A phenotype from tumor stroma based on the expression of metalloproteases and their inhibitors, associated with prognosis in breast cancer

Abstract

Keywords: Breast cancer, cancer-associated fibroblast, matrix-metalloproteases, mononuclear inflammatory cell, tumor stroma Abbreviations: bFGF, fibroblast growth factor; CAF, cancer-associated fibroblast; CI, confidence interval; ECM, extracellular matrix; EGF, epidermal growth factor; EMT, epithelial-mesenchymal transition; EGF, epidermal growth factor; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HGF, hepatocyte growth factor; IGFs, insulin growth factors; IGFBPs, IGF binding protein; IL, interleukin; MIC, mononuclear inflammatory cell; MMP, matrix metalloprotease; NFkB, nuclear factor kappa B; PgR, progesterone receptor, TA, tissue array; TGFß, transforming growth factor ß; TIMP, tissue inhibitors of metalloproteases.The objective of the present work was to evaluate the impact of the phenotype of both mononuclear inflammatory cells (MICs) and cancer-associated fibroblast (CAFs) in early breast cancer patients, specifically assessed as to their expression of MMP/TIMP relative to their position within the tumor (i.e., localization at the tumor center or invasive front) and the occurrence of distant metastases.. An immunohistochemical study was performed using tissue arrays and specific antibodies against matrix metalloproteinase (MMP)¡1, ¡2, ¡7, ¡9, ¡11, ¡13 and ¡14, tissue inhibitors of metalloproteinase (TIMP)¡1, ¡2 and ¡3, both at tumor center and at invasive front, in 107 patients with primary ductal invasive breast tumors. Data were analyzed by unsupervised hierarchical clustering analysis. Our results indicated that MMP-11 expression by MICs, and TIMP-2 expression by CAFs at either the tumor center or the invasive front, were the most potent independent prognostic factors for predicting the clinical outcome of patients. Using the unsupervised hierarchical clustering analysis, we found well-defined clusters of cases identifying subgroups of tumors showing a high molecular profile of MMPs/TIMPs expression by stromal cells (CAFs and MICs), both at the tumor center and at the invasive front, which were strongly associated with a higher prevalence of distant metastasis. In addition, we found combinations of these clusters defining subpopulations of breast carcinomas differing widely in their clinical outcome. The results presented here identify biologic markers useful to categorize patients into different subgroups based on their tumor stroma, which may contribute to improved understanding of the prognosis of breast cancer patients.

The critical role of EGF-β-catenin signaling in the epithelial-mesenchymal transition in human glioblastoma

“…Increasing reports indicate that a complex cross-talk exists between the β-catenin pathway and other signaling molecules, and EMT-corresponding effectors 22–24. In the present study, we identified the in vitro effect of β-catenin on different malignant phenotypes in U87 glioblastoma cells.…”

MMP1 and MMP11 expression in Peripheral Blood Mononuclear Cells upon their interaction with Breast Cancer Cells and Fibroblasts

“…In previous studies, we have proved that tumor-in ltrating immune cells expressing high levels of MMPs had higher rate of distant metastasis development compared with tumors with MMP's low expression pro le in immune cells (6)(7)(8)(9)(10)(11). In particular, the expression of MMP11 in tumor-in ltrating immune cells, was highly associated with both, distant metastasis development and high in ammatory pro le in breast cancer (10,(12)(13)(14).…”

Matrix-metalloproteinases as targets for controlled delivery in cancer: An analysis of upregulation and expression

“…MMP-9 is most abundantly found at the periphery in primary tumors, but within the tumor core in metastases[143,144]. The invasive front shows the highest expression of MMP-11[142,145]. The most prevalent tumor distribution of commonly studied active MMPs is illustratively represented in Figure 2, using data from the following studies [141–154].…”