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: A full understanding of tumor metabolism requires an appreciation of the convergence of cancer cell intrinsic metabolism and that of the tumor microenvironment including stromal and immune cells.
Abstract: Cancer metabolism as a field of research was founded almost 100 years ago by Otto Warburg, who described the propensity for cancers to convert glucose to lactate despite the presence of oxygen, which in yeast diminishes glycolytic metabolism known as the Pasteur effect. In the past 20 years, the resurgence of interest in cancer metabolism provided significant insights into processes involved in maintenance metabolism of non-proliferating cells and proliferative metabolism, which is regulated by proto-oncogenes and tumor suppressors in normal proliferating cells. In cancer cells, depending on the driving oncogenic event, metabolism is re-wired for nutrient import, redox homeostasis, protein quality control, and biosynthesis to support cell growth and division. In general, resting cells rely on oxidative metabolism, while proliferating cells rewire metabolism toward glycolysis, which favors many biosynthetic pathways for proliferation. Oncogenes such as MYC, BRAF, KRAS, and PI3K have been documented to rewire metabolism in favor of proliferation. These cell intrinsic mechanisms, however, are insufficient to drive tumorigenesis because immune surveillance continuously seeks to destroy neo-antigenic tumor cells. In this regard, evasion of cancer cells from immunity involves checkpoints that blunt cytotoxic T cells, which are also attenuated by the metabolic tumor microenvironment, which is rich in immuno-modulating metabolites such as lactate, 2-hydroxyglutarate, kynurenine, and the proton (low pH). As such, a full understanding of tumor metabolism requires an appreciation of the convergence of cancer cell intrinsic metabolism and that of the tumor microenvironment including stromal and immune cells.
27 citations
Cites background from "Metabolic reprogramming of cancer-a..."
...Highly glycolytic CAFs then secret lactate, which can then be utilized by presumably less glycolytic cancer cells (Zhang et al., 2015)....
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TL;DR: The decreased ability to handle ER stress, partly due to the presence of excessive oxidative stress, may contribute to increased susceptibility of the aging kidney to acute injury.
Abstract: The aged kidney is susceptible to acute injury due presumably to its decreased ability to handle additional challenges, such as endoplasmic reticulum (ER) stress. This was tested by giving tunicamycin, an ER stress inducer, to either old or young mice. Injection of high dose caused renal failure in old mice, not in young mice. Moreover, injection of low dose resulted in severe renal damage in old mice, confirming the increased susceptibility of aged kidney to ER stress. There existed an abnormality in ER stress response kinetics in aged kidney, characterized by a loss of XBP-1 splicing and decreased PERK-eIF2α phosphorylation at late time point. The presence of excessive oxidative stress in aged kidney may play a role since high levels of oxidation increased ER stress-induced cell death and decreased IRE1 levels and XBP-1 splicing. Importantly, treatment with antioxidants protected old mice from kidney injury and normalized IRE1 and XBP-1 responses. Furthermore, older mice (6 months old) transgenic with antioxidative stress AGER1 were protected from ER stress-induced kidney injury. In conclusion, the decreased ability to handle ER stress, partly due to the presence of excessive oxidative stress, may contribute to increased susceptibility of the aging kidney to acute injury.
27 citations
Cites background from "Metabolic reprogramming of cancer-a..."
...Previous reports have demonstrated that the levels of AGEs were increased in cases of acute kidney injury caused by various reasons including ischemia or endotoxin [45, 51, 52]....
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...Although inhibition of IRE-1 has been shown to reduce apoptosis [36] and activation of PERK-eIF2α may promote apoptosis by inducing CHOP [36], these may not be a general phenomenon since both IRE1-XBP-1 signaling and PERK-eIF2α phosphorylation pathways have also been shown to be critical in maintaining cell survival during ER stress [36, 45]....
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TL;DR: Historical and current views of intratumoral heterogeneity are reviewed, with an emphasis on summarizing the emerging data that begin to illuminate just how vast the spectrum of metabolic strategies a tumor can employ may be, and what this means for how to interpret other tumor characteristics, such as mutational landscape, contribution of microenvironmental influences, and treatment resistance.
Abstract: Tumor functional heterogeneity has been recognized for decades, and technological advancements are fueling renewed interest in uncovering the cell-intrinsic and extrinsic factors that influence tumor development and therapeutic response. Intratumoral heterogeneity is now arguably one of the most-studied topics in tumor biology, leading to the discovery of new paradigms and reinterpretation of old ones, as we aim to understand the profound implications that genomic, epigenomic, and functional heterogeneity hold with regard to clinical outcomes. In spite of our improved understanding of the biological complexity of cancer, characterization of tumor metabolic heterogeneity has lagged behind, lost in a century-old controversy debating whether glycolysis or mitochondrial respiration is more influential. But is tumor metabolism really so simple? Here, we review historical and current views of intratumoral heterogeneity, with an emphasis on summarizing the emerging data that begin to illuminate just how vast the spectrum of metabolic strategies a tumor can employ may be, and what this means for how we might interpret other tumor characteristics, such as mutational landscape, contribution of microenvironmental influences, and treatment resistance.
