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Metabolic reprogramming: the emerging concept and associated therapeutic strategies.

Yoshida GJ - J. Exp. Clin. Cancer Res. (2015)

Bottom Line: 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.In addition, metabolic heterogeneity is responsible for the failure to induce the same therapeutic effect against cancer cells as a whole.This type of altered metabolic reprogramming leads to adaptive/acquired resistance to anti-tumor therapy.

View Article: PubMed Central - PubMed

Affiliation: Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan. medical21go@yahoo.co.jp.

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.

No MeSH data available.


Related in: MedlinePlus

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
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Fig5: 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

Mentions: It should be emphasized, however, that this reverse Warburg effect is not necessarily present in all tumor types. Tumors expressing high levels of MCT4 or mesenchymal phenotype do not tend to exhibit the reverse Warburg phenomenon. Instead, cancer cells exhibit hierarchical metabolic heterogeneity: MCT4-expressing tumor cells perform glycolysis and secrete lactate via MCT4, whereas MCT1-expressing cells import lactate via MCT1 and perform OXPHOS. In addition, the amount of glucose uptake is lower in MCT1-positive cancer cells than in MCT4-positive cells [19, 20] (Fig. 5). This metabolic heterogeneity is referred to as metabolic symbiosis, and this kind of lactate shuttle is also observed between neurons and astrocytes in the normal brain tissue [44]. It is notable that normal and cancerous tissues share finely regulated mechanisms of metabolic symbiosis.Fig. 5


Metabolic reprogramming: the emerging concept and associated therapeutic strategies.

Yoshida GJ - J. Exp. Clin. Cancer Res. (2015)

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4595070&req=5

Fig5: 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
Mentions: It should be emphasized, however, that this reverse Warburg effect is not necessarily present in all tumor types. Tumors expressing high levels of MCT4 or mesenchymal phenotype do not tend to exhibit the reverse Warburg phenomenon. Instead, cancer cells exhibit hierarchical metabolic heterogeneity: MCT4-expressing tumor cells perform glycolysis and secrete lactate via MCT4, whereas MCT1-expressing cells import lactate via MCT1 and perform OXPHOS. In addition, the amount of glucose uptake is lower in MCT1-positive cancer cells than in MCT4-positive cells [19, 20] (Fig. 5). This metabolic heterogeneity is referred to as metabolic symbiosis, and this kind of lactate shuttle is also observed between neurons and astrocytes in the normal brain tissue [44]. It is notable that normal and cancerous tissues share finely regulated mechanisms of metabolic symbiosis.Fig. 5

Bottom Line: 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.In addition, metabolic heterogeneity is responsible for the failure to induce the same therapeutic effect against cancer cells as a whole.This type of altered metabolic reprogramming leads to adaptive/acquired resistance to anti-tumor therapy.

View Article: PubMed Central - PubMed

Affiliation: Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan. medical21go@yahoo.co.jp.

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.

No MeSH data available.


Related in: MedlinePlus