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Molecular Links between Cancer and Metabolic Diseases: New Perspectives and Therapeutic Strategies for Cancer Prevention and Treatment by Targeting Nutritional Patterns and Metabolic Alterations

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (20 September 2022) | Viewed by 35702

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Special Issue Editors

Prof. Dr. Hamid Morjani

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Guest Editor

Faculty of Pharmacy, University of Reims, BioSpecT EA7506, F-54000 Nancy, France
Interests: cellular and tumour microenvironement factors mediating cell proliferation and survival

Prof. Dr. Mohamed Zaiou

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Guest Editor

School of Pharmacy & The Institute of Jean-Lamour, The University of Lorraine, UMR 7198 CNRS, CEDEX, 54505 Vandoeuvre les Nancy, France
Interests: gene expression; metabolic diseases; biomarkers; epigenetics; precision medicine
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Special Issue Information

Dear Colleagues,

Cancer and metabolic disease are among the leading causes of death worldwide. Beside genomic instability, accumulating evidence from epidemiological and prospective has linked nutrition and metabolic disorders such as diabetes, obesity, nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome, to increased risk for the development of several types of cancer. For instance, the incidence of gastrointestinal, and reproductive tract cancers is significantly higher in patients with metabolic abnormalities as compared to the general population. Moreover, evidence suggests that diabetes may affect cancer biology via hyperglycemia and hyperinsulinemia.

The mechanisms linking metabolic dysregulation and some cancers incidence and progression are incompletely understood. Acceleration of the global nutrition transition, the food system transformation and the increase in metabolic abnormalities could be among contributors to increased relative risk of cancer. Furthermore, metabolic diseases are characterized by low grade of persistent inflammation, a critical factor that is also involved in cancer initiation and progression.

Researchers now view new strategies for metabolomics research as promising fields that are likely to shed light on cancer etiology and diagnostic biomarker profiles, particularly for different cancers including colorectum, liver, pancreas, and breast cancer. Bioactive dietary components with anticancer properties are of particular interest as they may influence gene expression through epigenetic mechanisms and therefore some of them may be used in conjunction with other cancer prevention and chemotherapeutic therapies. Finally, the convergence of cancer cellular mechanisms and alterations in signaling pathways that control metabolism and proliferation on one hand and overall metabolic alterations suggest that new prevention and therapeutic strategies should target key effectors responsible for both cancer and metabolic diseases.

This Special Issue of “Cancers” will focus on the biological links between metabolic diseases (diabetes, obesity, NAFLD, metabolic syndrome, …) and some cancers, and that from genetic and epigenetic drivers and nutritional and metabolic point of view. Original articles, reviews, meta-analyses/systematic review, and case reports that address up-to-date and relevant findings with respect to the above area are welcome. Finally, on a personal side, we look forward with excitement to what the future holds for these complex and challenging potentially connected multigenic diseases (metabolic diseases and some cancers).

Prof. Dr. Hamid Morjani
Prof. Dr. Mohamed Zaiou
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

metabolic diseases
colorectal cancer
oral cancer
obesity
metabolic pathways
nutrients
dietary intervention, molecular profiles, diagnosis and prognosis
LAFLD
hepatocellular carcinoma (HCC)

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Published Papers (9 papers)

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Editorial

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3 pages, 194 KiB

Open AccessEditorial

Molecular Links between Cancer and Metabolic Diseases: New Perspectives and Therapeutic Strategies for Cancer Prevention and Treatment by Targeting Nutritional Patterns and Metabolic Alterations

by Mohamed Zaiou and Hamid Morjani

Cancers 2023, 15(4), 1350; https://doi.org/10.3390/cancers15041350 - 20 Feb 2023

Cited by 2 | Viewed by 1797

Abstract

Cancer-related mortality is reported to be elevated in cases with metabolic dysfunction [...] Full article

(This article belongs to the Special Issue Molecular Links between Cancer and Metabolic Diseases: New Perspectives and Therapeutic Strategies for Cancer Prevention and Treatment by Targeting Nutritional Patterns and Metabolic Alterations)

Research

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20 pages, 6543 KiB

Open AccessArticle

Rewiring Lipid Metabolism by Targeting PCSK9 and HMGCR to Treat Liver Cancer

by Malak Alannan, Véronique Trézéguet, Nivea Dias Amoêdo, Rodrigue Rossignol, Walid Mahfouf, Hamid Reza Rezvani, Franziska Dittrich-Domergue, Patrick Moreau, Sabrina Lacomme, Etienne Gontier, Christophe F. Grosset, Bassam Badran, Hussein Fayyad-Kazan and Aksam J. Merched

