Metabolic reprogramming of cancer-associated fibroblasts by IDH3α downregulation.
TL;DR: It is reported that TGF-β1- or PDGF-induced CAFs switch from oxidative phosphorylation to aerobic glycolysis, and downregulation of isocitrate dehydrogenase 3α (IDH3α) is identified as a marker for this switch.
About: This article is published in Cell Reports.The article was published on 2015-03-03 and is currently open access. It has received 249 citations till now. The article focuses on the topics: Anaerobic glycolysis & Oxidative phosphorylation.
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TL;DR: Improved understanding of how metabolism in the TME modulates cancer development and evasion of tumour-suppressive mechanisms may provide clues for novel anticancer therapeutics directed to metabolic targets.
113 citations
TL;DR: It is proposed that as cancer progresses, tumor cells influence their surrounding stroma to move from a cancer restraining phenotype into a cancer supportive role and a dual function of fibrosis which evolves during the continuum of cancer growth is supported.
109 citations
TL;DR: Results show that TGF‐β1 induces PFKFB3 expression through activation of the p38 MAPK and PI3K/Akt signaling pathways that complement and converge with early activation of Smad signaling, which suggests that PFK FB3 induction by TGF•β1 can be one of the main mechanisms mediating the reprogramming of glioma cells.
Abstract: In human cancers, transforming growth factor-β1 (TGF-β1) plays a dual role by acting as both a tumor suppressor and a promoter of tumor metastasis. Although TGF-β1 contributes to the metabolic reprogramming of cancer cells and tumor-associated stromal cells, little is known of the molecular mechanisms connecting this cytokine with enhanced glycolysis. PFKFB3 is a homodymeric bifunctional enzyme, belonging to the family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases, that controls the conversion of fructose-6-phosphate (Fru-6-P) to fructose-2,6-bisphosphate (Fru-2,6-P2 ). This metabolite is important for the dynamic regulation of glycolytic flux by allosterically activating phosphofructokinase-1, a rate-limiting enzyme in glycolysis. The PFKFB3 gene is involved in cell proliferation via its role in carbohydrate metabolism. Here, we studied the mechanisms connecting TGF-β1, glucose metabolism, and PFKFB3 in glioblastoma cell lines. We demonstrate that TGF-β1 upregulates PFKFB3 mRNA and protein expression resulting in an increase in fructose 2,6-bisphosphate concentration, glucose uptake, glycolytic flux and lactate production. Moreover, these increases in PFKFB3 mRNA and protein expression and Fru-2,6-P2 concentration were reduced when the Smad3, p38 mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways were inhibited. We demonstrate that inhibition of PFKFB3 activity with 3PO or siRNA-mediated knockdown of PFKFB3 significantly eliminated the capacity of the T98G cells to form colonies by TGF-β1, one of the hallmarks of transformation. Taken together, these results show that TGF-β1 induces PFKFB3 expression through activation of the p38 MAPK and PI3K/Akt signaling pathways that complement and converge with early activation of Smad signaling. This suggests that PFKFB3 induction by TGF-β1 can be one of the main mechanisms mediating the reprogramming of glioma cells.
108 citations
TL;DR: The results provide a new insight into the mechanism of CRC metastasis and suggest FASN of CAFs or CD36 of CRC cells may be potential targets for anti-metastasis treatment in the future.
Abstract: Metabolic interaction between cancer-associated fibroblasts (CAFs) and colorectal cancer (CRC) cells plays a major role in CRC progression. However, little is known about lipid alternations in CAFs and how these metabolic reprogramming affect CRC cells metastasis. Here, we uncover CAFs conditioned medium (CM) promote the migration of CRC cells compared with normal fibroblasts CM. CAFs undergo a lipidomic reprogramming, and accumulate more fatty acids and phospholipids. CAFs CM after protein deprivation still increase the CRC cells migration, which suggests small molecular metabolites in CAFs CM are responsible for CRC cells migration. Then, we confirm that CRC cells take up the lipids metabolites that are secreted from CAFs. Fatty acids synthase (FASN), a crucial enzyme in fatty acids synthesis, is significantly increased in CAFs. CAF-induced CRC cell migration is abolished by knockdown of FASN by siRNA or reducing the uptake of fatty acids by CRC cells by sulfo-N-succinimidyloleate sodium in vitro and CD36 monoclonal antibody in vivo. To conclude, our results provide a new insight into the mechanism of CRC metastasis and suggest FASN of CAFs or CD36 of CRC cells may be potential targets for anti-metastasis treatment in the future.
106 citations
TL;DR: The study ofCAFs metabolic reprogramming could contribute to better understand their activation process, the interaction between stroma, and cancer cells and could offer innovative tools for the development of new therapeutic strategies able to eradicate the protumorigenic activity of CAFs.
