Metabolic Reprogramming: the Emerging Concept and Associated Therapeutic Strategies

Yoshida, Go J.

doi:10.1186/s13046-015-0221-y

Cited by 716Cancer, Hypoxia, and MetabolismMetabolism, Diabetes, and CancerCancer Cells and Metastasis

Metabolic Reprogramming: the Emerging Concept and Associated Therapeutic Strategies

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Yoshida, Go J.·2015·Journal of Experimental & Clinical Cancer Research

DOI 10.1186/s13046-015-0221-yPMC PMC4595070

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Abstract

Tumor tissue is composed of cancer cells and surrounding stromal cells with diverse genetic/epigenetic backgrounds, a situation known as intra-tumoral heterogeneity. Cancer cells are surrounded by a totally different microenvironment than that of normal cells; consequently, tumor cells must exhibit rapidly adaptive responses to hypoxia and hypo-nutrient conditions. This phenomenon of changes of tumor cellular bioenergetics, called "metabolic reprogramming", has been recognized as one of 10 hallmarks of cancer. Metabolic reprogramming is required for both malignant transformation and tumor development, including invasion and metastasis. Although the Warburg effect has been widely accepted as a common feature of metabolic reprogramming, accumulating evidence has revealed that tumor cells depend on mitochondrial metabolism as well as aerobic glycolysis. Remarkably, cancer-associated fibroblasts in tumor stroma tend to activate both glycolysis and autophagy in contrast to neighboring cancer cells, which leads to a reverse Warburg effect. Heterogeneity of monocarboxylate transporter expression reflects cellular metabolic heterogeneity with respect to the production and uptake of lactate. In tumor tissue, metabolic heterogeneity induces metabolic symbiosis, which is responsible for adaptation to drastic changes in the nutrient microenvironment resulting from chemotherapy. In addition, metabolic heterogeneity is responsible for the failure to induce the same therapeutic effect against cancer cells as a whole. In particular, cancer stem cells exhibit several biological features responsible for resistance to conventional anti-tumor therapies. Consequently, cancer stem cells tend to form minimal residual disease after chemotherapy and exhibit metastatic potential with additional metabolic reprogramming. This type of altered metabolic reprogramming leads to adaptive/acquired resistance to anti-tumor therapy. Collectively, complex and dynamic metabolic reprogramming should be regarded as a reflection of the "robustness" of tumor cells against unfavorable conditions. This review focuses on the concept of metabolic reprogramming in heterogeneous tumor tissue, and further emphasizes the importance of developing novel therapeutic strategies based on drug repositioning.

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In an oxygenated environment, tumorous or even normal cells can consume the excreted metabolites of other cells located in the stroma.
“In oxygenated environment, tumorous or even normal cells can consume the excreted metabolites of other cells located in the stroma.”
From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [37]
Lactate produced during "lactic glycolysis" of hypoxic or pseudo-hypoxic cells can be utilized by other cells in an oxygenated environment.
“lactate produced during “lactic glycolysis” of hypoxic or pseudo-hypoxic cells can be utilized in this manner [37] (Figure 6).”
From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [37]

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The impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer
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Sun, X., Yan, P., Zou, C., Wong, Y., Shu, Y., Lee, Y. M., Zhang, C., Yang, N., Wang, J., & Zhang, J. (2019) · Medicinal Research Reviews · doi:10.1002/med.21580 · Cited by 113 · see citing works
Betulinic Acid Suppresses Breast Cancer Metastasis by Targeting GRP78-Mediated Glycolysis and ER Stress Apoptotic Pathway
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Hypoxia Signaling in Cancer: From Basics to Clinical Practice
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The Role of Tumour Metabolism in Cisplatin Resistance
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The anti-tumor efficacy of CDK4/6 inhibition is enhanced by the combination with PI3K/AKT/mTOR inhibitors through impairment of glucose metabolism in TNBC cells
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Authors: Yoshida, G. J.
Affiliations: Tokyo Medical and Dental University (JP)
Corresponding author: Yoshida, Go J.
ORCID: Yoshida, Go J.
Venue: Journal of Experimental & Clinical Cancer Research
Publisher: Springer Science and Business Media LLC
Published: 2015-10-06
Volume: 34
Issue: 1
Pages: 111-111
ISSN: 0392-9078 (ISSN-L)
1756-9966
DOI: 10.1186/s13046-015-0221-y
PMC: PMC4595070
OpenAlex: W2114090713
Cited by: 716
References: 89
Citations by year: 2026: 60 · 2025: 83 · 2024: 99 · 2023: 77 · 2022: 80 · 2021: 91 · 2020: 71 · 2019: 46 · 2018: 45 · 2017: 35 · 2016: 27 · 2015: 2
FWCI: 3.55
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: Journal of Experimental & Clinical Cancer Research (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: Keio University
Japan Society for the Promotion of Science (15J02898)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords: metabolic reprogramming, Warburg effect, aerobic glycolysis, mitochondrial metabolism, tumor microenvironment, cancer-associated fibroblasts, reverse Warburg effect, monocarboxylate transporters, lactate, metabolic heterogeneity, metabolic symbiosis, cancer stem cells, chemoresistance, drug repurposing, tumor stroma, tumor heterogeneity
MeSH terms: Cellular Reprogramming Techniques, Antineoplastic Agents, Cell Transformation, Neoplastic, Energy Metabolism, Glycolysis, Humans, Mitochondria, Neoplasms, Oxidative Phosphorylation, Neoplastic Stem Cells, Drug Resistance, Neoplasm, Tumor Microenvironment

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