scholarly journals Metabolism in tumour-associated macrophages: a quid pro quo with the tumour microenvironment

2020 ◽  
Vol 29 (157) ◽  
pp. 200134
Author(s):  
Xiang Zheng ◽  
Siavash Mansouri ◽  
Annika Krager ◽  
Friedrich Grimminger ◽  
Werner Seeger ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Acid Metabolism ◽  
Environmental Changes ◽  
Tumour Progression ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Metabolic Reprogramming ◽  
High Plasticity ◽  
Functional Alteration

Lung cancer is the leading cause of death from cancer worldwide. Recent studies demonstrated that the tumour microenvironment (TME) is pivotal for tumour progression, providing multiple targeting opportunities for therapeutic strategies. As one of the most abundant stromal cell types in the TME, tumour-associated macrophages (TAMs) exhibit high plasticity. Malignant cells alter their metabolic profiles to adapt to the limited availability of oxygen and nutrients in the TME, resulting in functional alteration of TAMs. The metabolic features of TAMs are strongly associated with their functional plasticity, which further impacts metabolic profiling in the TME and contributes to tumourigenesis and progression. Here, we review the functional determination of the TME by TAM metabolic alterations, including glycolysis as well as fatty acid and amino acid metabolism, which in turn are influenced by environmental changes. Additionally, we discuss metabolic reprogramming of TAMs to a tumouricidal phenotype as a potential antitumoural therapeutic strategy.

scholarly journals Tumour Microenvironment: Roles of the Aryl Hydrocarbon Receptor, O-GlcNAcylation, Acetyl-CoA and Melatonergic Pathway in Regulating Dynamic Metabolic Interactions across Cell Types—Tumour Microenvironment and Metabolism

2020 ◽  
Vol 22 (1) ◽  
pp. 141
Author(s):  
George Anderson
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Glycogen Synthase ◽  
Tumour Progression ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Future Research ◽  
Acetyl Coa ◽  
Dynamic Interactions ◽  
Aryl Hydrocarbon ◽  
Metabolic Interactions

This article reviews the dynamic interactions of the tumour microenvironment, highlighting the roles of acetyl-CoA and melatonergic pathway regulation in determining the interactions between oxidative phosphorylation (OXPHOS) and glycolysis across the array of cells forming the tumour microenvironment. Many of the factors associated with tumour progression and immune resistance, such as yin yang (YY)1 and glycogen synthase kinase (GSK)3β, regulate acetyl-CoA and the melatonergic pathway, thereby having significant impacts on the dynamic interactions of the different types of cells present in the tumour microenvironment. The association of the aryl hydrocarbon receptor (AhR) with immune suppression in the tumour microenvironment may be mediated by the AhR-induced cytochrome P450 (CYP)1b1-driven ‘backward’ conversion of melatonin to its immediate precursor N-acetylserotonin (NAS). NAS within tumours and released from tumour microenvironment cells activates the brain-derived neurotrophic factor (BDNF) receptor, TrkB, thereby increasing the survival and proliferation of cancer stem-like cells. Acetyl-CoA is a crucial co-substrate for initiation of the melatonergic pathway, as well as co-ordinating the interactions of OXPHOS and glycolysis in all cells of the tumour microenvironment. This provides a model of the tumour microenvironment that emphasises the roles of acetyl-CoA and the melatonergic pathway in shaping the dynamic intercellular metabolic interactions of the various cells within the tumour microenvironment. The potentiation of YY1 and GSK3β by O-GlcNAcylation will drive changes in metabolism in tumours and tumour microenvironment cells in association with their regulation of the melatonergic pathway. The emphasis on metabolic interactions across cell types in the tumour microenvironment provides novel future research and treatment directions.

scholarly journals A Complex Metabolic Network Confers Immunosuppressive Functions to Myeloid-Derived Suppressor Cells (MDSCs) within the Tumour Microenvironment

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2700
Author(s):  
Francesca Hofer ◽  
Gianna Di Sario ◽  
Chiara Musiu ◽  
Silvia Sartoris ◽  
Francesco De Sanctis ◽  
...  
Keyword(s):  
Metabolic Network ◽  
Cancer Progression ◽  
Immune Cells ◽  
Energy Demand ◽  
Tumour Progression ◽  
Suppressor Cells ◽  
Tumour Microenvironment ◽  
Metabolic Reprogramming ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Proliferation And Differentiation

