Cancers

Research

17 pages, 2311 KiB

Open AccessArticle

Metabolomics-Guided Identification of a Distinctive Hepatocellular Carcinoma Signature

by Vincent Tambay, Valérie-Ann Raymond, Corentine Goossens, Louise Rousseau, Simon Turcotte and Marc Bilodeau

Cancers 2023, 15(12), 3232; https://doi.org/10.3390/cancers15123232 - 18 Jun 2023

Viewed by 1410

Abstract

Background: Hepatocellular carcinoma (HCC) is a major contributor to cancer-related morbidity and mortality burdens globally. Given the fundamental metabolic activity of hepatocytes within the liver, hepatocarcinogenesis is bound to be characterized by alterations in metabolite profiles as a manifestation of metabolic reprogramming. Methods: [...] Read more.

Background: Hepatocellular carcinoma (HCC) is a major contributor to cancer-related morbidity and mortality burdens globally. Given the fundamental metabolic activity of hepatocytes within the liver, hepatocarcinogenesis is bound to be characterized by alterations in metabolite profiles as a manifestation of metabolic reprogramming. Methods: HCC and adjacent non-tumoral liver specimens were obtained from patients after HCC resection. Global patterns in tissue metabolites were identified using non-targeted ¹H Nuclear Magnetic Resonance (¹H-NMR) spectroscopy whereas specific metabolites were quantified using targeted liquid chromatography–mass spectrometry (LC/MS). Results: Principal component analysis (PCA) within our ¹H-NMR dataset identified a principal component (PC) one of 53.3%, along which the two sample groups were distinctively clustered. Univariate analysis of tissue specimens identified more than 150 metabolites significantly altered in HCC compared to non-tumoral liver. For LC/MS, PCA identified a PC1 of 45.2%, along which samples from HCC tissues and non-tumoral tissues were clearly separated. Supervised analysis (PLS–DA) identified decreases in tissue glutathione, succinate, glycerol-3-phosphate, alanine, malate, and AMP as the most important contributors to the metabolomic signature of HCC by LC/MS. Conclusions: Together, ¹H-NMR and LC/MS metabolomics have the capacity to distinguish HCC from non-tumoral liver. The characterization of such distinct profiles of metabolite abundances underscores the major metabolic alterations that result from hepatocarcinogenesis. Full article

(This article belongs to the Special Issue Metabolic Alterations in Cancer)

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11 pages, 2444 KiB

Open AccessCommunication

Epiploic Adipose Tissue (EPAT) in Obese Individuals Promotes Colonic Tumorigenesis: A Novel Model for EPAT-Dependent Colorectal Cancer Progression

by Rida Iftikhar, Patricia Snarski, Angelle N. King, Jenisha Ghimire, Emmanuelle Ruiz, Frank Lau and Suzana D. Savkovic

Cancers 2023, 15(3), 977; https://doi.org/10.3390/cancers15030977 - 03 Feb 2023

Cited by 2 | Viewed by 1939

Abstract

The obesity epidemic is associated with increased colorectal cancer (CRC) risk and progression, the mechanisms of which remain unclear. In obese individuals, hypertrophic epiploic adipose tissue (EPAT), attached to the colon, has unique characteristics compared to other fats. We hypothesized that this understudied [...] Read more.

The obesity epidemic is associated with increased colorectal cancer (CRC) risk and progression, the mechanisms of which remain unclear. In obese individuals, hypertrophic epiploic adipose tissue (EPAT), attached to the colon, has unique characteristics compared to other fats. We hypothesized that this understudied fat could serve as a tumor-promoting tissue and developed a novel microphysiological system (MPS) for human EPAT-dependent colorectal cancer (CRC-MPS). In CRC-MPS, obese EPAT, unlike lean EPAT, considerably attracted colon cancer HT29-GFP cells and enhanced their growth. Conditioned media (CM) from the obese CRC-MPS significantly increased the growth and migration of HT29 and HCT116 cells (p < 0.001). In HT29 cells, CM stimulated differential gene expression (hOEC₈₆₇) linked to cancer, tumor morphology, and metabolism similar to those in the colon of high-fat-diet obese mice. The hOEC₈₆₇ signature represented pathways found in human colon cancer. In unsupervised clustering, hOEC₈₆₇ separated transcriptomes of colon cancer samples from normal with high significance (PCA, p = 9.6 × 10⁻¹¹). These genes, validated in CM-treated HT29 cells (p < 0.05), regulate the cell cycle, cancer stem cells, methylation, and metastasis, and are similarly altered in human colon cancer (TCGA). These findings highlight a tumor-promoting role of EPAT in CRC facilitated with obesity and establishes a platform to explore critical mechanisms and develop effective treatments. Full article

