Fragments of Citrullinated and MMP-degraded Vimentin and MMP-degraded Type III Collagen Are Novel Serological Biomarkers to Differentiate Crohn’s Disease from Ulcerative Colitis

Mortensen, Joachim Høg; Godskesen, Line E.; Jensen, Michael D.; Haaften, Wouter T. van; Klinge, Lone; Olinga, Peter; Dijkstra, Gerard; Kjeldsen, Jens; Karsdal, Morten A.; Bay‐Jensen, Anne‐Christine; Krag, Aleksander

doi:10.1093/ecco-jcc/jjv123

Cited by 76 publications

(77 citation statements)

References 44 publications

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“…Similarly, degradation products of collagen and laminin also have been shown to have biologic functions that the intact molecules do not trigger [1]. While function of these ECM fragments have yet to be directly investigated in IBD, circulating levels of the neo-epitopes of collagen, laminin and vimentin were found to correlate with subtypes of IBD, and may be useful for discriminating ulcerative colitis from Crohn’s Disease [2, 8, 9]. …”

Section: Ecm Alterations In Ibdmentioning

confidence: 99%

“…Collagen degradation products produced by MMPs are released into the surrounding tissue, where these ECM fragments act as chemokines capable of enhancing neutrophil recruitment [25, 32]. MMP degradation products are also present in the serum of IBD patients at different levels in UC and CD, suggesting that ECM remodeling may be different in these disease states due to differences in leukocyte populations or MMP expression [8]. …”

Section: Submucosamentioning

confidence: 99%

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The extracellular matrix in IBD

Petrey

Motte²

2017

Current Opinion in Gastroenterology

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Purpose of review The extracellular matrix (ECM) is a frequently overlooked component of the pathogenesis of inflammatory bowel disease (IBD). However, the functional and clinically significant interactions between immune as well as non-immune cells with the ECM have important implications for disease pathogenesis. In this review, we discuss how the ECM participates in process associated with IBD that involves diverse cell types of the intestine. Recent findings Remodeling of the ECM is a consistent feature of IBD, and studies have implicated key ECM molecules in IBD pathogenesis. While the majority of prior studies have focused on ECM degradation by proteases, more recent studies have uncovered additional degrading enzymes, identified fragments of ECM components as potential biomarkers, and revealed that ECM synthesis is increased in IBD. These new studies support the notion that the ECM, rather than acting as a passive element, is an active participant in promoting inflammation. Summary New studies have offered exciting clues about the function of the ECM during IBD pathogenesis. The balance of ECM synthesis and turnover is altered in IBD, and the molecules involved exhibit discreet biological functions that regulate inflammation on the basis of specific cell type and matrix molecule.

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Section: Ecm Alterations In Ibdmentioning

confidence: 99%

Section: Submucosamentioning

confidence: 99%

The extracellular matrix in IBD

Petrey

Motte²

2017

Current Opinion in Gastroenterology

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“…Whether the elevated C3M levels are a result of specific ongoing inflammatory processes or altered cancer or stromal cell activities in the tumor remains to be established. However, C3M has been associated with inflammatory diseases of the gut (14), suggesting that C3M may reflect the extent of ongoing inflammation in the tumor tissue.…”

Section: Discussionmentioning

confidence: 99%

“…Levels of C3M and VICM have been revealed to be elevated in serum from patients with inflammatory bowel disease (14). Levels of C3M have also been revealed to be increased in serum from patients with pancreatic (15), breast and ovarian cancer (16), and levels of VICM have been revealed to be elevated in lung cancer (17).…”

Section: Unique Insight Into Microenvironmental Changes In Colorectalmentioning

confidence: 99%

Unique insight into microenvironmental changes in colorectal cancer: Ex vivo assessment of matrix metalloprotease-mediated molecular changes in human colorectal tumor tissue and corresponding non-neoplastic adjacent tissue

et al. 2017

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Abstract. Matrix metalloprotease (MMP)-mediated tissue remodeling is one of the malignant changes driving colorectal cancer. Measurement of altered MMP expression/activity is not sufficient to fully understand the effect of MMP-mediated tissue remodeling. Biomarkers are required that specifically reflect the dynamic processes of the MMP-mediated degradation of signature proteins from colorectal tissue. The aim of the present study was to profile and characterize the release of MMP-degraded type III collagen (C3M) and citrullinated and MMP-degraded vimentin (VICM) from tumor tissue and corresponding non-neoplastic adjacent tissue (NAT) in a human colorectal cancer ex vivo model. Colorectal tumor tissue and NAT biopsies from tissue removed during resection of colorectal cancer patients (n=13) were cut into pieces of 2 mm 2 and cultured for 24 h in growth medium. C3M and VICM were evaluated by ELISA. As part of the characterization, C3M was determined subsequent to the tumor tissue being cleaved with recombinant MMP-2/-9 and trypsin. C3M was generated by MMP-2/-9, but not by trypsin. In addition, the level of C3M was significantly elevated in the conditioned medium from tumor tissues (3.7 ng/ml) compared with that observed in the conditioned medium from the NATs (2.2 ng/ml) and in the growth medium alone (1.9 ng/ml). The level of VICM was significantly elevated in the tumor tissues (0.51 ng/ml) and NATs (0.52 ng/ml) compared with that in the growth medium alone (0.03 ng/ml). No differences were detected between the tumor tissues and NATs. No correlation was observed between biomarker levels from the tumor tissue and corresponding NAT, and the biomarker levels did not correlate with tumor stage. In conclusion, the present study provided support of the concept that C3M and VICM are applicable as tools to investigate dynamic tissue changes of colorectal tumor tissue and corresponding NAT. By the assessment of these specific MMP-mediated molecular changes, the present study provides novel and relevant insight into the dynamic changes of colorectal tumor tissue and corresponding NAT. IntroductionColorectal cancer is not only an accumulation of malignant cells but may be interpreted as an abnormal tissue composed of cancer cells and their stroma, the tumor microenvironment, which is composed of various cell types such as fibroblast, endothelial cells and different cells of the immune system (1). These cells are embedded in, or interact with, the extracellular matrix (ECM). The ECM contains proteins such as collagens, proteoglycans and glycoproteins, and forms a three-dimensional protein structure supporting the cells and tissue (2). In addition to the ECM, multiple proteins such as secreted intracellular proteins, various growth factors and different types of enzymes are also part of the tumor microenvironment (1-3).During cancer progression, the tumor microenvironment is heavily remodeled due to altered proteolytic activity (3). Matrix metalloproteases (MMPs) are the main proteases responsible for the degradation of ext...

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“…Also, some products of MMPs catalysis were considered as the potential biomarkers. Citrullinated and MMP-degraded vimentin (VICM) simultaneously and in combination with others markers revealed good potential to differentiate ulcerative colitis form noninflammatory bowel diseases [11]. …”

mentioning

confidence: 99%