Cancers 2023, 15(1), 3; https://doi.org/10.3390/cancers15010003 - 20 Dec 2022

Cited by 10 | Viewed by 3081

Abstract

Alterations in lipid handling are an important hallmark in cancer. Our aim here is to target key metabolic enzymes to reshape the oncogenic lipid metabolism triggering irreversible cell breakdown. We targeted the key metabolic player proprotein convertase subtilisin/kexin type 9 (PCSK9) using a pharmacological inhibitor (R-IMPP) alone or in combination with 3-hydroxy 3-methylglutaryl-Coenzyme A reductase (HMGCR) inhibitor, simvastatin. We assessed the effect of these treatments using 3 hepatoma cell lines, Huh6, Huh7 and HepG2 and a tumor xenograft in chicken choriorallantoic membrane (CAM) model. PCSK9 deficiency led to dose-dependent inhibition of cell proliferation in all cell lines and a decrease in cell migration. Co-treatment with simvastatin presented synergetic anti-proliferative effects. At the metabolic level, mitochondrial respiration assays as well as the assessment of glucose and glutamine consumption showed higher metabolic adaptability and surge in the absence of PCSK9. Enhanced lipid uptake and biogenesis led to excessive accumulation of intracellular lipid droplets as revealed by electron microscopy and metabolic tracing. Using xenograft experiments in CAM model, we further demonstrated the effect of anti-PCSK9 treatment in reducing tumor aggressiveness. Targeting PCSK9 alone or in combination with statins deserves to be considered as a new therapeutic option in liver cancer clinical applications. Full article

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14 pages, 4807 KiB

Open AccessArticle

Ligustilide Inhibits Tumor Angiogenesis by Downregulating VEGFA Secretion from Cancer-Associated Fibroblasts in Prostate Cancer via TLR4

by Jing Ma, Xu Chen, Yumo Chen, Ning Tao and Zhihai Qin

Cancers 2022, 14(10), 2406; https://doi.org/10.3390/cancers14102406 - 13 May 2022

Cited by 13 | Viewed by 2823

Abstract

CAFs secrete VEGFA in the tumor microenvironment to induce angiogenesis and promote tumor growth. The downregulation of VEGFA secretion from CAFs helps block angiogenesis and exerts an anti-tumor effect. In vivo experiments showed that the angiogenesis of the tumor-bearing mice in the ligustilide group was significantly reduced. The results of MTT, tube formation, Transwell and scratch experiments showed that ligustilide did not affect the proliferation of HUVECs in a certain concentration range (<60 μM), but it inhibited the proliferation, tube formation and migration of HUVECs induced by CAFs. At this concentration, ligustilide did not inhibit CAF proliferation. The qPCR and WB results revealed that ligustilide downregulated the level of VEGFA in CAFs via the TLR4-ERK/JNK/p38 signaling pathway, and the effect was attenuated by blockers of the above molecules. Ligustilide also downregulated the autocrine VEGFA of HUVECs induced by CAFs, which inhibited angiogenesis more effectively. In addition, ligustilide inhibited glycolysis and HIF-1 expression in CAFs. Overall, ligustilide downregulated the VEGFA level in CAFs via the TLR4-ERK/JNK/p38 signaling pathway and inhibited the promotion of angiogenesis. This study provides a new strategy for the anti-tumor effect of natural active molecules, namely, blockade of angiogenesis, and provides a new candidate molecule for blocking angiogenesis in the tumor microenvironment. Full article

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9 pages, 868 KiB

Open AccessArticle

Overweight and Obesity Determine the Risk for Gastrointestinal Cancer in a Sex-Dependent Manner: A Retrospective Cohort Study of 287,357 Outpatients in Germany

by Sven H. Loosen, Christoph Roderburg, Markus S. Jördens, Georg Fluegen, Tom Luedde and Karel Kostev

Cancers 2022, 14(4), 931; https://doi.org/10.3390/cancers14040931 - 13 Feb 2022

Cited by 16 | Viewed by 3109

Abstract

Cancer represents the second leading cause of death worldwide, implementing a major health care and socioeconomic burden. Overweight and obesity, both of which are dramatically on the rise in both highly and less developed regions worldwide, have been established as modifiable risk factors for the development of various tumor entities including gastrointestinal (GI) cancers such as colorectal or gastric cancer. However, systematic data on an association between excessive body fat and GI cancer development from Germany are missing. Methods: A total of 287,357 adult outpatients with an available BMI value between 2010 and 2019 were identified from the Disease Analyzer database (IQVIA). The main outcome was the association between pre-obesity (BMI 25–30 kg/m²) and obesity (BMI ≥ 30 kg/m²) compared to normal weight (BMI 18.5–25 kg/m²) and the incident of a GI cancer diagnoses (including colon, rectum, stomach, pancreas, and liver cancer). Results: Within the observation period, the proportion of colon cancer patients increased stepwise from 0.5% and 0.64% in normal weight to 0.71% and 0.91% in obese female and male patients, respectively, which was confirmed in multivariable regression models (OR_{female obesity}: 1.23; 95% CI: 1.03–1.48; OR_{male obesity}: 1.43, 95% CI: 1.17–1.74). In contrast, multivariable regression models revealed that obesity was significantly associated with rectal cancer (OR: 1.36, 95% CI: 1.01–1.84) as well as liver cancer (OR: 1.79, 95% CI: 1.17–2.73) in men only. Conclusions: Our data suggest that obesity represents a decisive risk factor for the development of colon, rectal, and liver cancer, partly in a sex-dependent manner. Since overweight and obesity are modifiable risk factors, the current results may help to establish appropriate prevention and lifestyle programs to reduce both the incidence as well as the high morbidity and mortality of GI tumors in the future. Full article

