Regular Article

British Journal of Cancer (2000) 83, 1387–1393. doi:10.1054/bjoc.2000.1454 www.bjcancer.com
Published online 24 October 2000

Membrane-type 1 matrix metalloproteinase-mediated progelatinase A activation in non-tumorigenic and tumorigenic human keratinocytes

P Baumann1, P Zigrino1, C Mauch1, D Breitkreutz2 and R Nischt1

  1. 1Department of Dermatology, University of Cologne, Köln, 50924, Germany
  2. 2Division of Carcinogenesis and Differentiation, German Cancer Research Center, Heidelberg, 69120, Germany

Received 11 May 2000; Revised 12 July 2000; Accepted 18 July 2000.

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Abstract

Elevated expression of type IV collagenases (MMP-2 and MMP-9) has been strongly correlated with tumour progression and metastasis in various tumours. Here, we analysed expression and activation of these MMPs in non-tumourigenic HaCaT cells and the malignant HaCaT variant II-4rt. In monolayer cultures, both cell types secreted latent MMP-2 (proMMP-2) in comparable amounts, while MMP-9 production was clearly higher in II-4rtcells. Upon contact with fibrillar collagen type I the malignant II-4rtcells, but not the HaCaT cells, gained the capability to activate proMMP-2. This process is shown to be membrane-associated and mediated by MT1-MMP. Surprisingly, all membrane preparations from either HaCaT cells or II-4rtcells grown as monolayers, as well as within collagen gels, contained considerable amounts of active MT1-MMP. However, within collagen gels HaCaT cells showed significantly higher TIMP-2 levels compared to II-4rtcells. This indicates that TIMP-2 might play a central role for MT1-MMP-mediated gelatinolytic activity. Indeed, collagen type I-induced MT1-MMP-mediated proMMP-2 activation by II-4rtmembranes could be completely abolished by an excess of TIMP-2. In conclusion, our data suggest that MT1-MMP-mediated proMMP-2 activation might be associated with malignant progression of epidermal tumour cells. © 2000 Cancer Research Campaign

Keywords:

type IV collagenases, activation, keratinocytes, HaCaT-ras, cell–matrix interactions

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