A novel assay for extracellular matrix remodeling associated with liver fibrosis: An enzyme-linked immunosorbent assay (ELISA) for a MMP-9 proteolytically revealed neo-epitope of type III collagen

Barascuk, Natasha; Veidal, Sanne Skovgård; Larsen, Lise; Larsen, Dorthe Vang; Larsen, Martin R.; Wang, J; Zheng, Qiuju; Xing, Rui; Cao, Yongsheng; Rasmussen, Lars Melholt; Karsdal, Morten A.

doi:10.1016/j.clinbiochem.2010.03.012

Cited by 196 publications

(171 citation statements)

References 27 publications

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“…These findings are in accordance with previous reports which found elevated levels of type IV collagen in serum from breast and ovarian cancer patients [14,15] and elevated levels of collagen type I and III in the tissue of breast and ovarian cancer patients [7,16]. Furthermore, the desmoplatic reaction in cancer share many similarities with general fibrosis where the fragments of collagen type I [10], type III [11], and type IV [13] also have been found elevated in serum and linked to ECM remodeling.…”

Section: Discussionsupporting

confidence: 92%

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Collagen degradation products measured in serum can separate ovarian and breast cancer patients from healthy controls: A preliminary study

Bager

Willumsen

Leeming

et al. 2015

CBM

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Abstract. BACKGROUND: During cancer the otherwise tightly controlled homeostasis of the extracellular matrix (ECM) is disturbed. The protein composition changes, the ECM stiffens and increased levels of proteases are secreted. The combination of these processes result in release of specific protein fragments (e.g. collagens) to the circulation, which when measured may reflect disease pathogenesis. OBJECTIVE: To investigate if biomarkers of protease-degraded collagen could differentiate ovarian and breast cancer patients from healthy controls when measured in serum. METHODS: The levels of markers reflecting MMP-degradation of type I (C1M), type III (C3M) and type IV (C4M, C4M12) collagen were assessed in serum from ovarian cancer patients (n = 10), breast cancer patients (n = 14) and healthy controls (n = 49) using validated ELISAs. The markers were compared using one way ANOVA and AUC was calculated. RESULTS: All markers were significantly elevated in serum from ovarian cancer patients (p < 0.0001) and breast cancer patients (p < 0.04-0.0001) compared to healthy controls. Furthermore, diagnostically the markers were able to differentiate ovarian (AUROC 90%-93%) and breast cancer patients (AUROC 76%-93%) from healthy controls, with C1M being the strongest differentiator of disease vs. controls. CONCLUSION: Four serum biomarkers reflecting altered MMP-mediated collagen turnover were able to differentiate ovarian and breast cancer patients from healthy controls.Keywords: Cancer, extracellular matrix, collagen, biomarkers, breast cancer, ovarian cancer, matrix metalloproteinase, degradation, remodeling, tumor microenvironment BackgroundWomen's health is significantly influenced by the occurrence of cancers, such as breast and ovarian can- cers. Breast cancer is the leading cause of cancer death among women in the US and EU [1,2], and ovarian cancer, although less frequent, is often discovered in the late clinical stages where the cancer has already spread and no curative interventions are possible [3]. Taken together, the medical needs for breast and ovarian cancer are early diagnosis, prognosis and prediction of a therapeutic response. One of the best ways to achieve this is to use serum biomarkers [4].

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Section: Discussionsupporting

confidence: 92%

“…Using well-characterized and validated competitive ELISAs, levels of MMP 2, 9 and 13-degraded collagen type I (C1M) [10], MMP-9 degraded collagen type III (C3M) [11], and MMP-9 and 12 degraded collagen type IV (C4M, C4M12) [12,13] were assessed in the serum samples.…”

Section: Elisa Measurements and Proceduresmentioning

confidence: 99%

Collagen degradation products measured in serum can separate ovarian and breast cancer patients from healthy controls: A preliminary study

Bager

Willumsen

Leeming

et al. 2015

CBM

Self Cite

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“…Fibrosis is also a dynamic condition with accelerated ECM turnover in which both tissue formation and tissue degradation are highly upregulated (15,16,297,350), resulting in pathological collagen deposition and altered MMP expression profiles (353). Moreover, modifications to amino acids or proteolytic cleavage at specific locations by specific PTMs result in both immunologically and functionally different proteins (161).…”