(This article belongs to the Special Issue Metabolic Alterations in Cancer)

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24 pages, 7851 KiB

Open AccessArticle

Metabolomic and Mitochondrial Fingerprinting of the Epithelial-to-Mesenchymal Transition (EMT) in Non-Tumorigenic and Tumorigenic Human Breast Cells

by Elisabet Cuyàs, Salvador Fernández-Arroyo, Sara Verdura, Ruth Lupu, Jorge Joven and Javier A. Menendez

Cancers 2022, 14(24), 6214; https://doi.org/10.3390/cancers14246214 - 16 Dec 2022

Cited by 3 | Viewed by 1935

Abstract

Epithelial-to-mesenchymal transition (EMT) is key to tumor aggressiveness, therapy resistance, and immune escape in breast cancer. Because metabolic traits might be involved along the EMT continuum, we investigated whether human breast epithelial cells engineered to stably acquire a mesenchymal phenotype in non-tumorigenic and [...] Read more.

Epithelial-to-mesenchymal transition (EMT) is key to tumor aggressiveness, therapy resistance, and immune escape in breast cancer. Because metabolic traits might be involved along the EMT continuum, we investigated whether human breast epithelial cells engineered to stably acquire a mesenchymal phenotype in non-tumorigenic and H-Ras^V12-driven tumorigenic backgrounds possess unique metabolic fingerprints. We profiled mitochondrial–cytosolic bioenergetic and one-carbon (1C) metabolites by metabolomic analysis, and then questioned the utilization of different mitochondrial substrates by EMT mitochondria and their sensitivity to mitochondria-centered inhibitors. “Upper” and “lower” glycolysis were the preferred glucose fluxes activated by EMT in non-tumorigenic and tumorigenic backgrounds, respectively. EMT in non-tumorigenic and tumorigenic backgrounds could be distinguished by the differential contribution of the homocysteine-methionine 1C cycle to the transsulfuration pathway. Both non-tumorigenic and tumorigenic EMT-activated cells showed elevated mitochondrial utilization of glycolysis end-products such as lactic acid, β-oxidation substrates including palmitoyl–carnitine, and tricarboxylic acid pathway substrates such as succinic acid. Notably, mitochondria in tumorigenic EMT cells distinctively exhibited a significant alteration in the electron flow intensity from succinate to mitochondrial complex III as they were highly refractory to the inhibitory effects of antimycin A and myxothiazol. Our results show that the bioenergetic/1C metabolic signature, the utilization rates of preferred mitochondrial substrates, and sensitivity to mitochondrial drugs significantly differs upon execution of EMT in non-tumorigenic and tumorigenic backgrounds, which could help to resolve the relationship between EMT, malignancy, and therapeutic resistance in breast cancer. Full article

(This article belongs to the Special Issue Metabolic Alterations in Cancer)

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13 pages, 1161 KiB

Open AccessArticle

Hypoxia-Inducible Factor-1 Alpha Expression Is Predictive of Pathological Complete Response in Patients with Breast Cancer Receiving Neoadjuvant Chemotherapy

by César L. Ramírez-Tortosa, Rubén Alonso-Calderón, José María Gálvez-Navas, Cristina Pérez-Ramírez, José Luis Quiles, Pedro Sánchez-Rovira, Alberto Jiménez-Morales and MCarmen Ramírez-Tortosa

Cancers 2022, 14(21), 5393; https://doi.org/10.3390/cancers14215393 - 02 Nov 2022

Cited by 1 | Viewed by 1644

Abstract

To demonstrate the value of hypoxia-inducible factor-1α (HIF-1α) in predicting response in patients with breast cancer receiving standard neoadjuvant chemotherapy (NAC). Methods: Ninety-five women enrolled in two prospective studies underwent biopsies for the histopathological diagnosis of breast carcinoma before receiving NAC, based on [...] Read more.

