scholarly journals Epigenomic and Metabolomic Integration Reveals Dynamic Metabolic Regulation in Bladder Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2719
Author(s):  
Alba Loras ◽  
Cristina Segovia ◽  
José Luis Ruiz-Cerdá
Keyword(s):  
Bladder Cancer ◽  
Cancer Biology ◽  
Metabolic Regulation ◽  
Tumor Development ◽  
Dna Methyltransferases ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Oncogenic Signaling ◽  
Invasive Approach ◽  
Non Invasive

Bladder cancer (BC) represents a clinical, social, and economic challenge due to tumor-intrinsic characteristics, limitations of diagnostic techniques and a lack of personalized treatments. In the last decade, the use of liquid biopsy has grown as a non-invasive approach to characterize tumors. Moreover, the emergence of omics has increased our knowledge of cancer biology and identified critical BC biomarkers. The rewiring between epigenetics and metabolism has been closely linked to tumor phenotype. Chromatin remodelers interact with each other to control gene silencing in BC, but also with stress-inducible factors or oncogenic signaling cascades to regulate metabolic reprogramming towards glycolysis, the pentose phosphate pathway, and lipogenesis. Concurrently, one-carbon metabolism supplies methyl groups to histone and DNA methyltransferases, leading to the hypermethylation and silencing of suppressor genes in BC. Conversely, α-KG and acetyl-CoA enhance the activity of histone demethylases and acetyl transferases, increasing gene expression, while succinate and fumarate have an inhibitory role. This review is the first to analyze the interplay between epigenome, metabolome and cell signaling pathways in BC, and shows how their regulation contributes to tumor development and progression. Moreover, it summarizes non-invasive biomarkers that could be applied in clinical practice to improve diagnosis, monitoring, prognosis and the therapeutic options in BC.

scholarly journals Embryonic Origin and Subclonal Evolution of Tumor-Associated Macrophages Imply Preventive Care for Cancer

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 903
Author(s):  
Xiao-Mei Zhang ◽  
De-Gao Chen ◽  
Shengwen Calvin Li ◽  
Bo Zhu ◽  
Zhong-Jun Li
Keyword(s):  
Metabolic Regulation ◽  
Transcriptional Profiling ◽  
Tumor Development ◽  
Metabolic Reprogramming ◽  
Cancer Therapies ◽  
Functional Heterogeneity ◽  
Tumor Associated Macrophages ◽  
Metabolic Remodeling ◽  
And Function ◽  
Mapping Models

Macrophages are widely distributed in tissues and function in homeostasis. During cancer development, tumor-associated macrophages (TAMs) dominatingly support disease progression and resistance to therapy by promoting tumor proliferation, angiogenesis, metastasis, and immunosuppression, thereby making TAMs a target for tumor immunotherapy. Here, we started with evidence that TAMs are highly plastic and heterogeneous in phenotype and function in response to microenvironmental cues. We pointed out that efforts to tear off the heterogeneous “camouflage” in TAMs conduce to target de facto protumoral TAMs efficiently. In particular, several fate-mapping models suggest that most tissue-resident macrophages (TRMs) are generated from embryonic progenitors, and new paradigms uncover the ontogeny of TAMs. First, TAMs from embryonic modeling of TRMs and circulating monocytes have distinct transcriptional profiling and function, suggesting that the ontogeny of TAMs is responsible for the functional heterogeneity of TAMs, in addition to microenvironmental cues. Second, metabolic remodeling helps determine the mechanism of phenotypic and functional characteristics in TAMs, including metabolic bias from macrophages’ ontogeny in macrophages’ functional plasticity under physiological and pathological conditions. Both models aim at dissecting the ontogeny-related metabolic regulation in the phenotypic and functional heterogeneity in TAMs. We argue that gleaning from the single-cell transcriptomics on subclonal TAMs’ origins may help understand the classification of TAMs’ population in subclonal evolution and their distinct roles in tumor development. We envision that TAM-subclone-specific metabolic reprogramming may round-up with future cancer therapies.

