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Biological Interfaces in Gastrointestinal Cancer 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 15326

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Special Issue Editors

Dr. Andre Lechel

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Guest Editor

Department of Internal Medicine I, Ulm University, 89081 Ulm, Germany
Interests: liver carcinogenesis; tumor differentiation; chronic liver disease; liver stem cells; tumor stem cells; p53-signalling; aging; telomeres
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Reinhold Schirmbeck

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Guest Editor

Department of Internal Medicine I, Ulm University, 89081 Ulm, Germany
Interests: CD8 T cells; genetic vaccines; mouse models of chronic HBV infection; development of novel immune therapies against tumors and autoimmune type 1 diabetes; the aging immune system
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The focus of this Special Issue is on the role of communication in gastrointestinal cancers, involving cell-to-cell communication, like communication between the microenvironment or the immune system and the tumor cell, as well as communication on the molecular level, like Wnt, NF-kB, and Mtor, which play major roles in signal transduction.

Gastrointestinal cancer, like colorectal cancer, pancreatic cancer, and hepatocellular cancer, belong to the most common causes of cancer mortality and therfore present a major health problem. Gastrointestinal cancers are characterized by their huge heterogeneity, even if many mutations are present in several tumor entities.

A detailed molecular tumor analysis on biological interfaces is increasingly fundamental in choosing the most appropriate anti-cancer therapy for patients and opening new doors for the development of precision medicine. Interdisciplinary teamwork with colleagues in pathology, bioinformatics, immunology, molecular biology, and other disciplines will help oncologists, integrating data and expertise from the work of professionals involved in prevention, early-diagnosis, and basic and translational cancer research.

In this Special Issue, we invite your contributions, either in the form of original research articles, reviews, or shorter perspective articles on all aspects related to the theme of “Biological Interfaces in Gastrointestinal Cancer”.

Dr. Andre Lechel
Prof. Dr. Reinhold Schirmbeck
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

Liver cancer
Pancreatic cancer
Intestinal cancer
Gastric cancer
Tissue inflammation
Microenvironment
Innate and adaptive immune responses
Checkpoint inhibitors
Immunotherapy
Precision medicine
Model systems (e.g., transgenic mouse models, organoid culture)

Published Papers (5 papers)

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Research

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12 pages, 1333 KiB

Open AccessArticle

Establishment and Characterization of Novel Human Intestinal In Vitro Models for Absorption and First-Pass Metabolism Studies

by Randy Przybylla, Christina Susanne Mullins, Mathias Krohn, Stefan Oswald and Michael Linnebacher

Int. J. Mol. Sci. 2022, 23(17), 9861; https://doi.org/10.3390/ijms23179861 - 30 Aug 2022

Cited by 2 | Viewed by 1890

Abstract

Commonly used intestinal in vitro models are limited in their potential to predict oral drug absorption. They either lack the capability to form a tight cellular monolayer mimicking the intestinal epithelial barrier or the expression of cytochrome P450 3A4 (CYP3A4). The aim of this study was to establish a platform of colorectal cancer patient-derived cell lines for evaluation of human intestinal drug absorption and metabolism. We characterized ten 2D cell lines out of our collection with confluent outgrowth and long-lasting barrier forming potential as well as suitability for high throughput applications with special emphasis on expression and inducibility of CYP3A4. By assessment of the transepithelial electrical resistance (TEER) the cells barrier function capacity can be quantified. Very high TEER levels were detected for HROC60. A high basal CYP3A4 expression and function was found for HROC32. Eight cell lines showed higher CYP3A4 induction by stimulation via the vitamin D receptor compared to Caco-2 cells (5.1- to 16.8-fold change). Stimulation of the pregnane X receptor led to higher CYP3A4 induction in two cell lines. In sum, we identified the two cell lines HROC183 T0 M2 and HROC217 T1 M2 as useful tools for in vitro drug absorption studies. Due to their high TEER values and inducibility by drug receptor ligands, they may be superior to Caco-2 cells to analyze oral drug absorption and intestinal drug–drug interactions. Significance statement: Selecting appropriate candidates is important in preclinical drug development. Therefore, cell models to predict absorption from the human intestine are of the utmost importance. This study revealed that the human cell lines HROC183 T0 M2 and HROC217 T1 M2 may be better suited models and possess higher predictive power of pregnane X receptor- and vitamin D-mediated drug metabolism than Caco-2 cells. Consequently, they represent useful tools for predicting intestinal absorption and simultaneously enable assessment of membrane permeability and first-pass metabolism. Full article

