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Epithelial to Mesenchymal Transition and Cellular Plasticity in Colon Cancer Progression: Future Perspectives for Diagnosis and Target Therapy

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 15660

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Special Issue Editors

Prof. Dr. Marina De Rosa

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Guest Editor

1. Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
2. Ceinge Biotecnologie Avanzate, 80131 Naples, Italy
Interests: hereditary colorectal cancer; gastrointestinal polyposis syndromes; sporadic colorectal cancer; epithelial to mesenchymal transition; cancer stem cell; molecular diagnosis; precision medicines; cancer resistance to therapy
Special Issues, Collections and Topics in MDPI journals

Dr. Mimmo Turano

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Guest Editor

Department of Biology, University of Naples Federico II, 80126 Naples, Italy
Interests: biomarker; colon cancer; colorectal cancer

Special Issue Information

Dear Colleagues,

This Special Issue, “Epithelial to Mesenchymal Transition (EMT) and Cellular Plasticity in Colon Cancer Progression: Future Perspectives for Diagnosis and Target Therapy” will mainly focus on the principal roles that EMT plays in colorectal cancer progression and metastases development.

Colorectal cancer (CRC) is the second most common cause of cancer death and the third most prevalent cancer worldwide. Despite the increase in the incidence of CRC over the last 20 years, CRC mortality has decreased in many countries, probably due to prevention strategies, early detection and treatment improvements.

During tumor progression, epithelial cancer cells undergo the EMT transition program that is characterized by the acquisition of mesenchymal and stem-like cell properties, which confer the ability to invade the extracellular matrix and migrate into the surrounding tissues. They then join the endothelial cells from vessels and arrive in the lumen in a process known as ‘intravasation’. These cells can survive in the vessel lumen, then exit the vases (i.e., ‘extravasation’), disseminate into the adjacent organs, and colonize them to generate micrometastases. Chemo-radiotherapy often kills differentiated cancer cells, while the mesenchymal, stem-like cells are treatment-resistant and can give rise to a treatment-resistant tumor.

We thus consider this subject to be of particular interest, because new knowledge can help to prevent therapy failure and to contrast cancer progression.

We invite authors to submit original research and review articles that focus on the epithelial to mesenchymal transition and cellular plasticity in colon cancer progression, and their potentiality in diagnosis and target therapy. Potential topics include, but are not limited to, the following:

EMT in colorectal cancer progression;

MET in colorectal cancer progression;

New insights into EMT- and cell plasticity-specific proteins;

EMT proteins as diagnostic biomarkers for the follow-up of colorectal cancers;

EMT proteins as new targets for precision therapy.

Prof. Marina De Rosa
Dr. Mimmo Turano
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. Biomedicines is an international peer-reviewed open access monthly 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 2600 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.

Published Papers (6 papers)

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Research

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16 pages, 5486 KiB

Open AccessArticle

Role of AMPK in Regulation of Oxaliplatin-Resistant Human Colorectal Cancer

by Sun Young Park, Ye Seo Chung, So Yeon Park and So Hee Kim

Biomedicines 2022, 10(11), 2690; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10112690 - 25 Oct 2022

Cited by 4 | Viewed by 1767

Abstract

Oxaliplatin is a platinum analog that can interfere with DNA replication and transcription. Continuous exposure to oxaliplatin results in chemoresistance; however, this mechanism is not well known. In this study, oxaliplatin-resistant (OR) colorectal cancer (CRC) cells of HCT116, HT29, SW480 and SW620 were established by gradually increasing the drug concentration to 2.5 μM. The inhibitory concentrations of cell growth by 50% (IC₅₀) of oxaliplatin were 4.40–12.7-fold significantly higher in OR CRC cells as compared to their respective parental (PT) CRC cells. Phospho-Akt and phospho-mammalian target of rapamycin (mTOR) decreased in PT CRC cells but was overexpressed in OR CRC cells in response to oxaliplatin. In addition, an oxaliplatin-mediated decrease in phospho-AMP-activated protein kinase (AMPK) in PT CRC cells induced autophagy. Contrastingly, an increased phospho-AMPK in OR CRC cells was accompanied by a decrease in LC3B, further inducing the activity of glycolytic enzymes, such as glucose transporter 1 (GLUT1), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and phosphofructokinase 1 (PFK1), to mediate cell survival. Inhibition of AMPK in OR CRC cells induced autophagy through inactivation of Akt/mTOR pathway and a decrease in GLUT1, PFKFB3, and PFK1. Collectively, targeting AMPK may provide solutions to overcome chemoresistance in OR CRC cells and restore chemosensitivity to anticancer drugs. Full article

(This article belongs to the Special Issue Epithelial to Mesenchymal Transition and Cellular Plasticity in Colon Cancer Progression: Future Perspectives for Diagnosis and Target Therapy)

