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Cancers
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Epigenetic and Metabolic Alterations in the Tumor Microenvironment
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Epigenetic and Metabolic Alterations in the Tumor Microenvironment

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

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 26539

Special Issue Editors

Prof. Dr. Ciro Isidoro

E-Mail Website
Guest Editor
Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, Italy
Interests: autophagy and protein metabolism in cancer and in neurodegeneration; epigenetics in cancer; nutraceuticals and probiotics in cancer and infectious diseases
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Danny N. Dhanasekaran

E-Mail Website
Guest Editor
Stephenson Cancer Center, Oklahoma University Health Science Center, Oklahoma, OK 73104, USA
Interests: cancer; cell signaling; non-coding RNA; tumor microenvironment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is an organoid in which parenchymal cancer cells are embedded together with several other cell types in a complex matrix in which the presence of nutrients, oxygen, and signaling molecules (cytokines, growth factors) is subjected to dynamic changes. The intercellular communications between malignant cancer cells and cancer-associated fibroblasts and immune cells present in the stroma lead to continuous remodeling of the tumor microenvironment, which then impinges on the progression of cancer. In this scenario, epigenetic changes caused by microenvironmental factors play a major role in metabolic reprogramming and, consequently, in the behavior of cancer cells.

In this Special Issue, we wish to collect original research and review articles addressing the epigenetic and metabolic alterations occurring in the tumor environment that influence cancer progression through impacting the proliferation, migration and invasion, dormancy, stemness, and resistance to therapy of cancer cells.

Prof. Dr. Ciro Isidoro
Prof. Dr. Danny N. Dhanasekaran
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.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tumor microenvironment
  • hypoxia
  • inflammation
  • cytokines
  • epigenetics
  • metabolic cross-talk
  • cancer stroma cells
  • epigenetic alterations
  • cancer cell dormancy
  • cancer cell proliferation
  • cancer cell migration
  • cancer cell stemness

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Published Papers (7 papers)