Abstract: Cancer associated fibroblasts (CAFs) are the main stromal cell type of solid tumour microenvironment and undergo an activation process associated with secretion of growth factors, cytokines, and paracrine interactions. One of the important features of solid tumours is the metabolic reprogramming that leads to changes of bioenergetics and biosynthesis in both tumour cells and CAFs. In particular, CAFs follow the evolution of tumour disease and acquire a catabolic phenotype: in tumour tissues, cancer cells and tumour microenvironment form a network where the crosstalk between cancer cells and CAFs is associated with cell metabolic reprogramming that contributes to CAFs activation, cancer growth, and progression and evasion from cancer therapies. In this regard, the study of CAFs metabolic reprogramming could contribute to better understand their activation process, the interaction between stroma, and cancer cells and could offer innovative tools for the development of new therapeutic strategies able to eradicate the protumorigenic activity of CAFs. Therefore, this review focuses on CAFs metabolic reprogramming associated with both differentiation process and cancer and stromal cells crosstalk. Finally, therapeutic responses and potential anticancer strategies targeting CAFs metabolic reprogramming are reviewed.
92 citations
References
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TL;DR: It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration.
Abstract: Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.
12,395 citations
TL;DR: Pathological angiogenesis is a hallmark of cancer and various ischaemic and inflammatory diseases and integrated understanding is leading to the development of a number of exciting and bold approaches to treat cancer and other diseases, but owing to several unanswered questions, caution is needed.
Abstract: Pathological angiogenesis is a hallmark of cancer and various ischaemic and inflammatory diseases Concentrated efforts in this area of research are leading to the discovery of a growing number of pro- and anti-angiogenic molecules, some of which are already in clinical trials The complex interactions among these molecules and how they affect vascular structure and function in different environments are now beginning to be elucidated This integrated understanding is leading to the development of a number of exciting and bold approaches to treat cancer and other diseases But owing to several unanswered questions, caution is needed
8,561 citations
"Metabolic reprogramming of cancer-a..." refers background in this paper
...The development and progression of tumors are controlled not only by tumor cells but also by their surrounding stromal cells (Carmeliet and Jain, 2000; Rønnov-Jessen et al., 1996; Tlsty, 2001)....
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TL;DR: Using a coimplantation tumor xenograft model, it is demonstrated that carcinoma-associated fibroblasts extracted from human breast carcinomas promote the growth of admixed breast carcinoma cells significantly more than do normal mammaries derived from the same patients.
3,373 citations
"Metabolic reprogramming of cancer-a..." refers background in this paper
..., 1999), progression (Dimanche-Boitrel et al., 1994; Orimo et al., 2005), and metastasis (Grum-Schwensen et al....
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...Through specific communications with cancer cells, CAFs directly promote tumor initiation (Bhowmick et al., 2004; Olumi et al., 1999), progression (Dimanche-Boitrel et al., 1994; Orimo et al., 2005), and metastasis (Grum-Schwensen et al., 2005; Olaso et al., 1997)....
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TL;DR: The basement membrane (BM) as mentioned in this paper is a specialized form of extracellular matrix (ECM) which mediates tissue compartmentalization and sends signals to epithelial cells about the external microenvironment.
Abstract: In recent years, the basement membrane (BM)--a specialized form of extracellular matrix (ECM)--has been recognized as an important regulator of cell behaviour, rather than just a structural feature of tissues. The BM mediates tissue compartmentalization and sends signals to epithelial cells about the external microenvironment. The BM is also an important structural and functional component of blood vessels, constituting an extracellular microenvironment sensor for endothelial cells and pericytes. Vascular BM components have recently been found to be involved in the regulation of tumour angiogenesis, making them attractive candidate targets for potential cancer therapies.
1,560 citations
TL;DR: In this paper, the authors demonstrate that fibroblasts associated with carcinomas stimulate tumor progression of initiated nontumorigenic epithelial cells both in an in vivo tissue recombination system and in vitro coculture system.
Abstract: The present study demonstrates that fibroblasts associated with carcinomas stimulate tumor progression of initiated nontumorigenic epithelial cells both in an in vivo tissue recombination system and in an in vitro coculture system. Human prostatic carcinoma-associated fibroblasts grown with initiated human prostatic epithelial cells dramatically stimulated growth and altered histology of the epithelial population. This effect was not detected when normal prostatic fibroblasts were grown with the initiated epithelial cells under the same experimental conditions. In contrast, carcinoma-associated fibroblasts did not affect growth of normal human prostatic epithelial cells under identical conditions. From these data, we conclude that in this human prostate cancer model, carcinoma-associated fibroblasts stimulate progression of tumorigenesis. Thus, carcinoma-associated fibroblasts can direct tumor progression of an initiated prostate epithelial cell.
1,486 citations