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Journal ArticleDOI

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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Posted ContentDOI
23 Jan 2019-bioRxiv
TL;DR: A computational pipeline to analyze metabolic gene expression programs of single cells within human tumors is developed and malignant cells in general have higher metabolic activity and higher metabolic variation than previously observed from studies of bulk tumor comparisons.
Abstract: The tumor milieu consists of numerous cell types with each cell existing in a different nutritional environment. However, a characterization of intratumoral metabolic heterogeneity at the single-cell level in human cancer is not established. Here, we develop a computational pipeline to analyze metabolic gene expression programs of single cells within human tumors. In two representative cancer types, melanoma and head and neck, we apply this algorithm to define the single-cell metabolic landscape of human tumors. We find that malignant cells in general have higher metabolic activity and higher metabolic variation than previously observed from studies of bulk tumor comparisons. Indeed, most of the observed metabolic variation of single tumor and normal cells were found to be inconsistent with comparisons with bulk tumor samples. Variation in the expression of mitochondrial programs is the major contributor to intratumoral metabolic heterogeneity. Surprisingly, the expression of both glycolytic and mitochondrial programs strongly correlates with hypoxia in almost all cell types. Immune and stromal cells could also be distinguished by their metabolic features. Taken together this analysis establishes a computational framework for characterizing metabolism using single cell expression data and defines principles of intratumoral metabolic heterogeneity.

4 citations

Journal ArticleDOI
01 Aug 2022-Cancers
TL;DR: It is implied that NXPH4 contributes to the proliferation, migration, and invasion of bladder cancer by maintaining the stability of NDUFA4L2 and consequently activating reactive oxygen species and glycolysis.
Abstract: Simple Summary Bladder cancer is one of the most common malignant tumors of the urinary system, and its treatment is mainly surgical resection, supplemented by chemotherapy after surgery. Postoperative chemotherapy can significantly reduce the tumor recurrence rate and improve the prognosis of bladder cancer patients. However, chemotherapy resistance is one of the major challenges in the treatment of bladder cancer. Therefore, we conducted a series bioinformatic analyses and functional experiments to reveal the novel role of NXPH4 in bladder cancer. We found NXPH4 not only influenced the proliferation, migration, invasion ability of cancer cells, but also affected the level of glycolysis and reactive oxygen species and further promoted the gemcitabine resistance of bladder cancer. Our research has found a novel molecule that may play an important part in the neoplasia, which may provide another angle in the treatment of bladder cancer. Abstract Bladder cancer is one of the most prevalent kinds of cancer worldwide, and resistance to gemcitabine is a major problem for patients. The pathogenesis of bladder cancer and mechanism of resistance to chemotherapy remain to be explored. Through bioinformatics analysis, we first found that NXPH4 was independently related to the prognosis of patients with bladder cancer. Through wound healing assays, transwell invasion assays, and plate clone formation assays, we found that NXPH4 promoted the proliferation, migration, and invasion of bladder cancer cells. The induced gemcitabine resistance cell line also showed a higher expression of NXPH4. A glycolytic activity assay demonstrated that the expression of NXPH4 was positively related to glycolysis. A higher level of reactive oxygen species caused by enhanced levels of NXPH4 was found in gemcitabine-resistant cell lines. NDUFA4L2, glycolysis, and reactive oxygen species were shown to be essential for NXPH4-regulated functions through rescue assays in cell lines. The roles of NXPH4-regulated glycolysis, gemcitabine resistance, and NDUFA4L2 were validated in vivo as well. Our results imply that NXPH4 contributes to the proliferation, migration, and invasion of bladder cancer by maintaining the stability of NDUFA4L2 and consequently activating reactive oxygen species and glycolysis.

