Extracellular matrix proteins as diagnostic markers of breast carcinoma

Abstract

Changes in amount and composition of extracellular matrix (ECM) are considered a hallmark of tumor development. We tested the hypothesis that abnormal production of ECM components leads to blood-released ECM molecules representing tumor circulating biomarkers. Candidate genes were selected through class comparison in two publicly available datasets and confirmed in paired normal and tumor associated fibroblasts from breast carcinoma (BC) specimens. Production and release of ECM molecules were evaluated in normal human dermal fibroblasts (NHDFs) treated with conditioned media from three BC cell lines. Plasma samples from healthy donors and from patients with malignant or benign breast disease were tested by ELISA for the presence of collagen 11a1 (COL11A1), collagen oligomeric matrix protein (COMP), and collagen 10a1 (COL10A1). Selected ECM molecules were investigated by IHC in malignant and benign specimens. In silico analysis of gene expression profiles identified 11 ECM genes significantly up-regulated in tumor versus normal tissue. Western blot analyses revealed increased levels of molecules encoded by three of these genes, COL11A1, COMP, and COL10A1, in cell lysates and supernatants of conditioned NHDFs. Class comparison and class prediction analyses of two independent series of human plasma samples identified the combination of COL11A1, COMP, and COL10A1 as potentially informative in discriminating BC patients from those with benign disease. The three molecules resulted expressed in the stroma of BC tissue samples. Our results indicate that circulating COL11A1, COMP, and COL10A1 may be useful in diagnostic assessment of suspicious breast nodules and ECM molecules could represent an avenue to biomarker identification.

Bioinformatics analysis of prognostic significance of COL10A1 in breast cancer

“…COL10A1 showed an important role in differentiating in situ from invasive breast cancer and characterizing DCIS with a high risk developing IDC [11,15,16]. Additionally, the concentration of COL10A1 in the plasma could be a potential biomarker to discriminate breast cancer patients from those with benign disease [9]. Of interest, increased expression of COL10A1 correlate with poor pathologic response in breast tumors [17].…”

“…COL10A1 expression is elevated in many solid tumor types, such as colon cancer, esophagus cancer, and breast cancer, and displays vital roles in many critical cellular processes such as cell proliferation, migration, invasion and tumor vasculature [6][7][8]. COL10A1 protein levels in plasma might be a potential diagnostic predictor for early breast cancer [9]. Although COL10A1 was reported to be highly expressed in tumors by high throughput sequencing, the specific role of COL10A1 in breast cancer was unknown [10][11][12].…”

Challenges and Opportunities in Clinical Applications of Blood-Based Proteomics in Cancer

“…For example, a set of 10 potential BCa serum biomarkers and cancer antigens (haptoglobin, osteopontin (OPN), CA15-3, CA125, carbohydrate antigen 19-9 (CA19-9), CEA, prolactin, α-fetoprotein (AFP), leptin, and migration inhibitory factor (MIF)) were developed for diagnosis and screening, but none of them are detected to have a high specificity, particularly in detecting early stage disease [ 176 , 177 ]. Other plasma candidate biomarkers available used for the screening and diagnosis of BCa include serpin peptidase inhibitor (SERPINB4), secreted-clusterin (CLU), serum amyloid (SAA), and heat shock proteins (HSPs) [ 128 , 129 , 178 , 179 ], but have yet to be validated in large studies for population application strategies. The majority of the markers reported by single breast cancer studies are based on a limited number of samples, hence the validation of biomarker candidates by the targeted profiling analysis of large cohorts of samples and populations is crucial for implementing those in clinical application.…”

Diagnostic role of circulating extracellular matrix-related proteins in non-small cell lung cancer

“…However, in the last few years, the concept that each tumor is a complex system composed by both, cancer cells and the surrounding stroma, represented by a variety of cell types such as fibroblasts, immune and endothelial has been well established [ 11 ]. This notion has important implications for biomarkers research as novel candidates with diagnostic or prognostic value can potentially be obtained by analyzing molecules produced by stromal cells during their interactions with cancer cells [ 12 , 13 ].…”