Metabolic Reprogramming of Cancer Associated Fibroblasts: The Slavery of Stromal Fibroblasts

Avagliano, Angelica; Granato, Giuseppina; Ruocco, Maria Rosaria; Romano, Veronica; Belviso, Immacolata; Carfora, Antonia; Montagnani, Stefania; Arcucci, Alessandro

doi:10.1155/2018/6075403

Cited by 112 publications

(143 citation statements)

References 107 publications

(181 reference statements)

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“…[51][52][53]). Considerable evidence suggests that this metabolic rewiring of metabolism in stromal cells contributes to cancer malignancies [51][52][53][54][55][56][57][58][59]. Our results suggest that as the Gleason grade increases, rewiring of glutamine metabolism in the stromal cell compartment contributes to advancing malignancy.…”

Section: Biological Importance Of Gls1 and Glutaminase II Pathway Enzmentioning

confidence: 56%

High Levels of Glutaminase II Pathway Enzymes in Normal and Cancerous Prostate Suggest a Role in ‘Glutamine Addiction’

Dorai

Pinto

et al. 2019

Biomolecules

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Many tumors readily convert l-glutamine to α-ketoglutarate. This conversion is almost invariably described as involving deamidation of l-glutamine to l-glutamate followed by a transaminase (or dehydrogenase) reaction. However, mammalian tissues possess another pathway for conversion of l-glutamine to α-ketoglutarate, namely the glutaminase II pathway: l-Glutamine is transaminated to α-ketoglutaramate, which is then deamidated to α-ketoglutarate by ω-amidase.Here we show that glutamine transaminase and ω-amidase specific activities are high in normal rat prostate. Immunohistochemical analyses revealed that glutamine transaminase K (GTK) and ω-amidase are present in normal and cancerous human prostate and that expression of these enzymes increases in parallel with aggressiveness of the cancer cells. Our findings suggest that the glutaminase II pathway is important in providing anaplerotic carbon to the tricarboxylic acid (TCA) cycle, closing the methionine salvage pathway, and in the provision of citrate carbon in normal and cancerous prostate. Finally, our data also suggest that selective inhibitors of GTK and/or ω-amidase may be clinically important for treatment of prostate cancer. In conclusion, the demonstration of a prominent glutaminase II pathway in prostate cancer cells and increased expression of the pathway with increasing aggressiveness of tumor cells provides a new perspective on 'glutamine addiction' in cancers.

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Section: Biological Importance Of Gls1 and Glutaminase II Pathway Enzmentioning

confidence: 56%

High Levels of Glutaminase II Pathway Enzymes in Normal and Cancerous Prostate Suggest a Role in ‘Glutamine Addiction’

Dorai

Pinto

et al. 2019

Biomolecules

View full text Add to dashboard Cite

show abstract

“…The crosstalk between cancer cells and TME, especially stroma cells is widely discussed, which might be the major cause of tumour progression. 87 Fu et al showed CAFs could secrete and produce the energy metabolites, such as pyruvate and ketone bodies, in order to supply cancer cells. 88 Cancer-associated fibroblasts stimulate the growth and proliferation of tumour cells.…”

Section: Reg Ul Ati On Of C An Cer-a Sso Ciated Fib Rob L a S Ts Inmentioning

confidence: 99%

Crosstalk between cancer‐associated fibroblasts and immune cells in cancer

Liu

Chen

et al. 2019

J Cellular Molecular Medi

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Multiple studies have shown that cancer‐associated fibroblasts (CAFs) play an important role in tumour progression, including carcinogenesis, invasion, metastasis and the chemoresistance of cancer cells. Immune cells, including macrophages, natural killer cells, dendritic cells and T cells, play a dual role in the tumour microenvironment. Although increasing research has focused on studying interactions between distinct cells in the tumour microenvironment, the complex relationships between CAFs and immune cells remain unclear and need further study. Here, we summarize our current understanding of crosstalk between CAFs and immune cells, which may help clarify their diagnostic and therapeutic value in tumour progression.

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“…Our data, along with studies from others (Ding et al, 2017, Xie et al, 2015, demonstrate that 2-DG (an hexokinase inhibitor) drastically decreases collagen1 production in myofibroblasts in vitro. There is emerging evidence showing that augmented glycolysis in cancer stromal cells (also call cancer associated fibroblasts) support cancer progression through secreting lactate and other glycolytic intermediates (Avagliano, Granato et al, 2018). In addition, a decrease in microenviromental pH from lactic acid accumulation has been associated with increased TGFβ activity (Kottmann, Kulkarni et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Orphan nuclear receptor COUP-TFII drives the myofibroblast metabolic shift leading to fibrosis

Galichon

Xiao

et al. 2020

Preprint

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Recent studies demonstrated that metabolic disturbance, such as augmented glycolysis, contributes to fibrosis. The molecular regulation of this metabolic perturbation in fibrosis, however, has been elusive. COUP-TFII (also known as NR2F2) is an important regulator of glucose and lipid metabolism. Its contribution to organ fibrosis is undefined. Here, we found increased COUP-TFII expression in myofibroblasts in kidneys of patients with chronic kidney disease, fibrotic lungs of patients with idiopathic pulmonary fibrosis, fibrotic human kidney organoids, and fibrotic mouse kidneys after injury. Genetic ablation of COUP-TFII in mice resulted in attenuation of injury-induced kidney fibrosis. A non-biased proteomic study revealed the suppression of fatty acid oxidation and the enhancement of glycolysis pathways in COUP-TFII overexpressing fibroblasts. Overexpression of COUP-TFII in fibroblasts was sufficient to enhance glycolysis and increase alpha smooth muscle actin (αSMA) and collagen1 levels. Knockout of COUP-TFII decreased glycolysis and collagen1 levels in fibroblasts. Chip-qPCR assays revealed the binding of COUP-TFII on the promoter of PGC1α, a critical regulator of mitochondrial genesis and oxidative metabolism. Overexpression of COUP-TFII reduced the cellular level of PGC1α. In conclusion, COUP-TFII mediates fibrosis by serving as a key regulator of the shift in cellular metabolism of interstitial pericytes/fibroblasts from oxidative respiration to aerobic glycolysis. The fibrogenic response may share a common pathway in different organ injury and failure. Targeting COUP-TFII serves as a novel treatment approach for mitigating fibrosis in chronic kidney disease and potential other organ fibrosis.

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Metabolic Reprogramming of Cancer Associated Fibroblasts: The Slavery of Stromal Fibroblasts

Cited by 112 publications

References 107 publications

High Levels of Glutaminase II Pathway Enzymes in Normal and Cancerous Prostate Suggest a Role in ‘Glutamine Addiction’

High Levels of Glutaminase II Pathway Enzymes in Normal and Cancerous Prostate Suggest a Role in ‘Glutamine Addiction’

Crosstalk between cancer‐associated fibroblasts and immune cells in cancer

Orphan nuclear receptor COUP-TFII drives the myofibroblast metabolic shift leading to fibrosis

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