Section: Fibrosis and The Ecmmentioning

confidence: 99%

Novel insights into the function and dynamics of extracellular matrix in liver fibrosis

Karsdal

Manon‐Jensen

Genovese

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

207

168

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Emerging evidence suggests that altered components and posttranslational modifications of proteins in the extracellular matrix (ECM) may both initiate and drive disease progression. The ECM is a complex grid consisting of multiple proteins, most of which play a vital role in containing the essential information needed for maintenance of a sophisticated structure anchoring the cells and sustaining normal function of tissues. Therefore, the matrix itself may be considered as a paracrine/endocrine entity, with more complex functions than previously appreciated. The aims of this review are to 1) explore key structural and functional components of the ECM as exemplified by monogenetic disorders leading to severe pathologies, 2) discuss selected pathological posttranslational modifications of ECM proteins resulting in altered functional (signaling) properties from the original structural proteins, and 3) discuss how these findings support the novel concept that an increasing number of components of the ECM harbor signaling functions that can modulate fibrotic liver disease. The ECM entails functions in addition to anchoring cells and modulating their migratory behavior. Key ECM components and their posttranslational modifications often harbor multiple domains with different signaling potential, in particular when modified during inflammation or wound healing. This signaling by the ECM should be considered a paracrine/endocrine function, as it affects cell phenotype, function, fate, and finally tissue homeostasis. These properties should be exploited to establish novel biochemical markers and antifibrotic treatment strategies for liver fibrosis as well as other fibrotic diseases.collagen; cytokine; extracellular fibrogenesis; integrin; laminin; matrix metalloproteinase; posttranslational modification; proteoglycan; endocrine 45% OF ALL DEATHS IN THE DEVELOPED WORLD are associated with chronic fibroproliferative diseases (256, 378). Thus there is an increasing need to address fibroproliferative diseases because of their strong impact on the quality of life and health costs consequent to pain and organ failure, with an increased need for organ transplants despite dwindling availability, often followed by death. Moreover, their severity and perceived irreversibility in view of a current paucity of treatment options, coupled with a high prevalence in most and an orphan status in some fibrotic diseases, have just begun to attract biotechnology and big pharmaceutical companies to the field.The common denominator of fibroproliferative diseases is a dysregulated tissue remodeling leading to the excessive and abnormal accumulation of extracellular matrix (ECM) components, thereby generating an ECM with different structural and signaling properties in the affected tissues (285, 287, 289, 378 -380). Fibrosis can affect almost any organ or tissue and is therefore associated with a wide variety of diseases and injuries (287). Figure 1 illustrates the major fibroproliferative diseases with a significant impact on human health (20, ...

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“…57 Type III collagen has been mostly assiociated with various fibrotic diseases. [58][59][60][61] Type IV collagen is the main component of the BM, a specialized type of ECM that separates the epithelium from the stroma in all tissues in the body. It consists of three domains: N-terminal 7S domain, a central triple helix, and a large C-terminal NC1 globular domain.…”

Section: Ecm Proteinsmentioning

confidence: 99%

Extracellular Matrix Remodeling: The Common Denominator in Connective Tissue DiseasesPossibilities for Evaluation and Current Understanding of the Matrix as More Than a Passive Architecture, but a Key Player in Tissue Failure

Karsdal

Nielsen²,

Sand³

et al. 2013

ASSAY and Drug Development Technologies

232

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A novel assay for extracellular matrix remodeling associated with liver fibrosis: An enzyme-linked immunosorbent assay (ELISA) for a MMP-9 proteolytically revealed neo-epitope of type III collagen

Cited by 196 publications

References 27 publications

Collagen degradation products measured in serum can separate ovarian and breast cancer patients from healthy controls: A preliminary study

Collagen degradation products measured in serum can separate ovarian and breast cancer patients from healthy controls: A preliminary study

Novel insights into the function and dynamics of extracellular matrix in liver fibrosis

Extracellular Matrix Remodeling: The Common Denominator in Connective Tissue DiseasesPossibilities for Evaluation and Current Understanding of the Matrix as More Than a Passive Architecture, but a Key Player in Tissue Failure

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