To demonstrate the value of hypoxia-inducible factor-1α (HIF-1α) in predicting response in patients with breast cancer receiving standard neoadjuvant chemotherapy (NAC). Methods: Ninety-five women enrolled in two prospective studies underwent biopsies for the histopathological diagnosis of breast carcinoma before receiving NAC, based on anthracyclines and taxanes. For expression of HIF-1α, EGFR, pAKT and pMAPK, tumor samples were analyzed by immunohistochemistry in tissues microarrays. Standard statistical methods (Pearson chi-square test, Fisher exact test, Kruskal–Wallis test, Mann–Whitney test and Kaplan–Meier method) were used to study the association of HIF-1α with tumor response, survival and other clinicopathologic variables/biomarkers. Results: HIF-1α expression was positive in 35 (39.7%) cases and was significantly associated to complete pathological response (pCR) (p = 0.014). HIF-1α expression was correlated positively with tumor grade (p = 0.015) and Ki-67 expression (p = 0.001) and negativity with progesterone receptors (PR) (p = 0.04) and luminal A phenotype expression (p = 0.005). No correlation was found between HIF-1α expression and EGFR, pAKT and pMAPK. In terms of survival, HIF-1α expression was associated with a significantly shorter disease-free survival (p = 0.013), being identified as an independent prognostic factor in multivariate analysis. Conclusions: Overexpression of HIF-1α is a predictor of pCR and shorter DFS; it would be valuable to confirm these results in prospective studies. Full article

(This article belongs to the Special Issue Metabolic Alterations in Cancer)

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23 pages, 11548 KiB

Open AccessArticle

by Haosheng Zheng, Guojie Long, Yuzhen Zheng, Xingping Yang, Weijie Cai, Shiyun He, Xianyu Qin and Hongying Liao

Cancers 2022, 14(21), 5344; https://doi.org/10.3390/cancers14215344 - 29 Oct 2022

Cited by 9 | Viewed by 2844 | Correction

Abstract

SLC2A1 plays a pivotal role in cancer glycometabolism. SLC2A1 has been proposed as a putative driver gene in various cancers. However, a pan-cancer analysis of SLC2A1 has not yet been performed. In this study, we explored the expression and prognosis of SLC2A1 in [...] Read more.

SLC2A1 plays a pivotal role in cancer glycometabolism. SLC2A1 has been proposed as a putative driver gene in various cancers. However, a pan-cancer analysis of SLC2A1 has not yet been performed. In this study, we explored the expression and prognosis of SLC2A1 in pan-cancer across multiple databases. We conducted genetic alteration, epigenetic, and functional enrichment analyses of SLC2A. We calculated the correlation between SLC2A1 and tumor microenvironment using the TCGA pan-cancer dataset. We observed high expression levels of SLC2A1 with poor prognosis in most cancers. The overall genetic alteration frequency of SLC2A1 was 1.8% in pan-cancer, and the SLC2A1 promoter was hypomethylation in several cancers. Most m6A-methylation-related genes positively correlated with the expression of SLC2A1 in 33 TCGA cancers. Moreover, SLC2A1 was mainly related to the functions including epithelial–mesenchymal transition, glycolysis, hypoxia, cell-cycle regulation, and DNA repair. Finally, SLC2A1 positively associated with neutrophils and cancer-associated fibroblasts in the tumor microenvironment of most cancers and significantly correlated with TMB and MSI in various cancers. Notably, SLC2A1 was remarkably positively correlated with PD-L1 and CTLA4 in most cancers. SLC2A1 might serve as an attractive pan-cancer biomarker for providing new insights into cancer therapeutics. Full article

(This article belongs to the Special Issue Metabolic Alterations in Cancer)

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18 pages, 3835 KiB

Open AccessArticle

A Novel Role of SMG1 in Cholesterol Homeostasis That Depends Partially on p53 Alternative Splicing

by Muyang Li, Fredrick Philantrope, Alexandra Diot, Jean-Christophe Bourdon and Patricia Thompson

Cancers 2022, 14(13), 3255; https://doi.org/10.3390/cancers14133255 - 02 Jul 2022

Cited by 1 | Viewed by 2344

Abstract

SMG1, a phosphatidylinositol 3-kinase-related kinase (PIKK), essential in nonsense-mediated RNA decay (NMD), also regulates p53, including the alternative splicing of p53 isoforms reported to retain p53 functions. We confirm that SMG1 inhibition in MCF7 tumor cells induces p53β and show p53γ increase. Inhibiting [...] Read more.

