PROGRESSION OF MYCOSIS-FUNGOIDES IS ASSOCIATED WITH CHANGES IN ANGIOGENESIS AND EXPRESSION OF THE MATRIX-METALLOPROTEINASE-2 AND MATRIX-METALLOPROTEINASE-9

Changes in angiogenesis and expression of extracellular matrix-degradi ng enzymes have been substantiated during progression of solid tumours , whereas information on haematological tumours remains circumstantial . In this study, 57 biopsies of mycosis fungoides (IMF), a haematologi cal tumour of T-cell lineage, were investigated immunohistochemically for the extent of angiogenesis, and by in situ hybridisation for the e xpression of matrix metalloproteinases 2 (MMP-2, collagenase A) and 9 (MMP-9, collagenase B). The biopsies we grouped according to the stage of progression: patch --> plaque --> nodular (most advanced). The ext ent of angiogenesis, as microvessel area, of IMF lesions as a whole wa s significantly higher than that of normal uninjured skin, used as a c ontrol. When the stages of MF progression were compared, the values of IMF patch stage overlapped that of control skin, while values were si gnificantly higher in the plaque stage and even higher in the nodular stage. In these stages, microvessels were widely scattered in the tumo ur tissue, in close association with tumour cells, and they frequently displayed arborisation and microaneurysmatic dilation. In contrast, i n the patch stage microvessels were irregularly distributed around the tumour aggregates, and arborisation or dilated structures were only r arely seen. The expression of MMP-2 and MMP-9 mRNAs underwent signific ant upregulation in relation to advancing stage. Indeed, the upstaging was significantly associated with higher proportions of lesions posit ive for each mRNA or for both, and with lesions with the greatest inte nsity of expression for each mRNA. Besides tumour cells, the MMP-2 mRN A was expressed by microvascular endothelial cells of intratumour and peri-tumour vessels, and by fibroblasts which were especially abundant in the stroma adjacent to the tumour nodules. The MMP-9 mRNA was foun d to be present in a subset of tissue macrophages which were more freq uently located in close vicinity to the tumour nodules. In contrast, i n control skin, a weak positivity for the MMP-2 mRNA in very few micro vascular endothelial cells and no signal for the MMP-9 mRNA were obser ved. These in situ data suggest that angiogenesis and degradation of t he extracellular matrix occur simultaneously during IMF progression. T hey imply that interaction between tumour cells and their microvascula ture are all the more likely to occur during progression, occasionally with the contribution of tumour-associated stromal cells. (C) 1997 El sevier Science Ltd.