Comparative analysis of the expression patterns of metalloproteinases and their inhibitors in breast neoplasia, sporadic colorectal neoplasia, pulmonary carcinomas and malignant non-Hodgkin's lymphomas in humans

Abstract

Summary Matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases, TIMPs) play essential roles in the remodelling of the extracellular matrix (ECM). Results of in vivo and in vitro studies suggest that the balance between MMPs and TIMPs is altered in neoplasia, contributing to the invasive and metastatic properties of malignant tumours. In this study we have analysed the expression of five MMP genes and TIMP-1 and TIMP-2 in 37 benign and malignant lesions of human breast using Northern blot analysis. MMP-9 (92 kDa gelatinase) and MMP-l (stromelysin 3) were most consistently expressed by carcinomas. Based on detection of either MMP-9 or MMP-l mRNAs, we were able to distinguish between malignant and benign disease with a predictive accuracy of 90% with 94% sensitivity and 85% specificity. Subsequently, these results were compared with results for carcinomas of colon and lung and malignant nonHodgkin's lymphomas (NHL). Elevated MMP-9 and TIMP-1 expression was observed in all four systems. MMP-l characterised all carcinomas as well as carcinomas in situ but was not detectable in NHL. Our data therefore argue that there are remarkably similar patterns of specific functions involved in ECM remodelling that correlate with malignancy in different human tumours of different histogenesis. However, MMP-l expression is a characteristic of tumours of epithelial origin that is not found in lymphoid neoplasia. Thus it suggests that MMP-l may play a regulatory role in the invasion and metastasis of carcinomas.

Expression of tissue inhibitor of metalloproteinases TIMP-2 in human colorectal cancer - a predictor of tumour stage

“…The TIMP-2 positivity was most prominent in the tumour stroma, a finding also reported by others (Poulsom et al, 1992;Urbanski et al, 1993;Hoyhtya et al, 1994). Studies on the closely related TIMP-1 have shown similar distribution, predominantly to the ECM of colorectal tumours (Hewitt et al, 1991;Newell et al, 1994;Kossakowska et al, 1996), but we are not aware of any studies exploring the relation between TIMP-1 expression and tumour staging and survival in colorectal cancer.…”

“…Only a limited number of studies have reported on TIMP-1 and/or TIMP-2 and/or MMP-2, and/or MMP-9 in colorectal cancer (Nakajima et al, 1990;Poulsom et al, 1992;Pyke et al, 1993;Emmert-Buck et al, 1994;Hoyhtya et al, 1994;Kossakowska et al, 1996;Nielsen et al, 1996;Swallow et al, 1996) and the possible correlation with tumour stage (van der Stappen et al, 1990;Levy et al, 1991;Urbanski et al, 1993;Newell et al, 1994;Liabakk et al, 1996) and survival (Liabakk et al, 1996). 805 The aim of the present study was to search for differences in the expressions of the type IV collagenases MMP-2 and MMP-9 and the inhibitor TIMP-2 in various Dukes' stages and their possible prognostic impact, thus possibly enabling improved selection of patients for additional therapy and surveillance.…”

Comprehensive profiling and localisation of the matrix metalloproteinases in urothelial carcinoma

“…We found TIMP-1, TIMP-2 and TIMP-3 to be highly expressed both in normal tissue and in tumour tissue, with increased expression in high-grade tumours. Similar patterns have been reported in bladder, colorectal, breast and lung cancer (Grignon et al, 1996;Kossakowska et al, 1996). Several reports have postulated the MMP/TIMP ratio as significant in predicting either tumour recurrence or progression in bladder cancer, concentrating on MMPs 1, 2 and 9 and TIMPs 1 and 2 (Gohji et al, 1996;Durkan et al, 2003).…”

Integrin αvβ6-associated ERK2 mediates MMP-9 secretion in colon cancer cells

“…Matrix degradation by MMPs is crucial for growth, invasion, metastasis and angiogenesis of tumours and increased tissue expression of MMP-9 has been observed in the progression from benign to malignant colonic epithelium (Kossakowska et al, 1996). Maximal expression of MMPs has also been noted at the invading margin of tumour cell islands as in colon cancer (Hewitt et al, 1991) and plasma MMP levels are significantly elevated in patients with this disease (Zucker et al, 1995).…”