Expression of collagenases-1 and -3 and their inhibitors TIMP-1 and -3 correlates with the level of invasion in malignant melanomas

Abstract

Summary Since proteolysis of the dermal collagenous matrix and basement membranes is required for local invasive growth and early metastasis formation of cutaneous melanomas, we have analysed the activities/expression levels of certain metalloproteinases in melanomas and cultured melanoma cells by in situ hybridization and Northern analysis. In addition to collagenases-1 and -3 that have been implicated in invasive growth behaviour of various malignant tumours, we analysed the levels of 72-kDa gelatinase and its activators MT1-MMP and TIMP-2 in cultured melanoma cells. The lesions examined included three cases of lentigo maligna and 28 cases of Clark grade I-V melanomas. The premalignant as well as the grade I tumours were consistently negative for collagenase-1 and -3 and TIMP-1 and -3. The collagenases were predominantly expressed in the cancer cells of Clark grade III and IV tumours. TIMP-1 and -3 were abundantly expressed in the cancer and/or stromal cells of grade III and IV melanomas, while TIMP-2 protein was detected also in melanomas representing lower invasive potential. Northern analysis of seven melanoma cell lines showed that the expression of collagenase-1 and TIMPs-1 and -3 was associated with 72-kDa gelatinase positivity. All melanoma cell lines were positive for MTI-MMP and TIMP-2 mRNAs. Our results suggest that overexpression of collagenases-1 and -3 and TIMPs -1 and -3 is induced during melanoma progression. Expression of TIMPs may reflect host response to tumour invasion in an effort to control MMP activity and preserve extracellular matrix integrity. Keywords: MMP; cell invasion; angiogenesis; gelatinase 733British Journal of Cancer (1999) 80(5/6), 733-743 © 1999 Cancer Research Campaign Article no. bjoc.1998 Received 10 September 1998 Revised 3 December 1998 Accepted 3 December 1998Correspondence to: UK Saarialho-Kere type I, II and III collagens. Furthermore, MMP-13 is gelatinolytic and type IV collagenolytic (Knäuper et al, 1996, and MMP-1 has also some activity against full-length type IV collagen (Collier et al, 1988). Our objective was to determine the expression patterns and cellular localization of these MMPs during melanocytic tumour progression. Furthermore, as imbalance between TIMPs and MMPs is an important factor in tumour invasion, the expression levels of collagenase inhibitors TIMP-1 and -3 were also examined. Our results suggest that the induction of MMPs-1 and -13 and their tissue inhibitors is a late event in melanocytic tumour progression, and that these enzymes are involved in the regulation of melanoma invasion. MATERIALS AND METHODS Tissue specimensFormalin-fixed, paraffin-embedded specimens were obtained from the Department of Dermatopathology, Helsinki University Central Hospital, Helsinki, Finland. Invasion levels of the melanomas were determined by Clark's classification: level I with confinement of the malignant melanoma cells to the epidermis and its appendages; level II with extension to the papillary dermis so that only a few melanoma cells extended to the int...

Loss of dipeptidyl peptidase IV immunostaining discriminates malignant melanomas from deep penetrating nevi

“…24 Next to cellular proliferation, remodeling of the tumor-surrounding stroma by matrix metalloproteinases is considered as a most essential step for tumor progression. 25 In accordance with previous Dipeptidyl peptidase IV in deep penetrating nevi A Roesch et al studies on MMP expression in melanomas, 16,17,26 MMP-1, MMP-2, integrin b3 and MT1-MMP were specifically overexpressed at the dermo-invasive front of nodular malignant melanomas also in this series. But, a more important result of this study is that most of these 'major suspects' considered as integral parts of melanoma progression leading to metastatic disease were not much different in deep penetrating nevi.…”

“…In case of MMP-1, this upregulation in deep penetrating nevi even reached statistical significance. This is surprising since, the induction of MMP-1 has been suggested to be a pivotal late event in the progression of advanced melanomas not compatible with any benign condition 16,26,31 and even dysplastic nevi as well as early melanomas usually lack a significant MMP-1 and MMP-2 expression. 17,32,33 We conclude that among the 'major suspects' reflecting melanocytic tumor progress, DPPIV bears the highest potential to be further exploited as a marker in doubtful cases.…”

Activation of Smad signaling enhances collagenase-3 (MMP-13) expression and invasion of head and neck squamous carcinoma cells

“…However, the wide substrate specifity of MMP-13 suggests that it is also a powerful invasion tool for cancer cells. MMP-13 is one of the few MMPs primarily expressed by tumor cells in malignant tumors, such as breast carcinomas (Freije et al, 1994), squamous cell carcinomas (SCCs) of the head and neck (Airola et al, 1997;Johansson et al, 1997a), SCCs of the vulva (Johansson et al, 1999), and primary and metastatic melanomas (Airola et al, 1999;Nikkola et al, 2001). In SCCs of the head and neck and vulva, MMP-13 is expressed primarily by cancer cells at the invading edge of the tumor and the expression correlates with poor prognosis (Johansson et al, 1997a(Johansson et al, , 1999Cazorla et al, 1998).…”

Enhanced metastatic dissemination to multiple organs by melanoma and lymphoma cells in timp-3−/− mice

“…Clinical studies report silencing of TIMP-3 in a number of human cancers, and its reduction in stroma surrounding invasive colorectal cancers (Powe et al, 1997). On the other hand, TIMP-3 is highly expressed in invasive esophageal adenocarcinoma and melanoma (Airola et al, 1999;Salmela et al, 2003). Genetic manipulation of TIMP-3 expression significantly affects the primary tumor at the levels of tumor invasion, angiogenesis and growth.…”