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

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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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Fig. 1 Cancer stem cells and MRD formation. Heterogeneous tumor tissue with combined-modality therapy leads to the formation of MRD, which is clinically undetectable. Transiently reduced heterogeneity is observed in MRD, which is enriched in CSCs. Relapse or metastasis results in re-acquisition of a heterogeneous population that is more potentially aggressive in terms of its degree of “stemness”
Fig. 1 Cancer stem cells and MRD formation. Heterogeneous tumor tissue with combined-modality therapy leads to the formation of MRD, which is clinically undetectable. Transiently reduced heterogeneity is observed in MRD, which is enriched in CSCs. Relapse or metastasis results in re-acquisition of a heterogeneous population that is more potentially aggressive in terms of its degree of “stemness”CC BY · PubMed Central
Fig. 2 Tumor heterogeneity in metabolism. The degree of addiction to glucose or glutamate differs among various types of cancer cells. Tumor cells robustly importing glucose via the GLUT1 transporter are responsible for the high intensity of FDG-PET in the clinical settings. Cancer cells that express high levels of GLUT1 also induce a low-pH acidic tumor microenvironment, thereby increasing the invasive potential of tumors
Fig. 2 Tumor heterogeneity in metabolism. The degree of addiction to glucose or glutamate differs among various types of cancer cells. Tumor cells robustly importing glucose via the GLUT1 transporter are responsible for the high intensity of FDG-PET in the clinical settings. Cancer cells that express high levels of GLUT1 also induce a low-pH acidic tumor microenvironment, thereby increasing the invasive potential of tumorsCC BY · PubMed Central
Fig. 3 Iatrogenic activation of CSCs with altered metabolic reprogramming. Non-CSCs are susceptible to chemotherapy and undergo apoptosis. Released PGE2 awakens the dormant CSCs localized in the niche. Proliferating CSCs are likely to exhibit additional metabolic reprogramming, concomitant with up-regulation of OXPHOS-related molecules
Fig. 3 Iatrogenic activation of CSCs with altered metabolic reprogramming. Non-CSCs are susceptible to chemotherapy and undergo apoptosis. Released PGE2 awakens the dormant CSCs localized in the niche. Proliferating CSCs are likely to exhibit additional metabolic reprogramming, concomitant with up-regulation of OXPHOS-related moleculesCC BY · PubMed Central
Fig. 4 Interaction of caveolin 1-deficient CAFs with tumor cells. Cancer cells induce a pseudo-hypoxic microenvironment rich in ROS derived from metabolic reprogramming. By contrast, CAFs negative for caveolin 1 provide tumor cells with lactate, pyruvate, and ketone bodies. Notably, although cancer cells depend heavily on mitochondrial metabolism, CAFs exhibit the Warburg effect and activation of the autophagic pathway
Fig. 4 Interaction of caveolin 1-deficient CAFs with tumor cells. Cancer cells induce a pseudo-hypoxic microenvironment rich in ROS derived from metabolic reprogramming. By contrast, CAFs negative for caveolin 1 provide tumor cells with lactate, pyruvate, and ketone bodies. Notably, although cancer cells depend heavily on mitochondrial metabolism, CAFs exhibit the Warburg effect and activation of the autophagic pathwayCC BY · PubMed Central
Fig. 5 Metabolic symbiosis between oxidative/aerobic tumor cells and hypoxic/glycolytic cells. Tumor heterogeneity induces a lactate shuttle between hypoxic and oxidative cancer cells. While MCT4-positive hypoxic cells contribute to formation of an acidic microenvironment by aerobic glycolysis and secretion of lactate, MCT1-expressing oxidative cells utilize lactate as a substrate of the TCA cycle, and consequently exhibit stem-like characteristics. Notably, in contrast with MCT1-positive cancer cells, glucose uptake is robust in MCT4-expressing cells
Fig. 5 Metabolic symbiosis between oxidative/aerobic tumor cells and hypoxic/glycolytic cells. Tumor heterogeneity induces a lactate shuttle between hypoxic and oxidative cancer cells. While MCT4-positive hypoxic cells contribute to formation of an acidic microenvironment by aerobic glycolysis and secretion of lactate, MCT1-expressing oxidative cells utilize lactate as a substrate of the TCA cycle, and consequently exhibit stem-like characteristics. Notably, in contrast with MCT1-positive cancer cells, glucose uptake is robust in MCT4-expressing cellsCC BY · PubMed Central
Fig. 6 Metabolic reprogramming of amino acids due to coordinated transporters. ASCT2/LAT1 and xCT/CD98hc transporter complexes in tumor cells activate the mTORC1-SIRT4-GDH axis and glutathione synthesis, respectively. The former pathway promotes conversion of glutamate into alpha-KG, a substrate of the TCA cycle, whereas the latter pathway maintains redox status
Fig. 6 Metabolic reprogramming of amino acids due to coordinated transporters. ASCT2/LAT1 and xCT/CD98hc transporter complexes in tumor cells activate the mTORC1-SIRT4-GDH axis and glutathione synthesis, respectively. The former pathway promotes conversion of glutamate into alpha-KG, a substrate of the TCA cycle, whereas the latter pathway maintains redox statusCC BY · PubMed Central

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Metadata

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
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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