26 citations
Cites background from "Metabolic reprogramming of cancer-a..."
...This decreases the intracellular levels of α-ketoglutarate, which, in turn, stabilizes HIF1α by preventing its PHD2-mediated degradation [104]....
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TL;DR: The data suggest that miR-150 is involved in regulation of glycolysis in osteosarcoma cells by influencing Glut1 expression, and western blot and luciferase reporter assays showed that mi R-150 may function by regulating Glut 1 expression.
Abstract: Objective: Osteosarcoma (OS) is the most common malignant bone tumor in children and young adults. Many studies have shown that microRNAs play a critical role in proliferation and metastasis with this tumour type. However, whether aberrant expression might contribute to a metabolism switch in osteosarcoma cases is not clearly understood. In this study, we explored expression and function of miR-150 in osteosarcoma cells. Materials and methods: Expression of miR-150 was assessed by real-time PCR in cell lines and human patient tissues. Scramble siRNA, miR-150 inhibitor, and miR-150 mimics were transfected into osteosarcoma cells to determine their effects on proliferation rate, glucose uptake and lactate secretion. Finally, the relationship between Glut1 and the miR-150 level was explored by luciferase reporter assay and western blotting. Result: miR-150 was consistently decreased in cell lines and osteosarcoma tissues as compared to osteoblast cells and normal bone. Ectopic overexpression of miR-150 inhibited osteosarcoma cell proliferation and suppressed glucose uptake and lactate secretion. Loss of function of miR-150, on the other hand, enhanced osteosarcoma cell proliferation and increased glucose uptake and lactate secretion. Western blot and luciferase reporter assays showed that miR-150 may function by regulating Glut1 expression. Conclusion: These data suggest that miR-150 is involved in regulation of glycolysis in osteosarcoma cells by influencing Glut1 expression.
26 citations
Cites background from "Metabolic reprogramming of cancer-a..."
..., 2014), and miR-424 regulates metabolic reprogramming in cancer-associated fibroblasts by decreasing the expression of IDH3a (Zhang et al., 2015)....
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...For example, miR-181a mediates a metabolic switch in colon cancer cells by regulating the PTEN/AKT pathway (Wei et al., 2014), and miR-424 regulates metabolic reprogramming in cancer-associated fibroblasts by decreasing the expression of IDH3a (Zhang et al., 2015). miR-33a and miR-33b play critical roles in regulating cholesterol homeostasis and fatty acid degradation (Davalos et al., 2011), microRNA-495 regulates metabolic shift in glioma cells by targeting Glut1 (Nie et al., 2015), and knockdown of miR-182 is found to increase glucose uptake and glycolysis (Hu et al., 2014)....
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...…pathway (Wei et al., 2014), and miR-424 regulates metabolic reprogramming in cancer-associated fibroblasts by decreasing the expression of IDH3a (Zhang et al., 2015). miR-33a and miR-33b play critical roles in regulating cholesterol homeostasis and fatty acid degradation (Davalos et al., 2011),…...
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TL;DR: In this article, the authors focus on the inhibitory effects of CAFs on cancer development and describe the heterogeneous origin, markers, and metabolism in the CAFs population, and outline CAFs subpopulation and CAFs derived soluble factors that act as a tumor suppressor.
Abstract: Cancer-associated fibroblasts (CAFs) are the main stromal components of cancer, representing a group of heterogeneous cells Many studies indicate that CAFs promote tumor development Besides, evidence of the tumor suppression effects of CAFs keeps on merging In the tumor microenvironment, multiple stimuli can activate fibroblasts Notably, this does not necessarily mean the activated CAFs become strong tumor promoters immediately The varying degree of CAFs activation makes quiescent CAFs, tumor-restraining CAFs, and tumor-promoting CAFs Quiescent CAFs and tumor-restraining CAFs are more present in early-stage cancer, while comparatively, more tumor-promoting CAFs present in advanced-stage cancer The underlying mechanism that balances tumor promotion or tumor inhibition effects of CAFs is mostly unknown This review focus on the inhibitory effects of CAFs on cancer development We describe the heterogeneous origin, markers, and metabolism in the CAFs population Transgenetic mouse models that deplete CAFs or deplete CAFs activation signaling in the tumor stroma present direct evidence of CAFs protective effects against cancer Moreover, we outline CAFs subpopulation and CAFs derived soluble factors that act as a tumor suppressor Single-cell RNA-sequencing on CAFs population provides us new insight to classify CAFs subsets Understanding the full picture of CAFs will help translate CAFs biology from bench to bedside and develop new strategies to improve precision cancer therapy
26 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