A novel marker for assessment of liver matrix remodeling: An enzyme-linked immunosorbent assay (ELISA) detecting a MMP generated type I collagen neo-epitope (C1M)

Abstract

A competitive enzyme-linked immunosorbent assay (ELISA) for detection of a type I collagen fragment generated by matrix metalloproteinases (MMP) -2, -9 and -13, was developed (CO1-764 or C1M). The biomarker was evaluated in two preclinical rat models of liver fibrosis: bile duct ligation (BDL) and carbon tetra chloride (CCL4)-treated rats. The assay was further evaluated in a clinical study of prostate-, lung- and breast-cancer patients stratified according to skeletal metastases. A technically robust ELISA assay specific for a MMP-2, -9 and -13 neo-epitope was produced and seen to be statistically elevated in BDL rats compared to baseline levels as well as significantly elevated in CCL4 rats stratified according to the amount of total collagen in the livers. CO1-764 levels also correlated significantly with total liver collagen and type I collagen mRNA expression in the livers. Finally, the CO1-764 marker was not correlated with skeletal involvement or number of bone metastases. This ELISA has the potential to assess the degree of liver fibrosis in a non-invasive manner.

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

“…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.…”

“…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.…”

Remodeling of the Tumor Microenvironment Predicts Increased Risk of Cancer in Postmenopausal Women: The Prospective Epidemiologic Risk Factor (PERF I) Study

“…It is possible that the high levels of C1M, C4M, and VICM in the blood are results of a systemic effect where subjects with a general increased remodeling of the ECM and IF have a higher likelihood of developing cancer. Furthermore, all markers have been found elevated in a number of diseases characterized by ECM remodeling and tissue inflammation and are, therefore, not specific to cancer (7)(8)(9)(36)(37)(38)(39). Finally, it needs to be elucidated if the results of this study can be applied to populations of other ages and ethnic backgrounds and if the biomarkers are more useful for certain types of solid cancer.…”

“…C1M reflects interstitial matrix remodeling and measures a type I collagen degradation fragment generated by cleavage with MMP-2, -9, and -13 (8). Type I collagen is one of the most abundant interstitial ECM proteins.…”

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

“…195 Neoepitopes of these proteins may serve as valuable markers of liver ECMR. Promising candidates have been reported, including those derived from type IV collagen, 196,197 type I collagen, 198 type V collagen, 199 and type VI collagen. 200 Systemic approaches, such as global profiling of serum glycoproteins, have also been utilized, 201 and this technique is now being validated in rodent models (e.g., Fang et al, 202 Blomme et al,…”