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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

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
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Fig3: 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

Mentions: Tumor heterogeneity in regard to mitochondrial metabolism, in seeming contradiction to the Warburg effect, is considered to induce the diversity in activated metabolic pathways [36] (Fig. 2). Notably, MRD in several kinds of cancers is enriched in CSCs, leading to intra-tumoral heterogeneity and poor prognosis [1, 9, 10, 37]. Non-CSCs of bladder cancer, for instance, release prostaglandin E2 (PGE2) when they undergo apoptosis during the course of chemotherapy. PGE2 promotes the awakening of dormant G0-phased CSCs into the proliferative state [9]. Given that PGE2-mediated metabolic activation in mitochondria has been demonstrated in non-malignant cells [38], it is possible that activated CSCs undergo altered metabolic reprogramming (Fig. 3). Similarly, the survivors after transient depletion of a driver oncogene (i.e., activated mutant KRASG12D in pancreatic cancer) tend to depend heavily on OXPHOS in mitochondria rather than aerobic glycolysis. Comprehensive analysis of metabolic pathways of survivors after chemotherapy revealed the prominent expression of genes that regulate mitochondrial function, autophagy and lysosome degradation activity, as well as a strong reliance on mitochondrial respiration and diminished dependence on the Warburg effect [10]. Autophagy is a metabolic-recycling pathway involving proteasome-independent degradation of cellular components (e.g., old and dysfunctional mitochondria), which is partially responsible for cancer chemoresistance [39].Fig. 2


Metabolic reprogramming: the emerging concept and associated therapeutic strategies.

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

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: 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
Mentions: Tumor heterogeneity in regard to mitochondrial metabolism, in seeming contradiction to the Warburg effect, is considered to induce the diversity in activated metabolic pathways [36] (Fig. 2). Notably, MRD in several kinds of cancers is enriched in CSCs, leading to intra-tumoral heterogeneity and poor prognosis [1, 9, 10, 37]. Non-CSCs of bladder cancer, for instance, release prostaglandin E2 (PGE2) when they undergo apoptosis during the course of chemotherapy. PGE2 promotes the awakening of dormant G0-phased CSCs into the proliferative state [9]. Given that PGE2-mediated metabolic activation in mitochondria has been demonstrated in non-malignant cells [38], it is possible that activated CSCs undergo altered metabolic reprogramming (Fig. 3). Similarly, the survivors after transient depletion of a driver oncogene (i.e., activated mutant KRASG12D in pancreatic cancer) tend to depend heavily on OXPHOS in mitochondria rather than aerobic glycolysis. Comprehensive analysis of metabolic pathways of survivors after chemotherapy revealed the prominent expression of genes that regulate mitochondrial function, autophagy and lysosome degradation activity, as well as a strong reliance on mitochondrial respiration and diminished dependence on the Warburg effect [10]. Autophagy is a metabolic-recycling pathway involving proteasome-independent degradation of cellular components (e.g., old and dysfunctional mitochondria), which is partially responsible for cancer chemoresistance [39].Fig. 2

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