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Research

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25 pages, 4152 KiB  
Article
Exploring Metabolic Signatures of Ex Vivo Tumor Tissue Cultures for Prediction of Chemosensitivity in Ovarian Cancer
by Rita Mendes, Gonçalo Graça, Fernanda Silva, Ana C. L. Guerreiro, Patrícia Gomes-Alves, Jacinta Serpa, Erwin R. Boghaert, Paula M. Alves, Ana Félix, Catarina Brito and Inês A. Isidro
Cancers 2022, 14(18), 4460; https://doi.org/10.3390/cancers14184460 - 14 Sep 2022
Cited by 6 | Viewed by 2600
Abstract
Predicting patient response to treatment and the onset of chemoresistance are still major challenges in oncology. Chemoresistance is deeply influenced by the complex cellular interactions occurring within the tumor microenvironment (TME), including metabolic crosstalk. We have previously shown that ex vivo tumor tissue [...] Read more.
Predicting patient response to treatment and the onset of chemoresistance are still major challenges in oncology. Chemoresistance is deeply influenced by the complex cellular interactions occurring within the tumor microenvironment (TME), including metabolic crosstalk. We have previously shown that ex vivo tumor tissue cultures derived from ovarian carcinoma (OvC) resections retain the TME components for at least four weeks of culture and implemented assays for assessment of drug response. Here, we explored ex vivo patient-derived tumor tissue cultures to uncover metabolic signatures of chemosensitivity and/or resistance. Tissue cultures derived from nine OvC cases were challenged with carboplatin and paclitaxel, the standard-of-care chemotherapeutics, and the metabolic footprints were characterized by LC-MS. Partial least-squares discriminant analysis (PLS-DA) revealed metabolic signatures that discriminated high-responder from low-responder tissue cultures to ex vivo drug exposure. As a proof-of-concept, a set of potential metabolic biomarkers of drug response was identified based on the receiver operating characteristics (ROC) curve, comprising amino acids, fatty acids, pyrimidine, glutathione, and TCA cycle pathways. Overall, this work establishes an analytical and computational platform to explore metabolic features of the TME associated with response to treatment, which can leverage the discovery of biomarkers of drug response and resistance in OvC. Full article
(This article belongs to the Special Issue Epigenetic and Metabolic Alterations in the Tumor Microenvironment)
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24 pages, 5027 KiB  
Article
Resveratrol Contrasts IL-6 Pro-Growth Effects and Promotes Autophagy-Mediated Cancer Cell Dormancy in 3D Ovarian Cancer: Role of miR-1305 and of Its Target ARH-I
by Andrea Esposito, Alessandra Ferraresi, Amreen Salwa, Chiara Vidoni, Danny N. Dhanasekaran and Ciro Isidoro
Cancers 2022, 14(9), 2142; https://doi.org/10.3390/cancers14092142 - 25 Apr 2022
Cited by 26 | Viewed by 3224
Abstract
Tumor dormancy is the extended period during which patients are asymptomatic before recurrence, and it represents a difficult phenomenon to target pharmacologically. The relapse of tumors, for instance arising from the interruption of dormant metastases, is frequently observed in ovarian cancer patients and [...] Read more.
Tumor dormancy is the extended period during which patients are asymptomatic before recurrence, and it represents a difficult phenomenon to target pharmacologically. The relapse of tumors, for instance arising from the interruption of dormant metastases, is frequently observed in ovarian cancer patients and determines poor survival. Inflammatory cytokines present in the tumor microenvironment likely contribute to such events. Cancer cell dormancy and autophagy are interconnected at the molecular level through ARH-I (DIRAS3) and BECLIN-1, two tumor suppressors often dysregulated in ovarian cancers. IL-6 disrupts autophagy in ovarian cancer cells via miRNAs downregulation of ARH-I, an effect contrasted by the nutraceutical protein restriction mimetic resveratrol (RV). By using three ovarian cancer cell lines with different genetic background in 2D and 3D models, the latter mimicking the growth of peritoneal metastases, we show that RV keeps the cancer cells in a dormant-like quiescent state contrasting the IL-6 growth-promoting activity. Mechanistically, this effect is mediated by BECLIN-1-dependent autophagy and relies on the availability of ARH-I. We also show that ARH-I (DIRAS3) is a bona fide target of miR-1305, a novel oncomiRNA upregulated by IL-6 and downregulated by RV. Clinically relevant, bioinformatic analysis of a transcriptomic database showed that the high expression of DIRAS3 and MAP1LC3B mRNAs together with that of CDKN1A, directing a cellular dormant phenotype, predicts better overall survival in ovarian cancer patients, and this correlates with MIR1305 downregulation. The possibility of maintaining a permanent cell dormancy in ovarian cancer by the chronic administration of RV should be considered as a therapeutic option to prevent the “awakening” of cancer cells in response to a permissive microenvironment, thus limiting the risk of tumor relapse and metastasis. Full article
(This article belongs to the Special Issue Epigenetic and Metabolic Alterations in the Tumor Microenvironment)
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17 pages, 3028 KiB  
Article
Potential Metabolite Markers for Pancreatic Cancer Identified by Metabolomic Analysis of Induced Cancer-Associated Fibroblasts
by Yoshihiro Miyazaki, Nobuhito Mori, Yuka Akagi, Tatsuya Oda and Yasuyuki S. Kida
Cancers 2022, 14(6), 1375; https://doi.org/10.3390/cancers14061375 - 8 Mar 2022
Cited by 7 | Viewed by 3438
Abstract
Cancer-associated fibroblasts (CAFs) in the tumor microenvironment perform glycolysis to produce energy, i.e., ATP. Since the origin of CAFs is unidentified, it is not determined whether the intracellular metabolism transitions from oxidative phosphorylation (OXPHOS) to glycolysis when normal tissue fibroblasts differentiate into CAFs. [...] Read more.
Cancer-associated fibroblasts (CAFs) in the tumor microenvironment perform glycolysis to produce energy, i.e., ATP. Since the origin of CAFs is unidentified, it is not determined whether the intracellular metabolism transitions from oxidative phosphorylation (OXPHOS) to glycolysis when normal tissue fibroblasts differentiate into CAFs. In this study, we established an experimental system and induced the in vitro differentiation of mesenchymal stem cells (MSCs) to CAFs. Additionally, we performed metabolomic and RNA-sequencing analyses before and after differentiation to investigate changes in the intracellular metabolism. Consequently, we discovered that OXPHOS, which was the primary intracellular metabolism in MSCs, was reprogrammed to glycolysis. Furthermore, we analyzed the metabolites in pancreatic tumor tissues in a mice model. The metabolites extracted as candidates in the in vitro experiments were also detected in the in vivo experiments. Thus, we conclude that normal tissue fibroblasts that differentiate into CAFs undergo a metabolic reprogramming from OXPHOS to glycolysis. Moreover, we identified the CAF-specific metabolites expressed during metabolic reprogramming as potential future biomarkers for pancreatic cancer. Full article
(This article belongs to the Special Issue Epigenetic and Metabolic Alterations in the Tumor Microenvironment)
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25 pages, 10741 KiB  
Article
Cancer-Associated Fibroblast-Derived IL-6 Determines Unfavorable Prognosis in Cholangiocarcinoma by Affecting Autophagy-Associated Chemoresponse
by Suyanee Thongchot, Chiara Vidoni, Alessandra Ferraresi, Watcharin Loilome, Narong Khuntikeo, Sakkarn Sangkhamanon, Attapol Titapun, Ciro Isidoro and Nisana Namwat
Cancers 2021, 13(9), 2134; https://doi.org/10.3390/cancers13092134 - 28 Apr 2021
Cited by 39 | Viewed by 3485
Abstract
Background: Interleukin-6 (IL-6) released by cancer-associated fibroblasts (CAFs) has been shown to associate with the malignant behavior of cholangiocarcinoma (CCA). Here, we aimed to validate with clinical and molecular data the hypothesis that CAF infiltration and release of IL-6 predict poor prognosis in [...] Read more.
Background: Interleukin-6 (IL-6) released by cancer-associated fibroblasts (CAFs) has been shown to associate with the malignant behavior of cholangiocarcinoma (CCA). Here, we aimed to validate with clinical and molecular data the hypothesis that CAF infiltration and release of IL-6 predict poor prognosis in CCA patients following dysregulation of autophagy in cancer cells. Methods: Stromal IL-6 and cancer-cell-associated autophagy proteins LC3 and p62 were assayed by Tissue MicroArray immunohistochemistry and their expression correlated with overall survival (OS) in a cohort of 70 CCA patients. The 5-FU cytotoxicity and autophagy were determined in CCA cells cultured with CAF-conditioned medium. Results: We show that patients bearing a CCA with low production of stromal IL-6 and active autophagy flux in the cancer cells have the best prognosis and this correlates with a more effective response to post-operative chemotherapy. A similar trend was observed in CCA patients from the TCGA database. In vitro genetic manipulation of IL-6 production by primary CAFs isolated from human CCA showed that IL-6 impairs the autophagy-associated apoptotic response to 5-FU in human CCA cells. Stromal IL-6 inhibition of autophagy in cancer cells was confirmed in an animal model of CCA. Conclusion: Our data support a therapeutic strategy that includes autophagy-enhancing drugs along with adjuvants limiting the stromal inflammation (i.e., the secretion of IL-6) to improve the survival of CCA patients. Full article
(This article belongs to the Special Issue Epigenetic and Metabolic Alterations in the Tumor Microenvironment)
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Review

