International Journal of Molecular Sciences

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Dear Colleagues,

Fibrosis is a condition that develops in inflammations and cancer. It can be the result of disbalances in the homeostasis of the cells that form the stroma in a certain tissue. Anomalous stimulation of cells by signals from different origin can induce changes in their phenotype, which may result in increased proliferation and in the accumulation of components of the extracellular matrix. Different types of cells, including inflammatory cells, can enroll the tissue and enhance the deleterious conditions that are being set. Altogether will contribute to the formation of the termed tissue microenvironment. The growing fibrotic tissue can impair the functions of the part of the gastrointestinal system that is being affected. In general, the result will depend on the extent of the damage but, usually, might contribute to the development of inflammation or the growth of cancerous cells. The consequences are of major relevance to human health. Along the recent years, research has been focused onto the identification of regulators of fibrotic tissue. Nowadays it is accepted that the conditions developed within the stroma contribute significantly to the pathogenic process. Moreover, modulation of the interrelationships and/or communication established between different cell types of the stroma is emerging as potential regulator of pathophysiology. Therefore, understanding of cellular and molecular basis of cell-to-cell interconnections is of critical relevance and can be used to find keys to fight disease development and to find a potential cure.

Prof. Dr. Antonio Gonzalez
Guest Editor

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Keywords

digestive system
stroma
disease
inflammation
cancer

Published Papers (2 papers)

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Research

16 pages, 7601 KiB

Open AccessArticle

High CD142 Level Marks Tumor-Promoting Fibroblasts with Targeting Potential in Colorectal Cancer

by András Áron Soós, Andrea Kelemen, Adrián Orosz, Zsuzsanna Szvicsek, Tamás Tölgyes, Kristóf Dede, Attila Bursics and Zoltán Wiener

Int. J. Mol. Sci. 2023, 24(14), 11585; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241411585 - 18 Jul 2023

Cited by 2 | Viewed by 2604

Abstract

Colorectal cancer (CRC) has a high incidence and is one of the leading causes of cancer-related death. The accumulation of cancer-associated fibroblasts (CAF) induces an aggressive, stem-like phenotype in tumor cells, and it indicates a poor prognosis. However, cellular heterogeneity among CAFs and the targeting of both stromal and CRC cells are not yet well resolved. Here, we identified CD142^high fibroblasts with a higher stimulating effect on CRC cell proliferation via secreting more hepatocyte growth factor (HGF) compared to CD142^low CAFs. We also found that combinations of inhibitors that had either a promising effect in other cancer types or are more active in CRC compared to normal colonic epithelium acted synergistically in CRC cells. Importantly, heat shock protein 90 (HSP90) inhibitor selected against CD142^high fibroblasts, and both CRC cells and CAFs were sensitive to a BCL-xL inhibitor. However, targeting mitogen-activated protein kinase kinase (MEK) was ineffective in fibroblasts, and an epigenetic inhibitor selected for a tumor cell population with markers of aggressive behavior. Thus, we suggest BCL-xL and HSP90 inhibitors to eliminate cancer cells and decrease the tumor-promoting CD142^high CAF population. This may be the basis of a strategy to target both CRC cells and stromal fibroblasts, resulting in the inhibition of tumor relapse. Full article

(This article belongs to the Special Issue Challenging Stroma in Inflammation and Cancer in the Gastrointestinal System)

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18 pages, 3078 KiB

Open AccessArticle

Lacticaseibacillus rhamnosus dfa1 Attenuate Cecal Ligation-Induced Systemic Inflammation through the Interference in Gut Dysbiosis, Leaky Gut, and Enterocytic Cell Energy

by Tongthong Tongthong, Warerat Kaewduangduen, Pornpimol Phuengmaung, Wiwat Chancharoenthana and Asada Leelahavanichkul

Int. J. Mol. Sci. 2023, 24(4), 3756; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043756 - 13 Feb 2023

Cited by 4 | Viewed by 1607

Abstract

Despite an uncommon condition, the clinical management of phlegmon appendicitis (retention of the intra-abdominal appendiceal abscess) is still controversial, and probiotics might be partly helpful. Then, the retained ligated cecal appendage (without gut obstruction) with or without oral Lacticaseibacillus rhamnosus dfa1 (started at 4 days prior to the surgery) was used as a representative model. At 5 days post-surgery, the cecal-ligated mice demonstrated weight loss, soft stool, gut barrier defect (leaky gut using FITC-dextran assay), fecal dysbiosis (increased Proteobacteria with reduced bacterial diversity), bacteremia, elevated serum cytokines, and spleen apoptosis without kidney and liver damage. Interestingly, the probiotics attenuated disease severity as indicated by stool consistency index, FITC-dextran assay, serum cytokines, spleen apoptosis, fecal microbiota analysis (reduced Proteobacteria), and mortality. Additionally, impacts of anti-inflammatory substances from culture media of the probiotics were demonstrated by attenuation of starvation injury in the Caco-2 enterocyte cell line as indicated by transepithelial electrical resistance (TEER), inflammatory markers (supernatant IL-8 with gene expression of TLR4 and NF-κB), cell energy status (extracellular flux analysis), and the reactive oxygen species (malondialdehyde). In conclusion, gut dysbiosis and leaky-gut-induced systemic inflammation might be helpful clinical parameters for patients with phlegmon appendicitis. Additionally, the leaky gut might be attenuated by some beneficial molecules from probiotics. Full article

(This article belongs to the Special Issue Challenging Stroma in Inflammation and Cancer in the Gastrointestinal System)

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