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Cell Plasticity in Cancer Progression: Role of EMT, Epigenetic Regulation and Host Microenvironment

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

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 12045

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Special Issue Editors

Prof. Dr. Marco Trerotola

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Guest Editor

1. Laboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), University “G. D’Annunzio”, 66100 Chieti, Italy
2. Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio”, 66100 Chieti, Italy
Interests: cancer progression; membrane receptors; signaling; proteomics; colorectal cancer; breast cancer

Dr. Daniele Vergara

E-Mail Website
Guest Editor

Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, 73100 Lecce, Italy
Interests: cellular physiology, proteomics; cell plasticity; epithelial to mesenchymal transition, signal transduction
Special Issues, Collections and Topics in MDPI journals

Dr. Pasquale Simeone

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Guest Editor

1. Department of Medicine and Aging Sciences, University "G. D’Annunzio" Chieti-Pescara, 66100 Chieti, Italy
2. Center for Advanced Studies and Technology (C.A.S.T.), University "G.D’Annunzio" Chieti-Pescara, 66100 Chieti, Italy
Interests: flow cytometry; cell biology; cytomorphology; proteomics; cell plasticity; signal transduction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cell plasticity occurs at various stages of human physiology and is also a key mechanism in cancer progression. In physiological contexts, such as during embryogenesis and after injury, plasticity allows cells to give rise to novel tissues or to regenerate damaged tissue microenvironments. Pathological conditions including tumor progression are caused by altered regulation of the physiological mechanisms of cell plasticity, such that tumor cells frequently show novel functional properties. Several recently published studies have demonstrated that the activation of the epithelial to mesenchymal transition (EMT) process can provide malignant cells with enhanced motility, increased invasive potential and stemness properties. However, the molecular determinants underlying the plasticity of cancer cells and the functional relationships with the surrounding microenvironment are not completely understood. This represents an important challenge for the accurate diagnosis and treatment of human tumors.

The aim of this Special Issue is to shed light on novel signaling pathways and molecular players that contribute to regulate physiological and pathological cell plasticity through a finely tuned activation or inhibition of the EMT process. Moreover, considering the dynamic and complex nature of these events, important biological insights gained through the application and the integration of omics and novel experimental methods and analytical approaches in vitro and in vivo will be also considered.

We invite authors to contribute original research articles as well as review articles that address recent developments in the above areas.

Potential topics of this Special Issue include but are not limited to:

Signaling networks regulating cell plasticity;
Cell plasticity and EMT;
Plasticity and cancer stem cells;
Epigenetic regulation of plasticity in tumors;
Clinical impact of cancer cell plasticity;
Novel approaches to study cell plasticity in vivo during tumor progression.

Prof. Dr. Marco Trerotola
Prof. Dr. Daniele Vergara
Dr. Pasquale Simeone
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 short 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

EMT
tumor invasion
cancer stem cells
tumor dormancy

Published Papers (6 papers)

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Research

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20 pages, 4107 KiB

Open AccessArticle

Cholecystokinin Receptor Antagonist Induces Pancreatic Stellate Cell Plasticity Rendering the Tumor Microenvironment Less Oncogenic

by Gurbani Jolly, Tetyana Duka, Narayan Shivapurkar, Wenqiang Chen, Sunil Bansal, Amrita Cheema and Jill P. Smith

Cancers 2023, 15(10), 2811; https://doi.org/10.3390/cancers15102811 - 18 May 2023

Cited by 2 | Viewed by 1493

Abstract

CCK receptors are expressed on pancreatic cancer epithelial cells, and blockade with receptor antagonists decreases tumor growth. Activated pancreatic stellate cells or myofibroblasts have also been described to express CCK receptors, but the contribution of this novel pathway in fibrosis of the pancreatic cancer microenvironment has not been studied. We examined the effects of the nonselective CCK receptor antagonist proglumide on the activation, proliferation, collagen deposition, differential expression of genes, and migration in both murine and human PSCs. CCK receptor expression was examined using western blot analysis. Collagen production using activated PSCs was analyzed by mass spectroscopy and western blot. Migration of activated PSCs was prevented in vitro by proglumide and the CCK-B receptor antagonist, L365,260, but not by the CCK-A receptor antagonist L365,718. Proglumide effectively decreased the expression of extracellular matrix-associated genes and collagen-associated proteins in both mouse and human PSCs. Components of fibrosis, including hydroxyproline and proline levels, were significantly reduced in PSC treated with proglumide compared to controls. CCK peptide stimulated mouse and human PSC proliferation, and this effect was blocked by proglumide. These investigations demonstrate that targeting the CCK-B receptor signaling pathway with proglumide may alter the plasticity of PSC, rendering them more quiescent and leading to a decrease in fibrosis in the pancreatic cancer microenvironment. Full article

(This article belongs to the Special Issue Cell Plasticity in Cancer Progression: Role of EMT, Epigenetic Regulation and Host Microenvironment)

