Overexpression of matrix metalloproteinases and their inhibitors in mononuclear inflammatory cells in breast cancer correlates with metastasis-relapse

Abstract

An immunohistochemical study was performed using tissue microarrays and specific antibodies against matrix metalloproteinase (MMP)-1, -2, -7, -9, -11, -13 and -14, tissular inhibitors of metalloproteinase (TIMP)-1, -2 and -3. More than 2600 determinations on cancer specimens from 131 patients with primary ductal invasive tumours of the breast were performed. To identify specific groups of tumours with distinct expression profiles the data were analysed by unsupervised hierarchical cluster analysis by each cellular type. We did not find well-defined cluster of cases for tumour cells or fibroblastic cells. However, for mononuclear inflammatory cells the dendogram shows a first-order division of the tumours into two distinct MMP/TIMP molecular profiles, designated group 1 (n ¼ 89) and group 2 (n ¼ 42). Matrix metalloproteinase-7, -9, -11, -13 and -14, and TIMP-1 and -2, were identified as showing significant high expression in group 2 compared with group 1. Multivariate analysis demonstrated that clustering for mononuclear inflammatory cells was the most potent independent factor associated with distant relapse-free survival (group 2: 5.6 (3.5 -9.6), Po0.001). We identify a phenotype of mononuclear inflammatory cells infiltrating tumours, which is associated with the development of distant metastasis. Therefore, this finding suggests that these host inflammatory cells could be a possible target for inhibition of metastasis.

172: Serum endostatin levels are elevated in colorectal cancer and correlate with invasion and systemic inflammatory markers

“…Endostatin can be cleaved from collagen XVIII by several proteinases, such as MMPs-3, -7, -9, -13, -14 and -20, elastase and cathepsin L (Seppinen and Pihlajaniemi, 2011). Both tumour cells and tumour-associated local inflammatory cells are able to produce several of these enzymes (Nielsen et al, 1996;Brabletz et al, 1999;Heljasvaara et al, 2005;González et al, 2007). In accordance with an earlier report (Li et al, 2012), we found a significant correlation between high serum endostatin concentration and poor tumour differentiation.…”

Clinical Relevance of Matrix Metalloproteases and their Inhibitors in Breast Cancer

“…Thereby, multivariate analysis indicates that to belong to this cluster group is the most significant and independent prognostic factor to predict distant metastasis development in patients with IDC [132]. In addition, these two differential MICs phenotypes with distinct prognosis were also found in breast carcinomas with luminal A or in basal-like phenotype [133], which suggests the importance of the expression of MMPs/TIMPs by the stromal cells as prognostic factors independently of the signature of cancer cells.…”

“…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.…”

“…Also, we demonstrated that MMP-11 was the most frequently expressed protein in these prometastatic-related MICs (85.7% vs. 4.6% in the low MMPs/TIMPs profile group), and therefore its expression was considered as a useful biological marker in these MICs population [132]. Previously, high levels of MMP-11 had been associated with tumor progression and poor prognosis [71].…”

“…It is interesting to describe some biological characteristics of the MMPs expressed by this prometastatic-related MICs, specifically MMP-7, 9, 11, 13 and 14, and TIMP-1 and 2 [132]. MMP-7 (matrilysin 1) is a stromelysin which degrades type IV collagen, fibronectin and laminin, that is aberrantly expressed in human breast tumors, and whose elimination is associated with lower invasiveness and reduced tumor growth [135].…”