2016;16(5):330–9. 2019;5(1):eaau7314. 8. Cantor JR, Abu-Remaileh M, Kanarek N, Freinkman E, Gao X, Louissaint A Jr, Lewis CA, Sabatini DM. Physiologic medium Rewires Cellular Metabolism Publisher’s Note and reveals uric acid as an endogenous inhibitor of UMP synthase. Cell. Springer Nature remains neutral with regard to jurisdictional claims in 2017;169(2):258–72. e217. published maps and institutional affiliations. 9. DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016;2(5):e1600200. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Cancer Springer Journals

Is metabolism the magic bullet for targeted cancer therapy?

Trajkovic-Arsic, Marija; Subramani, Elavarasan
BMC Cancer , Volume 23 (1) – May 30, 2023
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Springer Journals
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Copyright © The Author(s) 2023
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1471-2407
DOI
10.1186/s12885-023-10999-9
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Abstract

Altered cellular metabolism has long been recognized as a hallmark of cancer. Oncogenic signaling cascades induce metabolic rewiring that further supports tumorigenesis, therapy resistance and metastasis. In view of this, the Collection on ‘Cancer Metabolism’ highlights the current views and focus of research on personalized medicine approach to target metabolism for cancer therapy. Background and anabolic processes that enable cancer cells to use The last years of research have taught us that cancer is a substitute resources and improvise as needed. very complex, multifaceted disease. Despite being “body- The history of cancer metabolism started nearly a hun - own”, cancer cells build up an aggressive, self-sustaining dred years ago when Otto Warburg discovered aerobic ecosystem with the aim of surviving, expanding and ulti- glycolysis and lactate production in cultured tumor slices mately defeating the host. No matter how different the despite the availability of sufficient oxygen [ 1]. Warburg cancer from a normal cell, they rely on the same funda- assumed that mitochondrial respiration is deficient in mental needs for nutrients and energy. While there are a cancers for unknown reasons. Nowadays, we know that few metabolic signatures that are unique to cancer cells mitochondria are rarely damaged in cancers and genes and not found in normal cells, the metabolic processes coding for mitochondrial enzymes are highly preserved are overall similar. The advantage of a cancer cell lies in and rarely mutated, suggesting how essential and con- its ability to rewire and adapt its metabolism to whatever served respiration in cancers is. The activation of glycoly - source of food and energy is available. Activated onco- sis as a process is nothing else but satisfying the need of genes and signaling networks trigger alternative catabolic a proliferating cancer cell for glycolytic inter-metabolites, ribose and hexose sugars that support nucleotide syn- thesis and protein glycosylation [2, 3]. Beyond glucose, cancer cells utilize alternative fuels to meet their energy demand which warrants further investigation for a com- *Correspondence: Marija Trajkovic-Arsic plete characterization of cancer metabolism. Recent marija.trajkovic-arsic@uk-essen.de works emphasize that glycolysis is necessary for the Elavarasan Subramani regeneration of high NAD + levels needed for increased esubramani@mdanderson.org Division of Solid Tumor Translational Oncology, German Cancer proliferation [4, 5]. Furthermore, cancer cells can scav- Consortium (DKTK, Partner Site Essen) and German Cancer Research enge the necessary nutrients from the microenvironment Center, DKFZ, Heidelberg, Germany 2 to promote the different steps of metastasis [ 6]. West German Cancer Center, Bridge Institute of Experimental Tumor Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, There are many factors to consider when performing Germany and interpreting metabolic experiments. The broad vari - Department of Cancer Systems Imaging, The University of Texas MD ety of models ranging from in vitro 2D-, 3D-, co-culture Anderson Cancer Center, Houston, TX, USA © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Trajkovic-Arsic and Subramani BMC Cancer (2023) 23:484 Page 2 of 3 cell systems to mouse models and even “in patient” in in translating these imaging approaches into effective vivo approaches offer platforms for addressing many methods for predicting and monitoring the response to metabolic questions. Cell culture has been instrumen- cancer-targeted therapies. In the current era of preci- tal in addressing groundbreaking questions about which sion medicine, such approaches would be invaluable in metabolic processes and nutrients are essential to main- providing better information on treatment response and tain cancer growth. However, there are at least two sig- ultimately improving patient outcomes. nificant drawbacks to cell culture systems which are Finally, we would like to draw attention to the emerg- especially discussed in metabolic terms. First, they lack ing subject of sexual dimorphism in cancer incidence and microenvironmental support that is, as we now know, mortality, which highlights the genetic, epigenetic, hor- an indispensable part of the cancer ecosystem. Second, monal, immune and metabolic differences between can - they rely on “non-physiological” concentrations of nutri- cers in males and females [15]. Not surprisingly, the same ents in the cell culture media. The standard cell culture cancer occurring in males or females may use different media used world-wide were originally not designed to metabolic strategies and resources to survive. Thus, we address metabolic questions but to support cell growth. need to acknowledge that the first step towards person - Thinking in metabolic terms, feeding the cells with dra - alized oncology is to appreciate the patients’ sex and the matically supraphysiological concentrations of glucose, metabolic specificities that it may bring. glutamine and other essential nutrients may bias the In recognition of this important field, we are now wel - metabolic findings and