Myeloid-derived suppressor cells (MDSCs) constitute a plastic and heterogeneous cell population among immune cells within the tumour microenvironment (TME) that support cancer progression and resistance to therapy. During tumour progression, cancer cells modify their metabolism to sustain an increased energy demand to cope with uncontrolled cell proliferation and differentiation. This metabolic reprogramming of cancer establishes competition for nutrients between tumour cells and leukocytes and most importantly, among tumour-infiltrating immune cells. Thus, MDSCs that have emerged as one of the most decisive immune regulators of TME exhibit an increase in glycolysis and fatty acid metabolism and also an upregulation of enzymes that catabolise essential metabolites. This complex metabolic network is not only crucial for MDSC survival and accumulation in the TME but also for enhancing immunosuppressive functions toward immune effectors. In this review, we discuss recent progress in the field of MDSC-associated metabolic pathways that could facilitate therapeutic targeting of these cells during cancer progression.

scholarly journals Macrophage-Mediated Subversion of Anti-Tumour Immunity

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 747 ◽  
Author(s):  
Valeria Quaranta ◽  
Michael C. Schmid
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Tumour Progression ◽  
Immune Surveillance ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Tumour Immunity ◽  
Cell Recruitment ◽  
Clinical Benefits

Despite the incredible clinical benefits obtained by the use of immune checkpoint blockers (ICBs), resistance is still common for many types of cancer. Central for ICBs to work is activation and infiltration of cytotoxic CD8+ T cells following tumour-antigen recognition. However, it is now accepted that even in the case of immunogenic tumours, the effector functions of CD8+ T cells are highly compromised by the presence of an immunosuppressive tumour microenvironment (TME) at the tumour site. Tumour-associated macrophages (TAMs) are among the most abundant non-malignant stromal cell types within the TME and they are crucial drivers of tumour progression, metastasis and resistance to therapy. TAMs are able to regulate either directly or indirectly various aspects of tumour immunity, including T cell recruitment and functions. In this review we discuss the mechanisms by which TAMs subvert CD8+ T cell immune surveillance and how their targeting in combination with ICBs represents a very powerful therapeutic strategy.

scholarly journals Metabolism of Amino Acids in Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Zhen Wei ◽  
Xiaoyi Liu ◽  
Chunming Cheng ◽  
Wei Yu ◽  
Ping Yi
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Therapeutic Strategy ◽  
Acid Metabolism ◽  
Epigenetic Modification ◽  
Mammalian Target Of Rapamycin ◽  
Metabolic Reprogramming ◽  
Mtorc1 Signaling ◽  
Uptake And Metabolism

Metabolic reprogramming has been widely recognized as a hallmark of malignancy. The uptake and metabolism of amino acids are aberrantly upregulated in many cancers that display addiction to particular amino acids. Amino acids facilitate the survival and proliferation of cancer cells under genotoxic, oxidative, and nutritional stress. Thus, targeting amino acid metabolism is becoming a potential therapeutic strategy for cancer patients. In this review, we will systematically summarize the recent progress of amino acid metabolism in malignancy and discuss their interconnection with mammalian target of rapamycin complex 1 (mTORC1) signaling, epigenetic modification, tumor growth and immunity, and ferroptosis. Finally, we will highlight the potential therapeutic applications.

scholarly journals Regulation of Extracellular Matrix Production in Activated Fibroblasts: Roles of Amino Acid Metabolism in Collagen Synthesis

2021 ◽  
Vol 11 ◽  
Author(s):  
Emily J. Kay ◽  
Grigorios Koulouras ◽  
Sara Zanivan
Keyword(s):  
Extracellular Matrix ◽  
Tumour Growth ◽  
Acid Metabolism ◽  
Tumour Progression ◽  
Tumour Microenvironment ◽  
Cancer Associated Fibroblasts ◽  
Secretory Phenotype ◽  
Matrix Production ◽  
Activated Fibroblasts ◽  
Translational Level