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11 pages, 2036 KiB

Open AccessArticle

Laminin-332 γ2 Monomeric Chain Promotes Adhesion and Migration of Hepatocellular Carcinoma Cells

by Rosanna Scialpi, Valentina Arrè, Gianluigi Giannelli and Francesco Dituri

Cancers 2023, 15(2), 373; https://doi.org/10.3390/cancers15020373 - 6 Jan 2023

Cited by 1 | Viewed by 2053

Abstract

Extracellular matrix (ECM) has a well-recognized impact on the progression of solid tumors, including hepatocellular carcinoma (HCC). Laminin 332 (Ln332) is a ECM molecule of epithelial basal lamina, composed of three polypeptide chains (α3, β3, and γ2), that is usually poorly expressed in the normal liver but is detected at high levels in HCC. This macromolecule was shown to promote the proliferation, epithelial-to-mesenchymal transition (EMT), and drug resistance of HCC cells. The monomeric γ2 chain is up-regulated and localized preferentially at the invasive edge of metastatic intrahepatic HCC nodules, suggesting its potential involvement in the acquisition of invasive properties of HCC cells. HCC cells were tested in in vitro adhesion, scattering, and transwell migration assays in response to fibronectin and the Ln332 and Ln332 γ2 chains, and the activation status of major signaling pathways involved was evaluated. Here, we show that the Ln332 γ2 chain promotes HCC the cell adhesion, migration, and scattering of HCC cells that express the Ln332 receptor α3β1 integrin, proving to be a causal factor of the EMT program achievement. Moreover, we found that efficient HCC cell adhesion and migration on γ2 require the activation of the small cytosolic GTPase Rac1 and ERKs signaling. These data suggest that the γ2 chain, independently from the full-length Ln332, can contribute to the pro-invasive potential of aggressive HCC cell subpopulations. Full article

(This article belongs to the Special Issue Cell Plasticity in Cancer Progression: Role of EMT, Epigenetic Regulation and Host Microenvironment)

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19 pages, 6101 KiB

Open AccessArticle

Resistin Promotes Nasopharyngeal Carcinoma Metastasis through TLR4-Mediated Activation of p38 MAPK/NF-κB Signaling Pathway

by Zongmeng Zhang, Jinlin Du, Qihua Xu, Yuyu Li, Sujin Zhou, Zhenggang Zhao, Yunping Mu, Allan Z. Zhao, Su-Mei Cao and Fanghong Li

Cancers 2022, 14(23), 6003; https://doi.org/10.3390/cancers14236003 - 5 Dec 2022

Cited by 3 | Viewed by 1284

Abstract

NPC is a type of malignant tumor with a high risk of local invasion and early distant metastasis. Resistin is an inflammatory cytokine that is predominantly produced from the immunocytes in humans. Accumulating evidence has suggested a clinical association of circulating resistin with the risk of tumorigenesis and a relationship between blood resistin levels and the risk of cancer metastasis. In this study, we explored the blood levels and the role of resistin in NPC. High resistin levels in NPC patients were positively associated with lymph node metastasis, and resistin promoted the migration and invasion of NPC cells in vitro. These findings were also replicated in a mouse model of NPC tumor metastasis. We identified TLR4 as a functional receptor in mediating the pro-migratory effects of resistin in NPC cells. Furthermore, p38 MAPK and NF-κB were intracellular effectors that mediated resistin-induced EMT. Taken together, our results suggest that resistin promotes NPC metastasis by activating the TLR4/p38 MAPK/NF-κB signaling pathways. Full article

(This article belongs to the Special Issue Cell Plasticity in Cancer Progression: Role of EMT, Epigenetic Regulation and Host Microenvironment)

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19 pages, 5145 KiB

Open AccessArticle

FTO Inhibits Epithelial Ovarian Cancer Progression by Destabilising SNAI1 mRNA through IGF2BP2

by Meige Sun, Xiaocui Zhang, Fangfang Bi, Dandan Wang, Xin Zhou, Xiao Li and Qing Yang

Cancers 2022, 14(21), 5218; https://doi.org/10.3390/cancers14215218 - 25 Oct 2022

Cited by 11 | Viewed by 1866

Abstract

Fat mass and obesity-associated protein (FTO) regulates critical pathways in various diseases, including malignant tumours. However, the functional link between FTO and its target genes in epithelial ovarian cancer (EOC) development remains to be elucidated. In this study, the biological functions of FTO were verified in vitro and in vivo. The m6A modification and the binding sites of SNAI1 mRNA were confirmed by m6A RNA immunoprecipitation (MeRIP) and RIP experiments. The actinomycin D assay was used to test the stability of RNA. We found that FTO was downregulated with increased m6A levels in EOC. Reduced expression of FTO was associated with a higher FIGO stage in patients with EOC. Mechanistically, FTO decreased the m6A level and stability of SNAI1 mRNA, causing downregulation of SNAI1 and inhibiting epithelial–mesenchymal transition (EMT). Furthermore, FTO-mediated downregulation of SNAI1 expression depended on IGF2BP2, which acted as an m6A reader binding to the 3′ UTR region of SNAI1 mRNA to promote its stability. In conclusion, FTO inhibits SNAI1 expression to attenuate the growth and metastasis of EOC cells in an m6A-IGF2BP2-dependent manner. Our findings suggest that the FTO-IGF2BP2-SNAI1 axis is a potential therapeutic target in EOC. Full article