induce different responses to drug coming submissions to our new Collection of articles treatments. Performing metabolic experiments in media titled ‘Cancer metabolism’. More details can be found with nutrient concentrations that resemble more what is here: https://www.biomedcentral.com/collections/CM. found in the tumor microenvironment may improve our Overall, a deeper understanding of metabolic changes views and understanding of what is metabolically really that support cellular growth and function will open new happening in the cancer cells. The recent introduction of horizons on how to utilize metabolism to fight against “physiological” media [7, 8], is certainly a step forward in cancer. optimizing cell culture for metabolic research needs. Acknowledgements The cancer’s ability to rewire the metabolic pathways, We are deeply grateful to the Editor, Dr. Chiara Cilibrasi, and the editorial board adapt to the availability of nutrients and activate the non- for the opportunity to be the guest editors of this Collection. canonical catabolic metabolism is its best adaptive fitness Authors’ contributions feature [9]. While metabolic rewiring is potentially the M.T. and E.S. have been involved in writing, editing, and submitting the best support to uncontrolled proliferation, the different manuscript. All authors read and approved the final manuscript. use of specific nutrients creates therapeutic vulnerabili - Funding ties that can be targeted. Currently, there is a discussion Not applicable. on how a specific diet can influence the cancer metabo - Data Availability lism and induce a metabolic dependency that can be tar- Not applicable. geted by keeping the cancer on a defined nutrient source. The most famous examples of dietary interventions in Declarations cancer are caloric restriction and the ketogenic diet, both showing varying levels of success and opposing effects in Ethics approval and consent to participate Not applicable. different cancer types [ 10, 11]. Recently, there has been a lot of attention focused on limiting dietary amino acids Consent for publication such as serine, glycine, methionine or glutamine, as their Not applicable. dietary removal has been shown to retard tumor growth Competing interests in different mouse models [ 12, 13]. Additionally, there is M.T. and E.S. serve as guest editors of the Collection “Cancer metabolism”. E.S. recent evidence suggesting that gut microbiota-derived is also serving as an editorial board member of BMC Cancer. metabolites, such as indole-3-acetic acid, influence the Received: 15 May 2023 / Accepted: 23 May 2023 response to chemotherapy in pancreatic ductal adeno- carcinoma patients, further supporting the rationale for nutritional interventions during cancer treatment [14]. Due to the important role of metabolism in malig- nancy, metabolic imaging is now emerging as a power- References ful tool with the development of new radiotracers and 1. Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309–14. MRI-based imaging agents that can provide real time 2. Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, Locasale JW, Son J, Zhang H, Coloff JL, et al. Oncogenic Kras maintains signatures of cancer metabolism in both basic research and clinical settings. However, there has been a delay Trajkovic-Arsic and Subramani BMC Cancer (2023) 23:484 Page 3 of 3 pancreatic tumors through regulation of anabolic glucose metabolism. Cell. 10. Lien EC, Westermark AM, Zhang Y, Yuan C, Li Z, Lau AN, Sapp KM, Wolpin BM. 2012;149(3):656–70. Vander Heiden MG: low glycaemic diets alter lipid metabolism to influence 3. Sharma NS, Gupta VK, Garrido VT, Hadad R, Durden BC, Kesh K, Giri B, Fer- tumour growth. Nature. 2021;599(7884):302–7. rantella A, Dudeja V, Saluja A, et al. Targeting tumor-intrinsic hexosamine 11. Lien EC, Vander Heiden MG. A framework for examining how diet impacts biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy. J Clin Invest. tumour metabolism. Nat Rev Cancer. 2019;19(11):651–61. 2020;130(1):451–65. 12. Maddocks ODK, Athineos D, Cheung EC, Lee P, Zhang T, van den Broek NJF, 4. Wang Y, Stancliffe E, Fowle-Grider R, Wang R, Wang C, Schwaiger-Haber M, Mackay GM, Labuschagne CF, Gay D, Kruiswijk F, et al. Modulating the thera- Shriver LP, Patti GJ. Saturation of the mitochondrial NADH shuttles drives peutic response of tumours to dietary serine and glycine starvation. Nature. aerobic glycolysis in proliferating cells. Mol Cell. 2022;82(17):3270–3283e3279. 2017;544(7650):372–6. 5. Luengo A, Li Z, Gui DY, Sullivan LB, Zagorulya M, Do BT, Ferreira R, Naamati 13. Maddocks OD, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E, Vousden A, Ali A, Lewis CA, et al. Increased demand for NAD(+) relative to ATP drives KH. Serine starvation induces stress and p53-dependent metabolic remodel- aerobic glycolysis. Mol Cell. 2021;81(4):691–707e696. ling in cancer cells. Nature. 2013;493(7433):542–6. 6. Faubert B, Solmonson A, DeBerardinis RJ. Metabolic reprogramming and 14. Tintelnot J, Xu Y, Lesker TR, Schonlein M, Konczalla L, Giannou AD, Pelczar P, cancer progression. Science 2020, 368(6487). Kylies D, Puelles VG, Bielecka AA, et al. Microbiota-derived 3-IAA influences 7. Vande Voorde J, Ackermann T, Pfetzer N, Sumpton D, Mackay G, Kalna G, chemotherapy efficacy in pancreatic cancer. Nature. 2023;615(7950):168–74. Nixon C, Blyth K, Gottlieb E, Tardito S. Improving the metabolic fidel - 15. Clocchiatti A, Cora E, Zhang Y, Dotto GP. Sexual dimorphism in cancer. Nat ity of cancer models with a physiological cell culture medium. Sci Adv. Rev Cancer. 2016;16(5):330–9. 2019;5(1):eaau7314. 8. Cantor JR, Abu-Remaileh M, Kanarek N, Freinkman E, Gao X, Louissaint A Jr, Lewis CA, Sabatini DM. Physiologic medium Rewires Cellular Metabolism Publisher’s Note and reveals uric acid as an endogenous inhibitor of UMP synthase. Cell. Springer Nature remains neutral with regard to jurisdictional claims in 2017;169(2):258–72. e217. published maps and institutional affiliations. 9. DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016;2(5):e1600200.

Journal

BMC Cancer – Springer Journals

Published: May 30, 2023

There are no references for this article.