scholarly journals Protein Acetylation at the Interface of Genetics, Epigenetics and Environment in Cancer

Metabolites ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 216
Author(s):  
Mio Harachi ◽  
Kenta Masui ◽  
Webster K. Cavenee ◽  
Paul S. Mischel ◽  
Noriyuki Shibata
Keyword(s):  
Cancer Cells ◽  
Intracellular Signaling ◽  
Cancer Biology ◽  
High Resolution Mass Spectrometry ◽  
Metabolic Reprogramming ◽  
Protein Acetylation ◽  
Protein Activity ◽  
Oncogenic Signaling ◽  
Intermediary Metabolites ◽  
Novel Therapeutic Strategies

Metabolic reprogramming is an emerging hallmark of cancer and is driven by abnormalities of oncogenes and tumor suppressors. Accelerated metabolism causes cancer cell aggression through the dysregulation of rate-limiting metabolic enzymes as well as by facilitating the production of intermediary metabolites. However, the mechanisms by which a shift in the metabolic landscape reshapes the intracellular signaling to promote the survival of cancer cells remain to be clarified. Recent high-resolution mass spectrometry-based proteomic analyses have spotlighted that, unexpectedly, lysine residues of numerous cytosolic as well as nuclear proteins are acetylated and that this modification modulates protein activity, sublocalization and stability, with profound impact on cellular function. More importantly, cancer cells exploit acetylation as a post-translational protein for microenvironmental adaptation, nominating it as a means for dynamic modulation of the phenotypes of cancer cells at the interface between genetics and environments. The objectives of this review were to describe the functional implications of protein lysine acetylation in cancer biology by examining recent evidence that implicates oncogenic signaling as a strong driver of protein acetylation, which might be exploitable for novel therapeutic strategies against cancer.

scholarly journals Non-invasive detection of bladder cancer through the analysis of driver gene mutations and aneuploidy

2017 ◽  
Author(s):  
Simeon Springer ◽  
Maria Del Carmen Rodriguez Pena ◽  
Lu Li ◽  
Christopher Douville ◽  
Yuxuan Wang ◽  
...  
Keyword(s):  
At Risk ◽  
Bladder Cancer ◽  
Gene Mutations ◽  
Urine Samples ◽  
Driver Gene ◽  
Low Grade ◽  
Invasive Approach ◽  
Non Invasive ◽  
Patients At Risk ◽  
Copy Number Changes

AbstractCurrent non-invasive approaches for bladder cancer (BC) detection are suboptimal. We report the development of non-invasive molecular test for BC using DNA recovered from cells shed into urine. This “UroSEEK” test incorporates assays for mutations in 11 genes and copy number changes on 39 chromosome arms. We first evaluated 570 urine samples from patients at risk for BC (microscopic hematuria or dysuria). UroSEEK was positive in 83% of patients that developed BC, but in only 7% of patients who did not develop BC. Combined with cytology, 95% of patients that developed BC were positive. We then evaluated 322 urine samples from patients soon after their BCs had been surgically resected. UroSEEK detected abnormalities in 66% of the urine samples from these patients, sometimes up to 4 years prior to clinical evidence of residual neoplasia, while cytology was positive in only 25% of such urine samples. The advantages of UroSEEK over cytology were particularly evident in low-grade tumors, wherein cytology detected none while UroSEEK detected 67% of 49 cases. These results establish the foundation for a new, non-invasive approach to the detection of BC in patients at risk for initial or recurrent disease.

scholarly journals Metabolic Reprogramming of Chemoresistant Cancer Cells and the Potential Significance of Metabolic Regulation in the Reversal of Cancer Chemoresistance