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11 pages, 2531 KiB

Open AccessArticle

Thymidylate Synthase Overexpression Drives the Invasive Phenotype in Colon Cancer Cells

by Wojciech M. Ciszewski, Małgorzata Chmielewska-Kassassir, Lucyna A. Wozniak and Katarzyna Sobierajska

Biomedicines 2022, 10(6), 1267; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061267 - 29 May 2022

Cited by 8 | Viewed by 2651

Abstract

Thymidylate synthase (TYMS) is the crucial enzymatic precursor for DNA biosynthesis and, therefore, the critical target for numerous types of chemotherapy, including the most frequently applied agent in colon cancer treatment 5-fluorouracil (5-FU). TYMS also seems to be associated with cancer metastasis and acquiring mesenchymal character by tumor cells during epithelial–mesenchymal transition (EMT). Based on that knowledge, we decided to investigate the role of TYMS in the modulation of invasive ability in colon cancer cells, where its effect on cancer metastasis has not been studied in detail before. We employed colon cancer cells isolated from different stages of tumor development, cells undergoing EMT, and TYMS overexpressing cells. The elongation ratio, cell migration, invasion assay, and MMP-7 secretion were applied to analyze the cell behavior. Important epithelial and mesenchymal markers characteristic of EMT were examined at the protein level by Western blot assay. Overall, our study showed a correlation between TYMS level and invasion ability in colon cancer cells and, above all, a crucial role of TYMS in the EMT regulation. We postulate that chemotherapeutics that decrease or inhibit TYMS expression could increase the effectiveness of the therapy in patients with colon cancer, especially in the metastatic stage. Full article

(This article belongs to the Special Issue Epithelial to Mesenchymal Transition and Cellular Plasticity in Colon Cancer Progression: Future Perspectives for Diagnosis and Target Therapy)

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18 pages, 3858 KiB

Open AccessArticle

Implication of Different Tumor Biomarkers in Drug Resistance and Invasiveness in Primary and Metastatic Colorectal Cancer Cell Lines

by Marta Sánchez-Díez, Nicolás Alegría-Aravena, Marta López-Montes, Josefa Quiroz-Troncoso, Raquel González-Martos, Adrián Menéndez-Rey, José Luis Sánchez-Sánchez, Juan Manuel Pastor and Carmen Ramírez-Castillejo

Biomedicines 2022, 10(5), 1083; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10051083 - 06 May 2022

Cited by 5 | Viewed by 2262

Abstract

Protein expression profiles are directly related to the different properties of cells and are conditioned by the cellular niche. As an example, they are the cause of the characteristic cell plasticity, epithelium–mesenchymal transition (EMT), and drug resistance of cancer cells. This article characterizes ten biomarkers related to these features in three human colorectal cancer cell lines: SW-480, SW-620, and DLD-1, evaluated by flow cytometry; and in turn, resistance to oxaliplatin is studied through dose–response trials. The main biomarkers present in the three studied lines correspond to EpCAM, CD-133, and AC-133, with the latter two in low proportions in the DLD-1 line. The biomarker CD166 is present in greater amounts in SW-620 and DLD-1 compared to SW-480. Finally, DLD-1 shows high values of Trop2, which may explain the aggressiveness and resistance of these cells to oxaliplatin treatments, as EpCAM is also highly expressed. Exposure to oxaliplatin slows cell growth but also helps generate resistance to the treatment. In conclusion, the response of the cell lines is variable, due to their genetic variability, which will condition protein expression and cell growth. Further analyses in this area will provide important information for better understanding of patients’ cellular response and how to prevent resistance. Full article

(This article belongs to the Special Issue Epithelial to Mesenchymal Transition and Cellular Plasticity in Colon Cancer Progression: Future Perspectives for Diagnosis and Target Therapy)

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Review

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16 pages, 1993 KiB

Open AccessReview

The Epithelial to Mesenchymal Transition in Colorectal Cancer Progression: The Emerging Role of Succinate Dehydrogenase Alterations and Succinate Accumulation

by Mimmo Turano, Rosario Vicidomini, Francesca Cammarota, Valeria D’Agostino, Francesca Duraturo, Paola Izzo and Marina De Rosa

Biomedicines 2023, 11(5), 1428; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11051428 - 11 May 2023