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17 pages, 3959 KiB

Open AccessArticle

Rescuing SLAMF3 Expression Restores Sorafenib Response in Hepatocellular Carcinoma Cells through the Induction of Mesenchymal-to-Epithelial Transition

by Grégory Fouquet, Constance Marié, Louison Collet, Catherine Vilpoux, Hakim Ouled-Haddou, Eric Nguyen-Khac, Jagadeesh Bayry, Mickaël Naassila, Ingrid Marcq and Hicham Bouhlal

Cancers 2022, 14(4), 910; https://doi.org/10.3390/cancers14040910 - 12 Feb 2022

Cited by 7 | Viewed by 2633

Abstract

Background: Acquired resistance to sorafenib in hepatocellular carcinoma (HCC) patients results in poor prognosis. Epithelial-to-mesenchymal transition (EMT) is the major mechanism implicated in the resistance to sorafenib. We have reported the tumor suppressor role of SLAMF3 (signaling lymphocytic activation molecules family 3) in HCC progression and highlighted its implication in controlling the MRP-1 transporter activity. These data suggest the implication of SLAMF3 in sorafenib resistance mechanisms. Methods: We evaluated the resistance to sorafenib in Huh-7 cells treated with progressive doses (Res cells). We investigated the link between acquired resistance to sorafenib and SLAMF3 expression by flow cytometry and Western blot methods. Furthermore, we analyzed the EMT and the stem cell potential of cells resistant to sorafenib. Results: Sorafenib resistance was confirmed in Res cells by analyzing the cell viability in the presence of sorafenib. The mesenchymal transition, in Res cells, was confirmed by high migratory index and the expression of EMT antigens. Interestingly, we found that loss of SLAMF3 expression corresponded to sorafenib-resistant phenotypes. The overexpression of SLAMF3 reversed EMT, decreased metastatic potential and inhibited mTOR/ERK1/2 in Res cells. Conclusions: We propose that rescuing SLAMF3 expression in resistant cells could represent a potential therapeutic strategy to enhance sorafenib efficacy in HCC patients. Full article

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Review

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54 pages, 2150 KiB

Open AccessReview

Epidemiologic, Genetic, Pathogenic, Metabolic, Epigenetic Aspects Involved in NASH-HCC: Current Therapeutic Strategies

by Jorge Gutiérrez-Cuevas, Silvia Lucano-Landeros, Daniel López-Cifuentes, Arturo Santos and Juan Armendariz-Borunda

Cancers 2023, 15(1), 23; https://doi.org/10.3390/cancers15010023 - 20 Dec 2022

Cited by 32 | Viewed by 4652

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the sixth most frequent cancer in the world, being the third cause of cancer-related deaths. Nonalcoholic steatohepatitis (NASH) is characterized by fatty infiltration, oxidative stress and necroinflammation of the liver, with or without fibrosis, which can progress to advanced liver fibrosis, cirrhosis and HCC. Obesity, metabolic syndrome, insulin resistance, and diabetes exacerbates the course of NASH, which elevate the risk of HCC. The growing prevalence of obesity are related with increasing incidence of NASH, which may play a growing role in HCC epidemiology worldwide. In addition, HCC initiation and progression is driven by reprogramming of metabolism, which indicates growing appreciation of metabolism in the pathogenesis of this disease. Although no specific preventive pharmacological treatments have recommended for NASH, dietary restriction and exercise are recommended. This review focuses on the molecular connections between HCC and NASH, including genetic and risk factors, highlighting the metabolic reprogramming and aberrant epigenetic alterations in the development of HCC in NASH. Current therapeutic aspects of NASH/HCC are also reviewed. Full article

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22 pages, 6176 KiB

Open AccessReview

The Good, the Bad and the New about Uric Acid in Cancer

by Simone Allegrini, Mercedes Garcia-Gil, Rossana Pesi, Marcella Camici and Maria Grazia Tozzi

Cancers 2022, 14(19), 4959; https://doi.org/10.3390/cancers14194959 - 10 Oct 2022