(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer 2.0)

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19 pages, 9852 KiB

Open AccessArticle

Recruitment of M1 Macrophages May Not Be Critical for Protection against Colitis-Associated Tumorigenesis

by Itzel Medina-Andrade, Jonadab E. Olguín, Stephanie Guerrero-García, Jossael A. Espinosa, Elizabeth Garduño-Javier, Victoria Hernández-Gómez, Felipe Vaca-Paniagua, Miriam Rodríguez-Sosa and Luis I. Terrazas

Int. J. Mol. Sci. 2021, 22(20), 11204; https://doi.org/10.3390/ijms222011204 - 18 Oct 2021

Cited by 2 | Viewed by 2062

Abstract

A close connection between inflammation and the risk of developing colon cancer has been suggested in the last few years. It has been estimated that patients diagnosed with some types of inflammatory bowel disease, such as ulcerative colitis or Crohn’s disease, have up to a 30% increased risk of developing colon cancer. However, there is also evidence showing that the activation of anti-inflammatory pathways, such as the IL-4 receptor-mediated pathway, may favor the development of colon tumors. Using an experimental model of colitis-associated colon cancer (CAC), we found that the decrease in tumor development in global IL4Rα knockout mice (IL4RαKO) was apparently associated with an inflammatory response mediated by the infiltration of M1 macrophages (F480⁺TLR2⁺STAT1⁺) and iNOS expression in colon tissue. However, when we developed mice with a specific deletion of IL4Rα in macrophages (LysMcreIL4Rα^−/lox mice) and subjected them to CAC, it was found that despite presenting a large infiltration of M1 macrophages into the colon, these mice were as susceptible to colon-tumorigenesis as WT mice. These data suggest that in the tumor microenvironment the absence of IL4Rα expression on macrophages, as well as the recruitment of M1 macrophages, may not be directly associated with resistance to developing colon tumors. Therefore, it is possible that IL4Rα expression in other cell types, such as colonic epithelial cells, could have an important role in promoting the development of colitis-associated colon tumorigenesis. Full article

(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer 2.0)

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14 pages, 4155 KiB

Open AccessArticle

MIR29A Impedes Metastatic Behaviors in Hepatocellular Carcinoma via Targeting LOX, LOXL2, and VEGFA

by Ya-Ling Yang, Ming-Chao Tsai, Yen-Hsiang Chang, Chen-Chen Wang, Pei-Yi Chu, Hung-Yu Lin and Ying-Hsien Huang

Int. J. Mol. Sci. 2021, 22(11), 6001; https://doi.org/10.3390/ijms22116001 - 1 Jun 2021

Cited by 15 | Viewed by 3316

Abstract

Primary liver cancer accounts for the third most deadly type of malignant tumor globally, and approximately 80% of the cases are hepatocellular carcinoma (HCC), which highly relies on the activity of hypoxia responsive pathways to bolster its metastatic behaviors. MicroRNA-29a (MIR29A) has been shown to exert a hepatoprotective effect on hepatocellular damage and liver fibrosis induced by cholestasis and diet stress, while its clinical and biological role on the activity hypoxia responsive genes including LOX, LOXL2, and VEGFA remains unclear. TCGA datasets were retrieved to confirm the differential expression and prognostic significance of all genes in the HCC and normal tissue. The Gene Expression Omnibus (GEO) dataset was used to corroborate the differential expression and diagnostic value of MIR29A. The bioinformatic identification were conducted to examine the interaction of MIR29A with LOX, LOXL2, and VEGFA. The suppressive activity of MIR29A on LOX, LOXL2, and VEGF was verified by qPCR, immunoblotting, and luciferase. The effect of overexpression of MIR29A-3p mimics in vitro on apoptosis markers (caspase-9, -3, and poly (ADP-ribose) polymerase (PARP)); cell viability and wound healing performance were examined using immunoblot and a WST-1 assay and a wound healing assay, respectively. The HCC tissue presented low expression of MIR29A, yet high expression of LOX, LOXL2, and VEGFA as compared to normal control. Serum MIR29A of HCC patients showed decreased levels as compared to that of normal control, with an area under curve (AUC) of 0.751 of a receiver operating characteristic (ROC) curve. Low expression of MIR29A and high expression of LOX, LOXL2, and VEGFA indicated poor overall survival (OS). MIR29A-3p was shown to target the 3′UTR of LOX, LOXL2, and VEGFA. Overexpression of MIR29A-3p mimic in HepG2 cells led to downregulated gene and protein expression levels of LOX, LOXL2, and VEGFA, wherein luciferase reporter assay confirmed that MIR29A-3p exerts the inhibitory activity via directly binding to the 3′UTR of LOX and VEGFA. Furthermore, overexpression of MIR29A-3p mimic induced the activity of caspase-9 and -3 and PARP, while it inhibited the cell viability and wound healing performance. Collectively, this study provides novel insight into a clinical-applicable panel consisting of MIR29, LOX, LOXL2, and VEGFA and demonstrates an anti-HCC effect of MIR29A via comprehensively suppressing the expression of LOX, LOXL2, and VEGFA, paving the way to a prospective theragnostic approach for HCC. Full article