SMG1, a phosphatidylinositol 3-kinase-related kinase (PIKK), essential in nonsense-mediated RNA decay (NMD), also regulates p53, including the alternative splicing of p53 isoforms reported to retain p53 functions. We confirm that SMG1 inhibition in MCF7 tumor cells induces p53β and show p53γ increase. Inhibiting SMG1, but not UPF1 (a core factor in NMD), upregulated several cholesterol pathway genes. SMG1 knockdown significantly increased ABCA1, a cholesterol efflux pump shown to be positively regulated by full-length p53 (p53α). An investigation of RASSF1C, an NMD target, increased following SMG1 inhibition and reported to inhibit miR-33a-5p, a canonical ABCA1-inhibiting miRNA, did not explain the ABCA1 results. ABCA1 upregulation following SMG1 knockdown was inhibited by p53β siRNA with greatest inhibition when p53α and p53β were jointly suppressed, while p53γ siRNA had no effect. In contrast, increased expression of MVD, a cholesterol synthesis gene upregulated in p53 deficient backgrounds, was sensitive to combined targeting of p53α and p53γ. Phenotypically, we observed increased intracellular cholesterol and enhanced sensitivity of MCF7 to growth inhibitory effects of cholesterol-lowering Fatostatin following SMG1 inhibition. Our results suggest deregulation of cholesterol pathway genes following SMG1 knockdown may involve alternative p53 programming, possibly resulting from differential effects of p53 isoforms on cholesterol gene expression. Full article

(This article belongs to the Special Issue Metabolic Alterations in Cancer)

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20 pages, 3805 KiB

Open AccessArticle

Ascorbate Plus Buformin in AML: A Metabolic Targeted Treatment

by Cristina Banella, Gianfranco Catalano, Serena Travaglini, Elvira Pelosi, Tiziana Ottone, Alessandra Zaza, Gisella Guerrera, Daniela Francesca Angelini, Pasquale Niscola, Mariadomenica Divona, Luca Battistini, Maria Screnci, Emanuele Ammatuna, Ugo Testa, Clara Nervi, Maria Teresa Voso and Nelida Ines Noguera

Cancers 2022, 14(10), 2565; https://doi.org/10.3390/cancers14102565 - 23 May 2022

Cited by 11 | Viewed by 2039

Abstract

In the present study, we characterized the metabolic background of different Acute Myeloid Leukemias’ (AMLs) cells and described a heterogeneous and highly flexible energetic metabolism. Using the Seahorse XF Agilent, we compared the metabolism of normal hematopoietic progenitors with that of primary AML [...] Read more.

In the present study, we characterized the metabolic background of different Acute Myeloid Leukemias’ (AMLs) cells and described a heterogeneous and highly flexible energetic metabolism. Using the Seahorse XF Agilent, we compared the metabolism of normal hematopoietic progenitors with that of primary AML blasts and five different AML cell lines. We assessed the efficacy and mechanism of action of the association of high doses of ascorbate, a powerful oxidant, with the metabolic inhibitor buformin, which inhibits mitochondrial complex I and completely shuts down mitochondrial contributions in ATP production. Primary blasts from seventeen AML patients, assayed for annexin V and live/dead exclusion by flow cytometry, showed an increase in the apoptotic effect using the drug combination, as compared with ascorbate alone. We show that ascorbate inhibits glycolysis through interfering with HK1/2 and GLUT1 functions in hematopoietic cells. Ascorbate combined with buformin decreases mitochondrial respiration and ATP production and downregulates glycolysis, enhancing the apoptotic effect of ascorbate in primary blasts from AMLs and sparing normal CD34+ bone marrow progenitors. In conclusion, our data have therapeutic implications especially in fragile patients since both agents have an excellent safety profile, and the data also support the clinical evaluation of ascorbate–buformin in association with different mechanism drugs for the treatment of refractory/relapsing AML patients with no other therapeutic options. Full article

(This article belongs to the Special Issue Metabolic Alterations in Cancer)

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Review

Jump to: Research, Other

14 pages, 1221 KiB

Open AccessReview

How Warburg-Associated Lactic Acidosis Rewires Cancer Cell Energy Metabolism to Resist Glucose Deprivation

by Zoé Daverio, Aneta Balcerczyk, Gilles J. P. Rautureau and Baptiste Panthu

Cancers 2023, 15(5), 1417; https://doi.org/10.3390/cancers15051417 - 23 Feb 2023

Cited by 8 | Viewed by 3647

Abstract

Lactic acidosis, a hallmark of solid tumour microenvironment, originates from lactate hyperproduction and its co-secretion with protons by cancer cells displaying the Warburg effect. Long considered a side effect of cancer metabolism, lactic acidosis is now known to play a major role in [...] Read more.