Viewed by 2014

Abstract

Colorectal cancer (CRC) stands as the third most significant contributor to cancer-related mortality worldwide. A major underlying reason is that the detection of CRC usually occurs at an advanced metastatic stage, rendering therapies ineffective. In the progression from the in situ neoplasia stage to the advanced metastatic stage, a critical molecular mechanism involved is the epithelial-to-mesenchymal transition (EMT). This intricate transformation consists of a series of molecular changes, ultimately leading the epithelial cell to relinquish its features and acquire mesenchymal and stem-like cell characteristics. The EMT regulation involves several factors, such as transcription factors, cytokines, micro RNAs and long noncoding RNAs. Nevertheless, recent studies have illuminated an emerging link between metabolic alterations and EMT in various types of cancers, including colorectal cancers. In this review, we delved into the pivotal role played by EMT during CRC progression, with a focus on highlighting the relationship between the alterations of the tricarboxylic acid cycle, specifically those involving the succinate dehydrogenase enzyme, and the activation of the EMT program. In fact, emerging evidence supports the idea that elucidating the metabolic modifications that can either induce or inhibit tumor progression could be of immense significance for shaping new therapeutic approaches and preventative measures. We conclude that an extensive effort must be directed towards research for the standardization of drugs that specifically target proteins such as SDH and SUCNR1, but also TRAP1, PDH, ERK1/2, STAT3 and the HIF1-α catabolism. Full article

(This article belongs to the Special Issue Epithelial to Mesenchymal Transition and Cellular Plasticity in Colon Cancer Progression: Future Perspectives for Diagnosis and Target Therapy)

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19 pages, 5843 KiB

Open AccessReview

Glycobiology of the Epithelial to Mesenchymal Transition

by Michela Pucci, Nadia Malagolini and Fabio Dall’Olio

Biomedicines 2021, 9(7), 770; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9070770 - 02 Jul 2021

Cited by 14 | Viewed by 3529

Abstract

Glycosylation consists in the covalent, enzyme mediated, attachment of sugar chains to proteins and lipids. A large proportion of membrane and secreted proteins are indeed glycoproteins, while glycolipids are fundamental component of cell membranes. The biosynthesis of sugar chains is mediated by glycosyltransferases, whose level of expression represents a major factor of regulation of the glycosylation process. In cancer, glycosylation undergoes profound changes, which often contribute to invasion and metastasis. Epithelial to mesenchymal transition (EMT) is a key step in metastasis formation and is intimately associated with glycosylation changes. Numerous carbohydrate structures undergo up- or down-regulation during EMT and often regulate the process. In this review, we will discuss the relationship with EMT of the N-glycans, of the different types of O-glycans, including the classical mucin-type, O-GlcNAc, O-linked fucose, O-linked mannose and of glycolipids. Finally, we will discuss the role in EMT of galectins, a major class of mammalian galactoside-binding lectins. While the expression of specific carbohydrate structures can be used as a marker of EMT and of the propensity to migrate, the manipulation of the glycosylation machinery offers new perspectives for cancer treatment through inhibition of EMT. Full article

(This article belongs to the Special Issue Epithelial to Mesenchymal Transition and Cellular Plasticity in Colon Cancer Progression: Future Perspectives for Diagnosis and Target Therapy)

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Other

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13 pages, 1557 KiB

Open AccessSystematic Review

The Role of Neuropilin-2 in the Epithelial to Mesenchymal Transition of Colorectal Cancer: A Systematic Review

by Cristina Lungulescu, Valentina Ghimpau, Dan Ionut Gheonea, Daniel Sur and Cristian Virgil Lungulescu

Biomedicines 2022, 10(1), 172; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10010172 - 14 Jan 2022

Cited by 5 | Viewed by 2146

Abstract

Neuropilin-2 (NRP-2) expression has been found in various investigations on the expression and function of NRP-2 in colorectal cancer. The link between NRP-2 and colorectal cancer, as well as the mechanism that regulates it, is still mostly unclear. This systematic review was carried out according to the Cochrane guidelines for systematic reviews. We searched PubMed, Embase^®, MEDLINE, Allied & Complementary Medicine^TM, Medical Toxicology & Environmental Health, DH-DATA: Health Administration for articles published before 1 October 2021. The following search terms were used: “neuropilin-2” “neuropilin 2”, “NRP2” and “NRP-2”, “colorectal cancer”, “colon cancer”. Ten articles researching either tumor tissue samples, cell lines, or mice models were included in this review. The majority of human primary and metastatic colon cancer cell lines expressed NRP-2 compared to the normal colonic mucosa. NRPs have been discovered in human cancers as well as neovasculature. The presence of NRP-2 appears to be connected to the epithelial–mesenchymal transition’s function in cancer dissemination and metastatic evolution. The studies were heterogeneous, but the data assessed indicates NRP-2 might have an impact on the metastatic potential of colorectal cancer cells. Nevertheless, further research is needed. Full article

(This article belongs to the Special Issue Epithelial to Mesenchymal Transition and Cellular Plasticity in Colon Cancer Progression: Future Perspectives for Diagnosis and Target Therapy)

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