Comparative analysis and clinical value of the expression of metalloproteases and their inhibitors by intratumor stromal fibroblasts and those at the invasive front of breast carcinomas

Abstract

An immunohistochemical study was performed using tissue arrays and specific antibodies against MMPs -1, -2, -7, -9, -11, -13, -14, and TIMPs -1, -2 and -3. More than 5,000 determinations on cancer specimens from 124 patients with invasive breast cancer were performed at the center of the tumor and the invasive front. Immunostaining for MMPs/TIMPs by fibroblasts was evaluated. To identify specific groups of tumors with distinct expression profiles, the data obtained from both fibroblast populations were analyzed by unsupervised hierarchical cluster analysis. Intratumor stromal fibroblasts more frequently showed expression of MMP-2, -7, and -14, and TIMP-3, but less frequently of MMP-9 than fibroblasts at the invasive front. Multivariate analysis showed that a high profile of MMPs and TIMPs staining in both fibroblast populations was the most potent predictor factor of distant metastases, whereas a low staining profile in fibroblasts was associated with a low risk of metastases.

Prognostic Value of Matrix Metalloproteinase 9 Expression in Breast Cancer Patients: A Meta-analysis

“…The use of a same cohort of patients in more than one published articles is existent. Through a strict review, two studies (Casar et al, 2009;Cheng et al, 2004) were excluded because identical cohorts of patients were used in other selected studies. This avoided the same patients being included in the meta-analysis repeatedly and diminished the potential bias.…”

“…MMP-9 protein expression was measured in serum in five studies (Lepp et al, 2004;Lepp et al, 2005;Mattilaet al, 2005;Quaranta et al, 2007;Sung et al, 2012) and one study measured MMP-9 expression in plasma (Ranuncolo et al, 2003). Two studies were excluded because duplicate cohorts of patients were used in other selected studies (Cheng et al, 2004;Casar et al, 2009). MMP-9 mRNA expression was evaluated in another study (Sieuwerts et al, 2005).…”

Clinical Relevance of Matrix Metalloproteases and their Inhibitors in Breast Cancer

“…These associations are relevant because these highly expressed genes have been associated with several biological mechanisms related to tumor progression [151][152][153][154][155][156][157]. It is also relevant the novel finding of the association between the expression of MMP-11 or TIMP-2 by the MICs at the tumor center and a high CD68/(CD3+CD20) ratio (macrophages (CD68 [158], since both proteins are the two principal factors defining the prometastatic phenotype of MICs in our previous studies [34,132,134,144]. In addition, if there is a high CD68/(CD3+CD20) ratio at the invasive front, most of MICs with a positive MMP-11 or TIMP-2 phenotype at the tumor center are macrophages, suggesting all these findings that a high CD68/(CD3+CD20) ratio at the invasive front contributes to polarize macrophages to achieve a high metastatic phenotype at the tumor center.…”

“…Thus, whereas in fibroblasts at the tumor center the expression of MMP-9, 13 and TIMP-3 was associated with distant metastases, in the fibroblasts at the invasive front was the expression of MMP-14 and TIMP-1. However, patients with high MMP/TIMP patterns in the fibroblast population at the tumor center as well as at the invasive front had the highest probability of distant metastases, whereas patients with low MMP/TIMP patterns in both fibroblast populations had the lowest risk of distant metastases [144].…”

“…Intratumoral fibroblasts showed a positive expression of MMP-2, 7 and 14, and TIMP-3 more frequently than fibroblasts at the invasive front, which showed a more frequently expression of MMP-9 ( Figure 2). This varied expression pattern of MMPs and TIMPs may correspond to differences in cellular density, which is higher in the tumor center, and/or to biological mechanisms of interaction between tumor cells and the fibroblast population of those two different tumor areas [144]. Accordingly, it has been shown that cell-cell contact between cancer cells and fibroblasts enhanced the production and activation of MMPs by cancer cells, promoting pericellular proteolysis, angiogenesis and tumor cell invasion [145,146].…”