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: This study uncovered the ITGB2high pro-tumoral CAFs that activated the PI3K/AKT/mTOR axis to promote tumor proliferation in OSCC by NADH oxidation in the mitochondrial oxidative phosphorylation system.
Abstract: Objectives: Integrins, the coordinator of extracellular and intracellular signaling, are often found to be aberrant in tumors and can reshape the tumor microenvironment. Although previous studies showed that integrin beta 2 (ITGB2) is important for host defense, its expression profile and role in tumors, especially in cancer associated fibroblasts (CAFs) are still unknown. Methods: Immunofluorescence stain and fluorescence activated cell sorting were used to analyze the ITGB2 expression profile in oral squamous cell carcinoma (OSCC). RT-PCR and western blot were used to compare ITGB2 expression in normal fibroblasts (NFs) and cancer associated fibroblasts (CAFs). Clinical data and function-based experiments were used to investigate the promoting tumor growth ability of ITGB2 expressing CAFs. Enhanced glycolysis activity was identified by using bioinformatics analyses and GC/MS assays. MCT1 knockdown OSCC cell lines were constructed to explore the pro-proliferative mechanisms of ITGB2 expressing CAFs in multiple in vitro and in vivo assays. Results: We found that CAFs exhibited significantly higher ITGB2 expression than the matched NFs. In addition, higher ITGB2 expression in CAFs was correlated with higher TNM stages and more Ki67+ tumor cells, indicating its ability to promote OSCC proliferation. Further, co-culture assay demonstrated that ITGB2-mediated lactate release in CAFs promoted OSCC cell proliferation. Mechanically, ITGB2 regulated PI3K/AKT/mTOR pathways to enhance glycolysis activity in CAFs. Accordingly, lactate derived from ITGB2-expressing CAFs was absorbed and metabolized in OSCC to generate NADH, which was then oxidized in the mitochondrial oxidative phosphorylation system (OXPHOS) to produce ATP. Notably, inhibiting the OXPHOS system with metformin delayed the proliferative capacity of OSCC cells cultured in the ITGB2-expressing CAFs medium. Conclusions: Our study uncovered the ITGB2high pro-tumoral CAFs that activated the PI3K/AKT/mTOR axis to promote tumor proliferation in OSCC by NADH oxidation in the mitochondrial oxidative phosphorylation system.
44 citations
Cites background from "Metabolic reprogramming of cancer-a..."
...For example, in breast cancer, prostate cancer and melanoma, the CAFs-mediated reverse Warburg effect, where CAFs undergo anaerobic glycolytic activity to release lactate to nearby tumor cells, has been reported [9-13]....
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...In melanoma, TGF-β1 or PDGF induced CAFs to switch from oxidative phosphorylation to anaerobic glycolysis [9]....
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TL;DR: Exosomes released by HT29 differentiating cells carried increased levels of miRNAs, induced an increased proliferation and motility of both colon cancer cells and normal fibroblasts, increased the colony-forming efficiency of cancer cells, and reduced the sodium butyrate-induced differentiation of HT29 cells.
Abstract: Exosomes are involved in intercellular communication. We previously reported that sodium butyrate–induced differentiation of HT29 colon cancer cells is associated with a reduced CD133 expression. Herein, we analyzed the role of exosomes in the differentiation of HT29 cells. Exosomes were prepared using ultracentrifugation. Gene expression levels were evaluated by real-time PCR. The cell proliferation rate was assessed by MTT assay and with the electric cell-substrate impedance sensing system, whereas cell motility was assessed using the scratch test and confocal microscopy. Sodium butyrate–induced differentiation of HT29 and Caco-2 cells increased the levels of released exosomes and their expression of CD133. Cell differentiation and the decrease of cellular CD133 expression levels were prevented by blocking multivesicular body maturation. Exosomes released by HT29 differentiating cells carried increased levels of miRNAs, induced an increased proliferation and motility of both colon cancer cells and normal fibroblasts, increased the colony-forming efficiency of cancer cells, and reduced the sodium butyrate–induced differentiation of HT29 cells. Such effects were associated with an increased phosphorylation level of both Src and extracellular signal regulated kinase proteins and with an increased expression of epithelial-to-mesenchymal transition–related genes. Release of exosomes is affected by differentiation of colon cancer cells; exosomes might be used by differentiating cells to get rid of components that are no longer necessary but might continue to exert their effects on recipient cells.
43 citations
TL;DR: How immune cells may be involved in shaping the metabolic features of cancer cells and how they might improve the anti‐tumor functions of tumor‐specific T cells by rewiring their metabolic regulations are postulated.