4 citations

Journal ArticleDOI
TL;DR: The most recent metabolomics approaches in cancer studies on the tumor-associated inflammatory microenvironment are discussed, highlighting the need to understand the metabolic changes that drive the interactions between tumor and stromal cells.
Abstract: Metabolomics is the last frontier of modern molecular biology, and the state-of-the-art technique for studying metabolism. Mass spectrometry and nuclear magnetic resonance spectroscopy are the main analytical approaches in metabolomics. Cellular metabolism plays a pivotal role during cell resting and activation. Immune cells exhibit remarkable metabolic plasticity, fundamental to support their adaptation to inflammatory environments and functional requirements. Cancer is a metabolic and inflammatory disease. A metabolic shift is crucial for oncogenesis, tumor cell survival, invasion, metastasis, and the associated inflammatory process. The tumor microenvironment is mainly orchestrated by immune-inflammatory cells and essential for the neoplastic process. Inflammatory cells from tumor stroma adapt to different metabolic pathways during tumor progression, and this metabolic reprogramming affects macrophages, neutrophils, T cells, and others. Targeting the metabolism of tumor and immune cells may lead to important therapeutic implications in cancer. Thus, understanding the metabolic changes that drive the interactions between tumor and stromal cells is a promising avenue advances in cancer diagnostics and therapies, leading to more accurate guidance. In this review, we discuss the most recent metabolomics approaches in cancer studies on the tumor-associated inflammatory microenvironment.

3 citations


Cites background from "Metabolic reprogramming of cancer-a..."

  • ...Furthermore, CAFs release lactate, which is metabolized by prostate cancer cells([83]) by the socalled “reverse Warburg effect”([84,85])....

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Journal ArticleDOI
TL;DR: A review of recent findings regarding the CRC-related changes in cellular metabolic pathways such as glycolysis, tricarboxylic acid cycle, fatty acid oxidation, and mitochondrial metabolism and an overview of novel pharmacological strategies for the treatment of CRC by targeting metabolic and signaling pathways.
Abstract: Colorectal cancer (CRC) is one of the most prevalent cancers globally. Despite recent progress in identifying etiologies and molecular genetics as well as new therapeutic approaches, the clinical outcome of current CRC therapies remains poor. This fact highlights the importance of further understanding of underlying mechanisms involved in colorectal tumor initiation and progression. Abnormal metabolic alterations offer an evolutional advantage for CRC tumor cells and enhance their aggressive phenotype. Therefore, dysregulation of cellular metabolism is intricately associated with colorectal tumorigenesis. This review summarizes recent findings regarding the CRC-related changes in cellular metabolic pathways such as glycolysis, tricarboxylic acid cycle, fatty acid oxidation, and mitochondrial metabolism. We describe the oncogenic signaling pathways associated with metabolic dysregulation during malignant transformation and tumor progression. Given the crucial role of metabolic pathway alterations in pathogenesis of CRC, we provide an overview of novel pharmacological strategies for the treatment of CRC by targeting metabolic and signaling pathways.

3 citations

Journal ArticleDOI
TL;DR: In this paper , the authors looked for an optimum media glucose concentration and compared glucose consumption in three vascular cell types, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and adventitial fibroblasts (AFs) with or without angiotensin II (AngII) stimulation.
Abstract: In this study, we have looked for an optimum media glucose concentration and compared glucose consumption in three vascular cell types, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and adventitial fibroblasts (AFs) with or without angiotensin II (AngII) stimulation. In a subconfluent 6-well experiment in 1 mL DMEM with a standard low (100 mg/dL), a standard high (450 mg/dL), or a mixed middle (275 mg/dL) glucose concentration, steady and significant glucose consumption was observed in all cell types. After 48-h incubation, media that contained low glucose was reduced to almost 0 mg/dL, media that contained high glucose remained significantly higher at ∼275 mg/dL, and media that contained middle glucose remained closer to physiological range. AngII treatment enhanced glucose consumption in AFs and VSMCs but not in ECs. Enhanced extracellular acidification rate by AngII was also observed in AFs. In AFs, AngII induction of target proteins at 48 h varied depending on the glucose concentration used. In low glucose media, induction of glucose regulatory protein 78 or hexokinase II was highest, whereas induction of VCAM-1 was lowest. Utilization of specific inhibitors further suggests essential roles of angiotensin II type-1 receptor and glycolysis in AngII-induced fibroblast activation. Overall, this study demonstrates a high risk of hypo- or hyperglycemic conditions when standard low or high glucose media is used with vascular cells. Moreover, these conditions may significantly alter experimental outcomes. Media glucose concentration should be monitored during any culture experiments and utilization of middle glucose media is recommended for all vascular cell types.

3 citations

References
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Journal ArticleDOI
19 Dec 2002-Nature
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

Journal ArticleDOI
14 Sep 2000-Nature
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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Journal ArticleDOI
06 May 2005-Cell
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)....

    [...]

Journal ArticleDOI
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

Journal ArticleDOI
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

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