Cited by 34 | Viewed by 9825

Abstract

Uric acid is the final product of purine catabolism in man and apes. The serum concentration of uric acid is sex-, age- and diet-dependent and is maintained close to its maximal solubility, indicating that it plays some important role. Indeed, it has been demonstrated that, at physiological concentrations, uric acid is a powerful antioxidant, while at high intracellular concentrations, it is a pro-oxidant molecule. In this review, we describe the possible causes of uric acid accumulation or depletion and some of the metabolic and regulatory pathways it may impact. Particular attention has been given to fructose, which, because of the complex correlation between carbohydrate and nucleotide metabolism, causes uric acid accumulation. We also present recent results on the positive and negative effects played by uric acid in cancer and some new findings and hypotheses about the implication of this metabolite in a variety of signaling pathways, which can play a role in the pathogenesis of diseases such as metabolic syndrome, diabetes, and inflammation, thus favoring the development of cancer. The loss of uricase in Homo sapiens and great apes, although exposing these species to the potentially adverse effects of uric acid, appears to be associated with evolutionary advantages. Full article

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14 pages, 552 KiB

Open AccessReview

Neuraminidase-1: A Sialidase Involved in the Development of Cancers and Metabolic Diseases

by Kévin Toussaint, Aline Appert-Collin, Hamid Morjani, Camille Albrecht, Hervé Sartelet, Béatrice Romier-Crouzet, Pascal Maurice, Laurent Duca, Sébastien Blaise and Amar Bennasroune

Cancers 2022, 14(19), 4868; https://doi.org/10.3390/cancers14194868 - 5 Oct 2022

Cited by 12 | Viewed by 3727

Abstract

Sialidases or neuraminidases (NEU) are glycosidases which cleave terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides. Four types of mammalian sialidases, which are encoded by different genes, have been described with distinct substrate specificity and subcellular localization: NEU-1, NEU-2, NEU-3 and NEU-4. Among them, NEU-1 regulates many membrane receptors through desialylation which results in either the activation or inhibition of these receptors. At the plasma membrane, NEU-1 also associates with the elastin-binding protein and the carboxypeptidase protective protein/cathepsin A to form the elastin receptor complex. The activation of NEU-1 is required for elastogenesis and signal transduction through this receptor, and this is responsible for the biological effects that are mediated by the elastin-derived peptides (EDP) on obesity, insulin resistance and non-alcoholic fatty liver diseases. Furthermore, NEU-1 expression is upregulated in hepatocellular cancer at the mRNA and protein levels in patients, and this sialidase regulates the hepatocellular cancer cells’ proliferation and migration. The implication of NEU-1 in other cancer types has also been shown notably in the development of pancreatic carcinoma and breast cancer. Altogether, these data indicate that NEU-1 plays a key role not only in metabolic disorders, but also in the development of several cancers which make NEU-1 a pharmacological target of high potential in these physiopathological contexts. Full article

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25 pages, 2006 KiB

Open AccessReview

Potential Role of Sphingolipidoses-Associated Lysosphingolipids in Cancer

by Patricia Dubot, Leonardo Astudillo, Nicole Therville, Lorry Carrié, Magali Pettazzoni, David Cheillan, Jérôme Stirnemann, Thierry Levade, Nathalie Andrieu-Abadie and Frédérique Sabourdy

Cancers 2022, 14(19), 4858; https://doi.org/10.3390/cancers14194858 - 5 Oct 2022

Cited by 2 | Viewed by 2415

Abstract

Sphingolipids play a key structural role in cellular membranes and/or act as signaling molecules. Inherited defects of their catabolism lead to lysosomal storage diseases called sphingolipidoses. Although progress has been made toward a better understanding of their pathophysiology, several issues still remain unsolved. In particular, whether lysosphingolipids, the deacylated form of sphingolipids, both of which accumulate in these diseases, are simple biomarkers or play an instrumental role is unclear. In the meanwhile, evidence has been provided for a high risk of developing malignancies in patients affected with Gaucher disease, the most common sphingolipidosis. This article aims at analyzing the potential involvement of lysosphingolipids in cancer. Knowledge about lysosphingolipids in the context of lysosomal storage diseases is summarized. Available data on the nature and prevalence of cancers in patients affected with sphingolipidoses are also reviewed. Then, studies investigating the biological effects of lysosphingolipids toward pro or antitumor pathways are discussed. Finally, original findings exploring the role of glucosylsphingosine in the development of melanoma are presented. While this lysosphingolipid may behave like a protumorigenic agent, further investigations in appropriate models are needed to elucidate the role of these peculiar lipids, not only in sphingolipidoses but also in malignant diseases in general. Full article

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Molecular Links between Cancer and Metabolic Diseases: New Perspectives and Therapeutic Strategies for Cancer Prevention and Treatment by Targeting Nutritional Patterns and Metabolic Alterations

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