ECM remodelling in IBD: innocent bystander or partner in crime? The emerging role of extracellular molecular events in sustaining intestinal inflammation

Shimshoni, Efrat; Yablecovitch, Doron; Baram, Liran; Dotan, Iris; Sagi, Irit

doi:10.1136/gutjnl-2014-308048

Cited by 108 publications

(105 citation statements)

References 77 publications

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“…Consistent with the above observations, MMP inhibition is protective in experimental models of lung injury . Increased detection of MMP‐3, MMP‐9, and MMP‐12 in the inflamed intestinal mucosa of individuals with IBD has also been reported . Elevated levels of MMP‐9 are associated with mucosal tissue damage and fistula formation in individuals with Crohn's disease , and MMP‐9 deficiency or inhibition is correlated with improved outcome and reduced tissue damage in animal models of IBD .…”

Section: Dysregulated Pmn Tem and Tissue Damagesupporting

confidence: 70%

Pathobiology of neutrophil–epithelial interactions

Brazil

Parkos

2016

Immunological Reviews

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Summary Polymorphonuclear neutrophils (PMNs) are innate immune system cells that play an essential role in eradicating invading pathogens. PMN migration to sites of infection/inflammation requires exiting the microcirculation and subsequent crossing of epithelial barriers in mucosa-lined organs such as the lungs and intestines. Although these processes usually occur without significant damage to surrounding host tissues, dysregulated/excessive PMN transmigration and resultant bystander-tissue damage are characteristic of numerous mucosal inflammatory disorders. Mechanisms controlling PMN extravasation have been well characterized, but the molecular details regarding regulation of PMN migration across mucosal epithelia are poorly understood. Given that PMN migration across mucosal epithelia is strongly correlated with disease symptoms in many inflammatory mucosal disorders, enhanced understanding of the mechanisms regulating PMN transepithelial migration should provide insights into clinically relevant tissue-targeted therapies aimed at ameliorating PMN-mediated bystander-tissue damage. This review will highlight current understanding of the molecular interactions between PMNs and mucosal epithelia and the associated functional consequences.

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Section: Dysregulated Pmn Tem and Tissue Damagesupporting

confidence: 70%

Pathobiology of neutrophil–epithelial interactions

Brazil

Parkos

2016

Immunological Reviews

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“…ECM homeostasis, which is critical for organ function, is maintained through a delicate balance between ECM protein synthesis, protein fibril assembly and polarization, posttranslational modification, remodeling, and degradation (41). Disrupting this balance results in various pathologic conditions, highlighting the correlation between altered ECM structural or biophysical properties and disease grade and subtype (42)(43)(44). Tissue engineering studies have demonstrated that changes in any of the physical properties or components of the ECM can affect cellular behavior.…”

Section: Discussionmentioning

confidence: 99%

Tumor Cell Invasion Can Be Blocked by Modulators of Collagen Fibril Alignment That Control Assembly of the Extracellular Matrix

et al. 2016

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Abnormal architectures of collagen fibers in the extracellular matrix (ECM) are hallmarks of many invasive diseases, including cancer. Targeting specific stages of collagen assembly in vivo presents a great challenge due to the involvement of various crosslinking enzymes in the multistep, hierarchical process of ECM build-up. Using advanced microscopic tools, we monitored stages of fibrillary collagen assembly in a native fibroblast-derived 3D matrix system and identified anti-lysyl oxidase-like 2 (LOXL2) antibodies that alter the natural alignment and width of endogenic fibrillary collagens without affecting ECM composition. The disrupted collagen morphologies interfered with the adhesion and invasion properties of human breast cancer cells. Treatment of mice bearing breast cancer xenografts with the inhibitory antibodies resulted in disruption of the tumorigenic collagen superstructure and in reduction of primary tumor growth. Our approach could serve as a general methodology to identify novel therapeutics targeting fibrillary protein organization to treat ECMassociated pathologies.

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“…It has also become evident that inflammatory responses in the tumor microenvironment affect ECM remodeling . Likewise, in UC, the ECM of the intestine is highly affected by chronic inflammation which leads to loss of tissue homeostasis and imbalanced collagen turnover . The chronic inflammation and the continuous turnover of epithelial cells contribute to development of dysplasia which may transform into CRC .…”

Section: Introductionmentioning

confidence: 99%

“…5,6 Likewise, in UC, the ECM of the intestine is highly affected by chronic inflammation which leads to loss of tissue homeostasis and imbalanced collagen turnover. 2,[7][8][9] The chronic inflammation and the continuous turnover of epithelial cells contribute to development of dysplasia which may transform into CRC. 10 Biomarkers reflecting this enhanced ECM remodeling may therefore be important to identify patients with disruption in tissue/ECM architecture responsible for development and progression of CRC and UC.…”

Section: Introductionmentioning

confidence: 99%

Serum type XVI collagen is associated with colorectal cancer and ulcerative colitis indicating a pathological role in gastrointestinal disorders

et al. 2018

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Altered extracellular matrix (ECM) remodeling is an important part of the pathology of gastrointestinal (GI) disorders. In the intestine, type XVI collagen (col‐16) plays a role in pathogenesis by affecting ECM architecture and induce cell invasion. Measuring col‐16 in serum may therefore have biomarker potential in GI disorders such as colorectal cancer (CRC) and ulcerative colitis (UC). The aim of this study was to determine whether col‐16 can serve as a biomarker for altered ECM remodeling in patients with CRC and UC. A monoclonal antibody was raised against the C‐terminal end of col‐16 (PRO‐C16), and a competitive enzyme‐linked immunosorbent assay (ELISA) was developed and technically validated. Levels of PRO‐C16 were measured in serum from patients with CRC (before (n = 50) and 3 months after (n = 23) tumor resections), UC (n = 39) and healthy controls (n = 50). The PRO‐C16 ELISA was specific toward the C‐terminal of col‐16. PRO‐C16 was significantly elevated both in serum from patients with CRC (P = 0.0026) and UC (P < 0.0001) compared to controls. No difference was detected in levels of PRO‐C16 between patients with CRC at baseline and 3 months after tumor resections (P > 0.999). Levels of PRO‐C16 identified patients with a GI disorder with a positive predictive value of 0.9 and an odds ratio of 12 (95%CI = 4.5‐29.5, P < 0.0001). The newly developed assay detected significantly elevated levels of PRO‐C16 in serum from patients with GI disorders compared to controls suggesting its potential as a biomarker in this setting. Future studies are needed to validate these findings.

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ECM remodelling in IBD: innocent bystander or partner in crime? The emerging role of extracellular molecular events in sustaining intestinal inflammation

Cited by 108 publications

References 77 publications

Pathobiology of neutrophil–epithelial interactions

Pathobiology of neutrophil–epithelial interactions

Tumor Cell Invasion Can Be Blocked by Modulators of Collagen Fibril Alignment That Control Assembly of the Extracellular Matrix

Serum type XVI collagen is associated with colorectal cancer and ulcerative colitis indicating a pathological role in gastrointestinal disorders

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