Human desmoid fibroblasts: matrix metalloproteinases, their inhibitors and modulation by Toremifene

Background: Desmoid tumours, which are frequently observed in Gardner's syndrome, are rare, slow-growing, histologically benign tumours caused by autosomal dominant gene mutation. They are , non metastasising neoplasm characterised by an elevated deposition of organic macromolecules in the extracellular matrix (ECM). The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of ECM macromolecules. The MMPs and their natural inhibitors (TIMPs) have been implicated in tumour growth, invasion and metastasis. In this study we provide evidence that the in vitro cultured cell line from desmoid tumour accumulates more collagen fibres in the ECM than healthy fibroblasts. Methods: We investigated collagen accumulation by 3H-thymidine incorporation, MMP expression by substrate gel zymography and TIMP expression by Western blot analysis. Results: Desmoid fibroblasts showed a reduction in MMP activity and an increase of type I and III collagen and TIMPs compared to normal fibroblasts. Conclusion: The present study investigates the rule of MMPs and TIMPs in the desmoid tumour and describes, for the first time, the effects of toremifene on MMPs and TIMPs The increase in collagen in desmoid fibroblasts was due to inhibited collagen degradation (reduction of MMP activity) rather than to increased collagen synthesis. Adding toremifene, an anti-estrogen triphenylethylene derivate, to desmoid fibroblasts reduced collagen accumulation by decreasing mRNA expression and increasing collagen degradation. The results provided evidence that toremifene reduced ECM accumulation by decreasing collagen synthesis and increasing collagen degradation.