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

Since proteolysis of the dermal collagenous matrix and basement membranes i s required for local invasive growth and early metastasis formation of cuta neous melanomas, we have analysed the activities/expression levels of certa in metalloproteinases in melanomas and cultured melanoma cells by in situ h ybridization and Northern analysis. In addition to collagenases-1 and -3 th at have been implicated in invasive growth behaviour of various malignant t umours, we analysed the levels of 72-kDa gelatinase and its activators MT1- MMP and TIMP-2 in cultured melanoma cells. The lesions examined included th ree 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 predominantl y expressed in the cancer cells of Clark grade ill and IV tumours. TIMP-1 a nd -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 w as associated with 72-kDa gelatinase positivity. All melanoma cell lines we re positive for MTI-MMP and TIMP-2 mRNAs. Our results suggest that overexpr ession of collagenases-1 and -3 and TIMPs -1 and -3 is induced during melan oma progression. Expression of TIMPs may reflect host response to tumour in vasion in an effort to control MMP activity and preserve extracellular matr ix integrity.