Metabolites ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 289 ◽  
Author(s):  
Xun Chen ◽  
Shangwu Chen ◽  
Dongsheng Yu
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Metabolic Regulation ◽  
Metabolic Response ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Drug Resistant ◽  
Chemotherapy Drugs

Metabolic reprogramming is one of the hallmarks of tumors. Alterations of cellular metabolism not only contribute to tumor development, but also mediate the resistance of tumor cells to antitumor drugs. The metabolic response of tumor cells to various chemotherapy drugs can be analyzed by metabolomics. Although cancer cells have experienced metabolic reprogramming, the metabolism of drug resistant cancer cells has been further modified. Metabolic adaptations of drug resistant cells to chemotherapeutics involve redox, lipid metabolism, bioenergetics, glycolysis, polyamine synthesis and so on. The proposed metabolic mechanisms of drug resistance include the increase of glucose and glutamine demand, active pathways of glutaminolysis and glycolysis, promotion of NADPH from the pentose phosphate pathway, adaptive mitochondrial reprogramming, activation of fatty acid oxidation, and up-regulation of ornithine decarboxylase for polyamine production. Several genes are associated with metabolic reprogramming and drug resistance. Intervening regulatory points described above or targeting key genes in several important metabolic pathways may restore cell sensitivity to chemotherapy. This paper reviews the metabolic changes of tumor cells during the development of chemoresistance and discusses the potential of reversing chemoresistance by metabolic regulation.

scholarly journals Integrative Metabolomic and Transcriptomic Analysis for the Study of Bladder Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 686 ◽  
Author(s):  
Alba Loras ◽  
Cristian Suárez-Cabrera ◽  
M. Carmen Martínez-Bisbal ◽  
Guillermo Quintás ◽  
Jesús M. Paramio ◽  
...  
Keyword(s):  
Amino Acids ◽  
Bladder Cancer ◽  
Tricarboxylic Acid Cycle ◽  
Tumor Biology ◽  
Magic Angle Spinning ◽  
Magic Angle ◽  
Tissue Samples ◽  
Invasive Approach ◽  
Non Invasive ◽  
Angle Spinning

Metabolism reprogramming is considered a hallmark of cancer. The study of bladder cancer (BC) metabolism could be the key to developing new strategies for diagnosis and therapy. This work aimed to identify tissue and urinary metabolic signatures as biomarkers of BC and get further insight into BC tumor biology through the study of gene-metabolite networks and the integration of metabolomics and transcriptomics data. BC and control tissue samples (n = 44) from the same patients were analyzed by High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance and microarrays techniques. Besides, urinary profiling study (n = 35) was performed in the same patients to identify a metabolomic profile, linked with BC tissue hallmarks, as a potential non-invasive approach for BC diagnosis. The metabolic profile allowed for the classification of BC tissue samples with a sensitivity and specificity of 100%. The most discriminant metabolites for BC tissue samples reflected alterations in amino acids, glutathione, and taurine metabolic pathways. Transcriptomic data supported metabolomic results and revealed a predominant downregulation of metabolic genes belonging to phosphorylative oxidation, tricarboxylic acid cycle, and amino acid metabolism. The urinary profiling study showed a relation with taurine and other amino acids perturbed pathways observed in BC tissue samples, and classified BC from non-tumor urine samples with good sensitivities (91%) and specificities (77%). This urinary profile could be used as a non-invasive tool for BC diagnosis and follow-up.

scholarly journals Liquid Biopsy Biomarkers in Bladder Cancer: A Current Need for Patient Diagnosis and Monitoring

2018 ◽  
Vol 19 (9) ◽  
pp. 2514 ◽  
Author(s):  
Iris Lodewijk ◽  
Marta Dueñas ◽  
Carolina Rubio ◽  
Ester Munera-Maravilla ◽  
Cristina Segovia ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Liquid Biopsy ◽  
Disease Surveillance ◽  
Great Promise ◽  
Liquid Biopsies ◽  
Recurrence Rates ◽  
Invasive Approach ◽  
Non Invasive ◽  
Social Challenge ◽  
High Incidence