Cancer associated fibroblasts (CAFs) are a major component of the tumour microenvironment in most tumours, and are key mediators of the response to tissue damage caused by tumour growth and invasion, contributing to the observation that tumours behave as ‘wounds that do not heal’. CAFs have been shown to play a supporting role in all stages of tumour progression, and this is dependent on the highly secretory phenotype CAFs develop upon activation, of which extracellular matrix (ECM) production is a key element. A collagen rich, stromal ECM has been shown to influence tumour growth and metastasis, exclude immune cells and impede drug delivery, and is associated with poor prognosis in many cancers. CAFs also extensively remodel their metabolism to support cancer cells, however, it is becoming clear that metabolic rewiring also supports intrinsic functions of activated fibroblasts, such as increased ECM production. In this review, we summarise how fibroblasts metabolically regulate ECM production, focussing on collagen production, at the transcriptional, translational and post-translational level, and discuss how this can provide possible strategies for effectively targeting CAF activation and formation of a tumour-promoting stroma.

scholarly journals The Metabolic Features of Tumor-Associated Macrophages: Opportunities for Immunotherapy?

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Sonja S. Mojsilovic ◽  
Slavko Mojsilovic ◽  
Victor H. Villar ◽  
Juan F. Santibanez
Keyword(s):  
Cancer Progression ◽  
Tumor Tissue ◽  
Acid Metabolism ◽  
Cell Types ◽  
Innate Immune ◽  
High Plasticity ◽  
Tumor Associated Macrophages ◽  
Cell Therapies ◽  
Physical Barriers ◽  
Cancer Immunotherapies

Besides transformed cells, the tumors are composed of various cell types that contribute to undesirable tumor progression. Tumor-associated macrophages (TAMs) are the most abundant innate immune cells in the tumor microenvironment (TME). Within the TME, TAMs exhibit high plasticity and undergo specific functional metabolic alterations according to the availability of tumor tissue oxygen and nutrients, thus further contributing to tumorigenesis and cancer progression. Here, we review the main functional TAM metabolic patterns influenced by TME, including glycolysis, amino acid, and fatty acid metabolism. Moreover, this review discusses antitumor immunotherapies that affect TAM functionality by inducing cell repolarizing and metabolic profiles towards an antitumoral phenotype. Also, new macrophage-based cell therapeutic technologies recently developed using chimeric antigen receptor bioengineering are exposed, which may overcome all solid tumor physical barriers impeding the current adoptive cell therapies and contribute to developing novel cancer immunotherapies.

scholarly journals Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4831
Author(s):  
Jiaqi Li ◽  
Jie Qing Eu ◽  
Li Ren Kong ◽  
Lingzhi Wang ◽  
Yaw Chyn Lim ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Immune Cells ◽  
Therapeutic Strategy ◽  
Treatment Resistance ◽  
Tumour Microenvironment ◽  
Therapeutic Strategies ◽  
Metabolic Reprogramming ◽  
Cancer Associated Fibroblasts ◽  
Tumour Metabolism

Targeting altered tumour metabolism is an emerging therapeutic strategy for cancer treatment. The metabolic reprogramming that accompanies the development of malignancy creates targetable differences between cancer cells and normal cells, which may be exploited for therapy. There is also emerging evidence regarding the role of stromal components, creating an intricate metabolic network consisting of cancer cells, cancer-associated fibroblasts, endothelial cells, immune cells, and cancer stem cells. This metabolic rewiring and crosstalk with the tumour microenvironment play a key role in cell proliferation, metastasis, and the development of treatment resistance. In this review, we will discuss therapeutic opportunities, which arise from dysregulated metabolism and metabolic crosstalk, highlighting strategies that may aid in the precision targeting of altered tumour metabolism with a focus on combinatorial therapeutic strategies.

scholarly journals The Role of Tumour Metabolism in Cisplatin Resistance

2021 ◽  
Vol 8 ◽  
Author(s):  
Lude Wang ◽  
Xiaoya Zhao ◽  
Jianfei Fu ◽  
Wenxia Xu ◽  
Jianlie Yuan
Keyword(s):  
Metabolic Pathways ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Cisplatin Resistance ◽  
Tumour Progression ◽  
Tumour Cells ◽  
Metabolic Reprogramming ◽  
Antitumour Effect ◽  
Damage Repair