(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer 2.0)

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Review

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16 pages, 930 KiB

Open AccessReview

Differential Actions of Muscarinic Receptor Subtypes in Gastric, Pancreatic, and Colon Cancer

by Alyssa Schledwitz, Margaret H. Sundel, Madeline Alizadeh, Shien Hu, Guofeng Xie and Jean-Pierre Raufman

Int. J. Mol. Sci. 2021, 22(23), 13153; https://doi.org/10.3390/ijms222313153 - 5 Dec 2021

Cited by 15 | Viewed by 3500

Abstract

Cancers arising from gastrointestinal epithelial cells are common, aggressive, and difficult to treat. Progress in this area resulted from recognizing that the biological behavior of these cancers is highly dependent on bioactive molecules released by neurocrine, paracrine, and autocrine mechanisms within the tumor microenvironment. For many decades after its discovery as a neurotransmitter, acetylcholine was thought to be synthesized and released uniquely from neurons and considered the sole physiological ligand for muscarinic receptor subtypes, which were believed to have similar or redundant actions. In the intervening years, we learned this former dogma is not tenable. (1) Acetylcholine is not produced and released only by neurons. The cellular machinery required to synthesize and release acetylcholine is present in immune, cancer, and other cells, as well as in lower organisms (e.g., bacteria) that inhabit the gut. (2) Acetylcholine is not the sole physiological activator of muscarinic receptors. For example, selected bile acids can modulate muscarinic receptor function. (3) Muscarinic receptor subtypes anticipated to have overlapping functions based on similar G protein coupling and downstream signaling may have unexpectedly diverse actions. Here, we review the relevant research findings supporting these conclusions and discuss how the complexity of muscarinic receptor biology impacts health and disease, focusing on their role in the initiation and progression of gastric, pancreatic, and colon cancers. Full article

(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer 2.0)

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21 pages, 1405 KiB

Open AccessReview

Limitations and Possibilities of Transarterial Chemotherapeutic Treatment of Hepatocellular Carcinoma

by Charlotte Ebeling Barbier, Femke Heindryckx and Hans Lennernäs

Int. J. Mol. Sci. 2021, 22(23), 13051; https://doi.org/10.3390/ijms222313051 - 2 Dec 2021

Cited by 15 | Viewed by 3596

Abstract

Because diagnostic tools for discriminating between hepatocellular carcinoma (HCC) and advanced cirrhosis are poor, HCC is often detected in a stage where transarterial chemoembolization (TACE) is the best treatment option, even though it provides a poor survival gain. Despite having been used worldwide for several decades, TACE still has many limitations. First, there is a vast heterogeneity in the cellular composition and metabolism of HCCs as well as in the patient population, which renders it difficult to identify patients who would benefit from TACE. Often the delivered drug does not penetrate sufficiently selectively and deeply into the tumour and the drug delivery system is not releasing the drug at an optimal clinical rate. In addition, therapeutic effectiveness is limited by the crosstalk between the tumour cells and components of the cirrhotic tumour microenvironment. To improve this widely used treatment of one of our most common and deadly cancers, we need to better understand the complex interactions between drug delivery, local pharmacology, tumour targeting mechanisms, liver pathophysiology, patient and tumour heterogeneity, and resistance mechanisms. This review provides a novel and important overview of clinical data and discusses the role of the tumour microenvironment and lymphatic system in the cirrhotic liver, its potential response to TACE, and current and possible novel DDSs for locoregional treatment. Full article

(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer 2.0)

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