Abstract: Cancer immunotherapy unleashing the power of host immunity on eliminating cancer cells represents a critical advance in cancer treatment; however, effective anti-tumor responses are largely dampened by the immunosuppressive tumor microenvironment (TME). Emerging studies have revealed that physiological features in the TME, including glucose deprivation, hypoxia and low pH, established by the metabolically dysregulated cancer cells restrict anti-tumor immunity by impeding the metabolic fitness of tumor-infiltrating cytotoxic CD8+ T cells and natural killer (NK) cells. Furthermore, infiltrating immunomodulatory cells with different metabolic preferences also facilitate the establishment of the immunosuppressive TME. Therefore, deciphering the metabolic cross-talk between immune cells and cancer cells in the TME and elucidating the impact of this process during tumorigenesis are needed to harness anti-tumor immunity more effectively. Herein, we summarize the immunosuppressive features of TME and how these features impair anti-tumor immunity. Moreover, we postulate how immune cells may be involved in shaping the metabolic features of cancer cells and discuss how we might improve the anti-tumor functions of tumor-specific T cells by rewiring their metabolic regulations.
43 citations
TL;DR: It is reported that transient receptor potential canonical (TRPC) 6 channels control hydroxylation and stability of HIF-1α in human glioma cells under hypoxia and regulated GLUT1 (also known as SLC2A1) expression in a manner that was dependent on Hif-1 α accumulation to affect glucose uptake during hypoxIA.
Abstract: Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor responsible for the expression of a broad range of genes that facilitate acclimatization to hypoxia. Its stability is predominantly controlled by rapid hydroxylation of two proline residues in its alpha-subunit. However, how the rapid hydroxylation of HIF-1 alpha is regulated is not fully understood. Here, we report that transient receptor potential canonical (TRPC) 6 channels control hydroxylation and stability of HIF-1 alpha in human glioma cells under hypoxia. TRPC6 was rapidly activated by IGF-1R-PLC gamma-IP3R pathway upon hypoxia. Inhibition of TRPC6 enhanced the levels of a-ketoglutarate and promoted hydroxylation of HIF-1 alpha to suppress HIF-1 alpha accumulation without affecting its transcription or translation. Dimethyloxalylglycine N-(methoxyoxoacetyl)-glycine methyl ester (DMOG), an analog of alpha-ketoglutarate, reversed the inhibition of HIF-1 alpha accumulation. Moreover, TRPC6 regulated GLUT1 (also known as SLC2A1) expression in a manner that was dependent on HIF-1 alpha accumulation to affect glucose uptake during hypoxia. Our results suggest that TRPC6 regulates metabolism to affect HIF-1 alpha stability and consequent glucose metabolism in human glioma cells under hypoxia.
42 citations
Cites methods from "Metabolic reprogramming of cancer-a..."
...The intracellular levels of α-ketoglutarate and succinate were analyzed by GC-MS as previously described (Zhang et al., 2015)....
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...GC-MS analysis of α-ketoglutarate and succinate The intracellular levels of α-ketoglutarate and succinate were analyzed by GC-MS as previously described (Zhang et al., 2015)....
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TL;DR: In this paper, metabolic, microRNAs, and ncRNAs alterations in cancer cells can be sorted and delivered either to intercellular matrix or to cancer adjacent cells to shape cancer microenvironment via media such as exosome.
Abstract: The changes associated with malignancy are not only in cancer cells but also in environment in which cancer cells live. Metabolic reprogramming supports tumor cell high demand of biogenesis for their rapid proliferation, and helps tumor cell to survive under certain genetic or environmental stresses. Emerging evidence suggests that metabolic alteration is ultimately and tightly associated with genetic changes, in particular the dysregulation of key oncogenic and tumor suppressive signaling pathways. Cancer cells activate HIF signaling even in the presence of oxygen and in the absence of growth factor stimulation. This cancer metabolic phenotype, described firstly by German physiologist Otto Warburg, insures enhanced glycolytic metabolism for the biosynthesis of macromolecules. The conception of metabolite signaling, i.e., metabolites are regulators of cell signaling, provides novel insights into how reactive oxygen species (ROS) and other metabolites deregulation may regulate redox homeostasis, epigenetics, and proliferation of cancer cells. Moreover, the unveiling of noncanonical functions of metabolic enzymes, such as the moonlighting functions of phosphoglycerate kinase 1 (PGK1), reassures the importance of metabolism in cancer development. The metabolic, microRNAs, and ncRNAs alterations in cancer cells can be sorted and delivered either to intercellular matrix or to cancer adjacent cells to shape cancer microenvironment via media such as exosome. Among them, cancer microenvironmental cells are immune cells which exert profound effects on cancer cells. Understanding of all these processes is a prerequisite for the development of a more effective strategy to contain cancers.
41 citations
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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