(This article belongs to the Special Issue Cell Plasticity in Cancer Progression: Role of EMT, Epigenetic Regulation and Host Microenvironment)

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18 pages, 18114 KiB

Open AccessArticle

ZEB2/TWIST1/PRMT5/NuRD Multicomplex Contributes to the Epigenetic Regulation of EMT and Metastasis in Colorectal Carcinoma

by Yayuan Zheng, Mingrui Dai, Yue Dong, Hanqiao Yu, Tianfu Liu, Xuejian Feng, Bin Yu, Haihong Zhang, Jiaxin Wu, Wei Kong, Xianghui Yu and Hui Wu

Cancers 2022, 14(14), 3426; https://doi.org/10.3390/cancers14143426 - 14 Jul 2022

Cited by 8 | Viewed by 2004

Abstract

(1) Background: The EMT plays a crucial role in tumor metastasis, which is the major cause for colorectal carcinoma-related mortality. However, the underlying regulators and mechanisms of EMT in CRC metastasis are still poorly understood; (2) Methods: The transcriptional regulators of EMT in CRC and their functions were examined using RT2212PCR, Western blotting, and luciferase reporter assay. The components of ZEB2/TWIST1 complex and their mutual interactions were identified via affinity purification, mass spectrometry, co-immunoprecipitation, and pull-down experiments. The functional mechanisms of ZEB2/TWIST1/PRMT5/NuRD axis were determined by chromatin immunoprecipitation and luciferase reporter assay. The contribution of ZEB2/TWIST1/PRMT5/NuRD complex in the CRC metastasis was investigated using wound healing, transwell assay, and in vivo xenograft mouse model; (3) Results: We found that ZEB2 and TWIST1 were both significantly upregulated in CRC tissues and EMT of CRC cells. ZEB2 could recruit TWIST1 to the E-cadherin promoter and synergistically repressed its transcription. In addition, ZEB2 physically interacted with TWIST1, PRMT5, and the nucleosome remodeling and deacetylase (NuRD) complex to form a novel repressive multicomplex, leading to epigenetic silencing of E-cadherin in CRC cells. Notably, the combined inhibition of ZEB2 and TWIST1 and epigenetic inhibition markedly reduced CRC metastasis in mice; (4) Conclusions: We revealed for the first time that ZEB2 could recruit TWIST1, PRMT5, and NuRD to form a repressive multicomplex and epigenetically suppresses the transcription of E-cadherin, thereby inducing the EMT process and metastasis in CRC. Our results also confirmed the therapeutic potential of epigenetic inhibitors in CRC. Full article

(This article belongs to the Special Issue Cell Plasticity in Cancer Progression: Role of EMT, Epigenetic Regulation and Host Microenvironment)

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Other

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15 pages, 820 KiB

Open AccessSystematic Review

Long Non-Coding RNAs as Potential Regulators of EMT-Related Transcription Factors in Colorectal Cancer—A Systematic Review and Bioinformatics Analysis

by Ana Pavlič, Nina Hauptman, Emanuela Boštjančič and Nina Zidar

Cancers 2022, 14(9), 2280; https://doi.org/10.3390/cancers14092280 - 3 May 2022

Cited by 11 | Viewed by 2448

Abstract

Epithelial–mesenchymal transition (EMT) plays a pivotal role in carcinogenesis, influencing cancer progression, metastases, stemness, immune evasion, metabolic reprogramming and therapeutic resistance. EMT in most carcinomas, including colorectal carcinoma (CRC), is only partial, and can be evidenced by identification of the underlying molecular drivers and their regulatory molecules. During EMT, cellular reprogramming is orchestrated by core EMT transcription factors (EMT-TFs), namely ZEB1/2, TWIST1/2, SNAI1 (SNAIL) and SNAI2 (SLUG). While microRNAs have been clearly defined as regulators of EMT, the role of long non-coding RNAs (lncRNAs) in EMT is poorly defined and controversial. Determining the role of lncRNAs in EMT remains a challenge, because they are involved in a number of cellular pathways and are operating through various mechanisms. Adding to the complexity, some lncRNAs have controversial functions across different tumor types, acting as EMT promotors in some tumors and as EMT suppressors in others. The aim of this review is to summarize the role of lncRNAs involved in the regulation of EMT-TFs in human CRC. Additional candidate lncRNAs were identified through a bioinformatics analysis. Full article

(This article belongs to the Special Issue Cell Plasticity in Cancer Progression: Role of EMT, Epigenetic Regulation and Host Microenvironment)

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