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: The impact of CAFs on breast cancer biology is discussed and their heterogeneity, origin and their role in tumor progression, ECM remodeling, therapy resistance, metastasis, and the challenges ahead of targeting CAFs to improve therapy response are highlighted.
Abstract: Tumor cells exist in close proximity with non-malignant cells. Extensive and multilayered crosstalk between tumor cells and stromal cells tailors the tumor microenvironment (TME) to support survival, growth, and metastasis. Fibroblasts are one of the largest populations of non-malignant host cells that can be found within the TME of breast, pancreatic, and prostate tumors. Substantial scientific evidence has shown that these cancer-associated fibroblasts (CAFs) are not only associated with tumors by proximity but are also actively recruited to developing tumors where they can influence other cells of the TME as well as influencing tumor cell survival and metastasis. This review discusses the impact of CAFs on breast cancer biology and highlights their heterogeneity, origin and their role in tumor progression, ECM remodeling, therapy resistance, metastasis, and the challenges ahead of targeting CAFs to improve therapy response.
134 citations
Cites background from "Metabolic reprogramming of cancer-a..."
...found that TGF-β or PDGFstimulated CAFs downregulated their isocitrate dehydrogenase 3a (IDH3a) levels which promoted a shift in metabolism toward glycolysis leading to sustained tumor growth [36]....
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TL;DR: This review focuses on the metabolic remodeling achieved through an active cooperation and competition among the three principal components of the TME—the tumor cells, the T cells, and the cancer-associated fibroblasts while discussing about the current strategies that target metabolism of TME components.
Abstract: The tumor microenvironment (TME) is an ensemble of non-tumor cells comprising fibroblasts, cells of the immune system and endothelial cells, besides various soluble secretory factors from all cellular components (including tumor cells). The TME forms a pro-tumorigenic cocoon around the tumor cells where reprogramming of the metabolism occurs in tumor and non-tumor cells that underlies the nature of interactions as well as competitions ensuring steady supply of nutrients and anapleoretic molecules for the tumor cells that fuels its growth even under hypoxic conditions. This metabolic reprogramming also plays a significant role in suppressing the immune attack on the tumor cells and in resistance to therapies. Thus, the metabolic cooperation and competition among the different TME components besides the inherent alterations in the tumor cells arising out of genetic as well as epigenetic changes supports growth, metastasis and therapeutic resistance. This review focuses on the metabolic remodeling achieved through an active cooperation and competition among the three principal component of the TME—the tumor cells, the T cells and the cancer associated fibroblasts while discussing about the current strategies that target metabolism of TME components. Further, we will also consider the probable therapeutic opportunities targeting the various metabolic pathways as well as the signaling molecules/transcription factors regulating them for development of novel treatment strategies for cancer.
133 citations
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...This imbalance in the relative abundance of TCA cycle metabolites leads to HIF1α stabilization and augment glycolysis (237)....
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...Recently, it has been reported that downregulation of isocitrate dehydrogenase 3α (IDH3α) in CAFs through a TGF-β or PDGFbased pathway might be the key factor that tips the balance toward glycolysis (237)....
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...TGF-β reportedly suppresses the TCA cycle enzyme isocitrate dehydrogenase (237) through a TGF-β/PDGF-mediated pathway thereby promoting glycolytic metabolism in CAF....
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TL;DR: Findings support the concept that selective inhibition of SAA1 in CAFs may provide potential therapeutic benefit to PDAC patients and provide genetic evidence that one of these genes, Saa3, plays a key role on the protumorigenic properties of the stroma, opening the door to the design of future therapeutic strategies.
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is characterized by the presence of abundant desmoplastic stroma primarily composed of cancer-associated fibroblasts (CAFs). It is generally accepted that CAFs stimulate tumor progression and might be implicated in drug resistance and immunosuppression. Here, we have compared the transcriptional profile of PDGFRα+ CAFs isolated from genetically engineered mouse PDAC tumors with that of normal pancreatic fibroblasts to identify genes potentially implicated in their protumorigenic properties. We report that the most differentially expressed gene, Saa3, a member of the serum amyloid A (SAA) apolipoprotein family, is a key mediator of the protumorigenic activity of PDGFRα+ CAFs. Whereas Saa3-competent CAFs stimulate the growth of tumor cells in an orthotopic model, Saa3-null CAFs inhibit tumor growth. Saa3 also plays a role in the cross talk between CAFs and tumor cells. Ablation of Saa3 in pancreatic tumor cells makes them insensitive to the inhibitory effect of Saa3-null CAFs. As a consequence, germline ablation of Saa3 does not prevent PDAC development in mice. The protumorigenic activity of Saa3 in CAFs is mediated by Mpp6, a member of the palmitoylated membrane protein subfamily of the peripheral membrane-associated guanylate kinases (MAGUK). Finally, we interrogated whether these observations could be translated to a human scenario. Indeed, SAA1, the ortholog of murine Saa3, is overexpressed in human CAFs. Moreover, high levels of SAA1 in the stromal component correlate with worse survival. These findings support the concept that selective inhibition of SAA1 in CAFs may provide potential therapeutic benefit to PDAC patients.
130 citations
Cites background from "Metabolic reprogramming of cancer-a..."
...This pathway is activated in Saa3-competent CAFs, possibly playing a role in providing metabolites to their neighboring tumor cells (25)....
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...We also observed significant reduction of P53-signaling–related genes, suggesting cell death evasion (24, 25)....
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TL;DR: It is demonstrated that CAFs exhibit a metabolic shift toward lactate and pyruvate production and fuel biosynthetic pathways of cancer cells, and their breast cancer-promoting phenotype is partly mediated by oxygen-dependent epigenetic modifications.
125 citations
TL;DR: How cell intrinsic and extrinsic factors such as oncogene mutations, nutrient and oxygen availability, and other microenvironmental factors influence fuel choice are described.
115 citations
Cites background from "Metabolic reprogramming of cancer-a..."
...Zhang et al. found that during the transition from naive fibroblasts to CAFs cells switch from oxidative phosphorylation to aerobic glycolysis, which was mediated by downregulation of IDH3a and HIF-1a stabilization (Zhang et al., 2015)....
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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