Bladder Cancer (BC) represents a clinical and social challenge due to its high incidence and recurrence rates, as well as the limited advances in effective disease management. Currently, a combination of cytology and cystoscopy is the routinely used methodology for diagnosis, prognosis and disease surveillance. However, both the poor sensitivity of cytology tests as well as the high invasiveness and big variation in tumour stage and grade interpretation using cystoscopy, emphasizes the urgent need for improvements in BC clinical guidance. Liquid biopsy represents a new non-invasive approach that has been extensively studied over the last decade and holds great promise. Even though its clinical use is still compromised, multiple studies have recently focused on the potential application of biomarkers in liquid biopsies for BC, including circulating tumour cells and DNA, RNAs, proteins and peptides, metabolites and extracellular vesicles. In this review, we summarize the present knowledge on the different types of biomarkers, their potential use in liquid biopsy and clinical applications in BC.

scholarly journals The Bidirectional Relationship Between Cancer Epigenetics and Metabolism

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Luke T. Izzo ◽  
Hayley C. Affronti ◽  
Kathryn E. Wellen
Keyword(s):  
Chromatin Remodeling ◽  
Cancer Biology ◽  
Metabolic Regulation ◽  
Annual Review ◽  
Publication Date ◽  
Dietary Interventions ◽  
Oncogenic Signaling ◽  
Cancer Epigenetics ◽  
Altered Expression ◽  
Bidirectional Relationship

Metabolic and epigenetic reprogramming are characteristics of cancer cells that, in many cases, are linked. Oncogenic signaling, diet, and tumor microenvironment each influence the availability of metabolites that are substrates or inhibitors of epigenetic modifying enzymes. Reciprocally, altered expression or activity of epigenetic modifying enzymes can exert direct and indirect effects on cellular metabolism. In this article, we discuss the bidirectional relationship between epigenetics and metabolism in cancer. First, we focus on epigenetic control of metabolism, highlighting evidence that alterations in histone modifications, chromatin remodeling, or the enhancer landscape can drive metabolic features that support growth and proliferation. We then discuss metabolic regulation of chromatin-modifying enzymes and roles in tumor growth and progression. Throughout, we highlight proposed therapeutic and dietary interventions that leverage metabolic-epigenetic cross talk and have the potential to improve cancer therapy. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals TERT Promoter Mutation Analysis of Whole-Organ Mapping Bladder Cancers

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 230
Author(s):  
Veronika Weyerer ◽  
Markus Eckstein ◽  
Pamela L. Strissel ◽  
Adrian Wullweber ◽  
Fabienne Lange ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Telomere Length ◽  
Hot Spot ◽  
Tumor Development ◽  
Non Invasive ◽  
Tert Promoter ◽  
Mutational Status ◽  
Tert Promoter Mutations ◽  
Promoter Mutations ◽  
Normal Urothelium