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14 pages, 1475 KiB  
Review
Fatty Acid Metabolism in Myeloid-Derived Suppressor Cells and Tumor-Associated Macrophages: Key Factor in Cancer Immune Evasion
by Sophiya Siddiqui and Rainer Glauben
Cancers 2022, 14(1), 250; https://doi.org/10.3390/cancers14010250 - 4 Jan 2022
Cited by 20 | Viewed by 4524
Abstract
The tumor microenvironment (TME) comprises various cell types, soluble factors, viz, metabolites or cytokines, which together play in promoting tumor metastasis. Tumor infiltrating immune cells play an important role against cancer, and metabolic switching in immune cells has been shown to affect activation, [...] Read more.
The tumor microenvironment (TME) comprises various cell types, soluble factors, viz, metabolites or cytokines, which together play in promoting tumor metastasis. Tumor infiltrating immune cells play an important role against cancer, and metabolic switching in immune cells has been shown to affect activation, differentiation, and polarization from tumor suppressive into immune suppressive phenotypes. Macrophages represent one of the major immune infiltrates into TME. Blood monocyte-derived macrophages and myeloid derived suppressor cells (MDSCs) infiltrating into the TME potentiate hostile tumor progression by polarizing into immunosuppressive tumor-associated macrophages (TAMs). Recent studies in the field of immunometabolism focus on metabolic reprogramming at the TME in polarizing tumor-associated macrophages (TAMs). Lipid droplets (LD), detected in almost every eukaryotic cell type, represent the major source for intra-cellular fatty acids. Previously, LDs were mainly described as storage sites for fatty acids. However, LDs are now recognized to play an integral role in cellular signaling and consequently in inflammation and metabolism-mediated phenotypical changes in immune cells. In recent years, the role of LD dependent metabolism in macrophage functionality and phenotype has been being investigated. In this review article, we discuss fatty acids stored in LDs, their role in modulating metabolism of tumor-infiltrating immune cells and, therefore, in shaping the cancer progression. Full article
(This article belongs to the Special Issue Epigenetic and Metabolic Alterations in the Tumor Microenvironment)
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17 pages, 1649 KiB  
Review
MicroRNA-Mediated Metabolic Shaping of the Tumor Microenvironment
by Federico Virga, Lorena Quirico, Stefania Cucinelli, Massimiliano Mazzone, Daniela Taverna and Francesca Orso
Cancers 2021, 13(1), 127; https://doi.org/10.3390/cancers13010127 - 3 Jan 2021
Cited by 12 | Viewed by 4283
Abstract
The metabolism of cancer cells is generally very different from what is found in normal counterparts. However, in a tumor mass, the continuous crosstalk and competition for nutrients and oxygen among different cells lead to metabolic alterations, not only in cancer cells, but [...] Read more.
The metabolism of cancer cells is generally very different from what is found in normal counterparts. However, in a tumor mass, the continuous crosstalk and competition for nutrients and oxygen among different cells lead to metabolic alterations, not only in cancer cells, but also in the different stromal and immune cells of the tumor microenvironment (TME), which are highly relevant for tumor progression. MicroRNAs (miRs) are small non-coding RNAs that silence their mRNA targets post-transcriptionally and are involved in numerous physiological cell functions as well as in the adaptation to stress situations. Importantly, miRs can also be released via extracellular vesicles (EVs) and, consequently, take part in the bidirectional communication between tumor and surrounding cells under stress conditions. Certain miRs are abundantly expressed in stromal and immune cells where they can regulate various metabolic pathways by directly suppressing enzymes or transporters as well as by controlling important regulators (such as transcription factors) of metabolic processes. In this review, we discuss how miRs can induce metabolic reprogramming in stromal (fibroblasts and adipocytes) and immune (macrophages and T cells) cells and, in turn, how the biology of the different cells present in the TME is able to change. Finally, we debate the rebound of miR-dependent metabolic alterations on tumor progression and their implications for cancer management. Full article
(This article belongs to the Special Issue Epigenetic and Metabolic Alterations in the Tumor Microenvironment)
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Other