Cisplatin is a chemotherapy drug commonly used in cancer treatment. Tumour cells are more sensitive to cisplatin than normal cells. Cisplatin exerts an antitumour effect by interfering with DNA replication and transcription processes. However, the drug-resistance properties of tumour cells often cause loss of cisplatin efficacy and failure of chemotherapy, leading to tumour progression. Owing to the large amounts of energy and compounds required by tumour cells, metabolic reprogramming plays an important part in the occurrence and development of tumours. The interplay between DNA damage repair and metabolism also has an effect on cisplatin resistance; the molecular changes to glucose metabolism, amino acid metabolism, lipid metabolism, and other metabolic pathways affect the cisplatin resistance of tumour cells. Here, we review the mechanism of action of cisplatin, the mechanism of resistance to cisplatin, the role of metabolic remodelling in tumorigenesis and development, and the effects of common metabolic pathways on cisplatin resistance.

par-4, a gene required for cytoplasmic localization and determination of specific cell types in Caenorhabditis elegans embryogenesis.

Genetics ◽  
1992 ◽  
Vol 130 (4) ◽  
pp. 771-790 ◽  
Author(s):  
D G Morton ◽  
J M Roos ◽  
K J Kemphues
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Types ◽  
Intestinal Cells ◽  
Specific Cell ◽  
Cytoplasmic Localization ◽  
Loss Of Function ◽  
Embryo Viability ◽  
Cell Stage ◽  
Maternal Genome

Abstract Specification of some cell fates in the early Caenorhabditis elegans embryo is mediated by cytoplasmic localization under control of the maternal genome. Using nine newly isolated mutations, and two existing mutations, we have analyzed the role of the maternally expressed gene par-4 in cytoplasmic localization. We recovered seven new par-4 alleles in screens for maternal effect lethal mutations that result in failure to differentiate intestinal cells. Two additional par-4 mutations were identified in noncomplementation screens using strains with a high frequency of transposon mobility. All 11 mutations cause defects early in development of embryos produced by homozygous mutant mothers. Analysis with a deficiency in the region indicates that it33 is a strong loss-of-function mutation. par-4(it33) terminal stage embryos contain many cells, but show no morphogenesis, and are lacking intestinal cells. Temperature shifts with the it57ts allele suggest that the critical period for both intestinal differentiation and embryo viability begins during oogenesis, about 1.5 hr before fertilization, and ends before the four-cell stage. We propose that the primary function of the par-4 gene is to act as part of a maternally encoded system for cytoplasmic localization in the first cell cycle, with par-4 playing a particularly important role in the determination of intestine. Analysis of a par-4; par-2 double mutant suggests that par-4 and par-2 gene products interact in this system.

scholarly journals Mechanism of NanR gene repression and allosteric induction of bacterial sialic acid metabolism

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Christopher R. Horne ◽  
Hariprasad Venugopal ◽  
Santosh Panjikar ◽  
David M. Wood ◽  
Amy Henrickson ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Dna Binding ◽  
Protein Interactions ◽  
Acid Metabolism ◽  
Environmental Changes ◽  
Dna Interaction ◽  
Protein Protein Interactions ◽  
Nutrient Source ◽  
Cryo Electron Microscopy ◽  
Close Proximity

AbstractBacteria respond to environmental changes by inducing transcription of some genes and repressing others. Sialic acids, which coat human cell surfaces, are a nutrient source for pathogenic and commensal bacteria. The Escherichia coli GntR-type transcriptional repressor, NanR, regulates sialic acid metabolism, but the mechanism is unclear. Here, we demonstrate that three NanR dimers bind a (GGTATA)3-repeat operator cooperatively and with high affinity. Single-particle cryo-electron microscopy structures reveal the DNA-binding domain is reorganized to engage DNA, while three dimers assemble in close proximity across the (GGTATA)3-repeat operator. Such an interaction allows cooperative protein-protein interactions between NanR dimers via their N-terminal extensions. The effector, N-acetylneuraminate, binds NanR and attenuates the NanR-DNA interaction. The crystal structure of NanR in complex with N-acetylneuraminate reveals a domain rearrangement upon N-acetylneuraminate binding to lock NanR in a conformation that weakens DNA binding. Our data provide a molecular basis for the regulation of bacterial sialic acid metabolism.

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