Background: Multifocal occurrence is a main characteristic of urothelial bladder cancer (UBC). Whether urothelial transformation is caused by monoclonal events within the urothelium, or by polyclonal unrelated events resulting in several tumor clones is still under debate. TERT promoter mutations are the most common somatic alteration identified in UBC. In this study, we analyzed different histological tissues from whole-organ mapping bladder cancer specimens to reveal TERT mutational status, as well as to discern how tumors develop. Methods: Up to 23 tissues from nine whole-organ mapping bladder tumor specimens, were tested for TERT promoter mutations including tumor associated normal urothelium, non-invasive urothelial lesions (hyperplasia, dysplasia, metaplasia), carcinoma in situ (CIS) and different areas of muscle invasive bladder cancers (MIBC). The mutational DNA hotspot region within the TERT promoter was analyzed by SNaPshot analysis including three hot spot regions (−57, −124 or −146). Telomere length was measured by the Relative Human Telomere Length Quantification qPCR Assay Kit. Results: TERT promoter mutations were identified in tumor associated normal urothelium as well as non-invasive urothelial lesions, CIS and MIBC. Analysis of separate regions of the MIBC showed 100% concordance of TERT promoter mutations within a respective whole-organ bladder specimen. Polyclonal events were observed in five out of nine whole-organ mapping bladder cancers housing tumor associated normal urothelium, non-invasive urothelial lesions and CIS where different TERT promoter mutations were found compared to MIBC. The remaining four whole-organ mapping bladders were monoclonal for TERT mutations. No significant differences of telomere length were observed. Conclusions: Examining multiple whole-organ mapping bladders we conclude that TERT promoter mutations may be an early step in bladder cancer carcinogenesis as supported by TERT mutations detected in tumor associated normal urothelium as well as non-invasive urothelial lesions. Since mutated TERT promoter regions within non-invasive urothelial lesions are not sufficient alone for the establishment of cancerous growth, this points to the contribution of other gene mutations as a requirement for tumor development.

scholarly journals Immunometabolism Modulation in Therapy

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 798
Author(s):  
Ezequiel Monferrer ◽  
Sabina Sanegre ◽  
Isaac Vieco-Martí ◽  
Amparo López-Carrasco ◽  
Fernando Fariñas ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Tumor Cells ◽  
Immune Cells ◽  
Therapeutic Intervention ◽  
Cancer Biology ◽  
Metabolic Regulation ◽  
Tumor Development ◽  
Molecular Bases

The study of cancer biology should be based around a comprehensive vision of the entire tumor ecosystem, considering the functional, bioenergetic and metabolic state of tumor cells and those of their microenvironment, and placing particular importance on immune system cells. Enhanced understanding of the molecular bases that give rise to alterations of pathways related to tumor development can open up new therapeutic intervention opportunities, such as metabolic regulation applied to immunotherapy. This review outlines the role of various oncometabolites and immunometabolites, such as TCA intermediates, in shaping pro/anti-inflammatory activity of immune cells such as MDSCs, T lymphocytes, TAMs and DCs in cancer. We also discuss the extraordinary plasticity of the immune response and its implication in immunotherapy efficacy, and highlight different therapeutic intervention possibilities based on controlling the balanced systems of specific metabolites with antagonistic functions.

scholarly journals Role of Copper on Mitochondrial Function and Metabolism

2021 ◽  
Vol 8 ◽  
Author(s):  
Lina M. Ruiz ◽  
Allan Libedinsky ◽  
Alvaro A. Elorza
Keyword(s):  
Cell Fate ◽  
Mitochondrial Function ◽  
Cancer Biology ◽  
Tumor Development ◽  
Copper Metabolism ◽  
Metabolic Reprogramming ◽  
Source Distribution ◽  
Cancer Therapies ◽  
Cellular Copper ◽  
Eukaryotic Organisms

Copper is essential for life processes like energy metabolism, reactive oxygen species detoxification, iron uptake, and signaling in eukaryotic organisms. Mitochondria gather copper for the assembly of cuproenzymes such as the respiratory complex IV, cytochrome c oxidase, and the antioxidant enzyme superoxide dismutase 1. In this regard, copper plays a role in mitochondrial function and signaling involving bioenergetics, dynamics, and mitophagy, which affect cell fate by means of metabolic reprogramming. In mammals, copper homeostasis is tightly regulated by the liver. However, cellular copper levels are tissue specific. Copper imbalances, either overload or deficiency, have been associated with many diseases, including anemia, neutropenia, and thrombocytopenia, as well as tumor development and cancer aggressivity. Consistently, new pharmacological developments have been addressed to reduce or exacerbate copper levels as potential cancer therapies. This review goes over the copper source, distribution, cellular uptake, and its role in mitochondrial function, metabolic reprograming, and cancer biology, linking copper metabolism with the field of regenerative medicine and cancer.

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