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18 pages, 2533 KiB  
Systematic Review
The Role of Biomimetic Hypoxia on Cancer Cell Behaviour in 3D Models: A Systematic Review
by Ye Liu, Zahra Mohri, Wissal Alsheikh and Umber Cheema
Cancers 2021, 13(6), 1334; https://doi.org/10.3390/cancers13061334 - 16 Mar 2021
Cited by 11 | Viewed by 3054
Abstract
The development of biomimetic, human tissue models is recognized as being an important step for transitioning in vitro research findings to the native in vivo response. Oftentimes, 2D models lack the necessary complexity to truly recapitulate cellular responses. The introduction of physiological features [...] Read more.
The development of biomimetic, human tissue models is recognized as being an important step for transitioning in vitro research findings to the native in vivo response. Oftentimes, 2D models lack the necessary complexity to truly recapitulate cellular responses. The introduction of physiological features into 3D models informs us of how each component feature alters specific cellular response. We conducted a systematic review of research papers where the focus was the introduction of key biomimetic features into in vitro models of cancer, including 3D culture and hypoxia. We analysed outcomes from these and compiled our findings into distinct groupings to ascertain which biomimetic parameters correlated with specific responses. We found a number of biomimetic features which primed cancer cells to respond in a manner which matched in vivo response. Full article
(This article belongs to the Special Issue Epigenetic and Metabolic Alterations in the Tumor Microenvironment)
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