Lactic acidosis, a hallmark of solid tumour microenvironment, originates from lactate hyperproduction and its co-secretion with protons by cancer cells displaying the Warburg effect. Long considered a side effect of cancer metabolism, lactic acidosis is now known to play a major role in tumour physiology, aggressiveness and treatment efficiency. Growing evidence shows that it promotes cancer cell resistance to glucose deprivation, a common feature of tumours. Here we review the current understanding of how extracellular lactate and acidosis, acting as a combination of enzymatic inhibitors, signal, and nutrient, switch cancer cell metabolism from the Warburg effect to an oxidative metabolic phenotype, which allows cancer cells to withstand glucose deprivation, and makes lactic acidosis a promising anticancer target. We also discuss how the evidence about lactic acidosis’ effect could be integrated in the understanding of the whole-tumour metabolism and what perspectives it opens up for future research. Full article

(This article belongs to the Special Issue Metabolic Alterations in Cancer)

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19 pages, 1437 KiB

Open AccessReview

Amino Acids in Cancer and Cachexia: An Integrated View

by Maurizio Ragni, Claudia Fornelli, Enzo Nisoli and Fabio Penna

Cancers 2022, 14(22), 5691; https://doi.org/10.3390/cancers14225691 - 19 Nov 2022

Cited by 15 | Viewed by 3638

Abstract

Rapid tumor growth requires elevated biosynthetic activity, supported by metabolic rewiring occurring both intrinsically in cancer cells and extrinsically in the cancer host. The Warburg effect is one such example, burning glucose to produce a continuous flux of biomass substrates in cancer cells [...] Read more.

Rapid tumor growth requires elevated biosynthetic activity, supported by metabolic rewiring occurring both intrinsically in cancer cells and extrinsically in the cancer host. The Warburg effect is one such example, burning glucose to produce a continuous flux of biomass substrates in cancer cells at the cost of energy wasting metabolic cycles in the host to maintain stable glycemia. Amino acid (AA) metabolism is profoundly altered in cancer cells, which use AAs for energy production and for supporting cell proliferation. The peculiarities in cancer AA metabolism allow the identification of specific vulnerabilities as targets of anti-cancer treatments. In the current review, specific approaches targeting AAs in terms of either deprivation or supplementation are discussed. Although based on opposed strategies, both show, in vitro and in vivo, positive effects. Any AA-targeted intervention will inevitably impact the cancer host, who frequently already has cachexia. Cancer cachexia is a wasting syndrome, also due to malnutrition, that compromises the effectiveness of anti-cancer drugs and eventually causes the patient’s death. AA deprivation may exacerbate malnutrition and cachexia, while AA supplementation may improve the nutritional status, counteract cachexia, and predispose the patient to a more effective anti-cancer treatment. Here is provided an attempt to describe the AA-based therapeutic approaches that integrate currently distant points of view on cancer-centered and host-centered research, providing a glimpse of several potential investigations that approach cachexia as a unique cancer disease. Full article

(This article belongs to the Special Issue Metabolic Alterations in Cancer)

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32 pages, 1280 KiB

Open AccessReview

The Mechanism of Action of Biguanides: New Answers to a Complex Question

by Laura Di Magno, Fiorella Di Pastena, Rosa Bordone, Sonia Coni and Gianluca Canettieri

Cancers 2022, 14(13), 3220; https://doi.org/10.3390/cancers14133220 - 30 Jun 2022

Cited by 15 | Viewed by 5854

Abstract

Biguanides are a family of antidiabetic drugs with documented anticancer properties in preclinical and clinical settings. Despite intensive investigation, how they exert their therapeutic effects is still debated. Many studies support the hypothesis that biguanides inhibit mitochondrial complex I, inducing energy stress and [...] Read more.

Biguanides are a family of antidiabetic drugs with documented anticancer properties in preclinical and clinical settings. Despite intensive investigation, how they exert their therapeutic effects is still debated. Many studies support the hypothesis that biguanides inhibit mitochondrial complex I, inducing energy stress and activating compensatory responses mediated by energy sensors. However, a major concern related to this “complex” model is that the therapeutic concentrations of biguanides found in the blood and tissues are much lower than the doses required to inhibit complex I, suggesting the involvement of additional mechanisms. This comprehensive review illustrates the current knowledge of pharmacokinetics, receptors, sensors, intracellular alterations, and the mechanism of action of biguanides in diabetes and cancer. The conditions of usage and variables affecting the response to these drugs, the effect on the immune system and microbiota, as well as the results from the most relevant clinical trials in cancer are also discussed. Full article

(This article belongs to the Special Issue Metabolic Alterations in Cancer)

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