title: Progression of mycosis fungoides is associated with changes in angiogenesis and expression of the matrix metalloproteinases 2 and 9.
abstract: Changes in angiogenesis and expression of extracellular matrix-degrading enzymes have been substantiated during progression of solid tumours, whereas information on haematological tumours remains circumstantial. In this study, 57 biopsies of mycosis fungoides (MF), a haematological tumour of T-cell lineage, were investigated immunohistochemically for the extent of angiogenesis, and by in situ hybridisation for the expression 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 extent of angiogenesis, as microvessel area, of MF lesions as a whole was significantly higher than that of normal uninjured skin, used as a control. When the stages of MF progression were compared, the values of MF patch stage overlapped that of control skin, while values were significantly higher in the plaque stage and even higher in the nodular stage. In these stages, microvessels were widely scattered in the tumour tissue, in close association with tumour cells, and they frequently displayed arborisation and microaneurysmatic dilation. In contrast, in the patch stage microvessels were irregularly distributed around the tumour aggregates, and arborisation or dilated structures were only rarely seen. The expression of MMP-2 and MMP-9 mRNAs underwent significant upregulation in relation to advancing stage. Indeed, the upstaging was significantly associated with higher proportions of lesions positive for each mRNA or for both, and with lesions with the greatest intensity of expression for each mRNA. Besides tumour cells, the MMP-2 mRNA 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 found to be present in a subset of tissue macrophages which were more frequently located in close vicinity to the tumour nodules. In contrast, in control skin, a weak positivity for the MMP-2 mRNA in very few microvascular endothelial cells and no signal for the MMP-9 mRNA were observed. These in situ data suggest that angiogenesis and degradation of the extracellular matrix occur simultaneously during MF progression. They imply that interaction between tumour cells and their microvasculature are all the more likely to occur during progression, occasionally with the contribution of tumour-associated stromal cells.
authors.affiliation: Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Vacca
authors.forename: S
authors.initials: S
authors.lastname: Moretti
authors.forename: D
authors.initials: D
authors.lastname: Ribatti
authors.forename: A
authors.initials: A
authors.lastname: Pellegrino
authors.forename: N
authors.initials: N
authors.lastname: Pimpinelli
authors.forename: B
authors.initials: B
authors.lastname: Bianchi
authors.forename: E
authors.initials: E
authors.lastname: Bonifazi
authors.forename: R
authors.initials: R
authors.lastname: Ria
authors.forename: G
authors.initials: G
authors.lastname: Serio
authors.forename: F
authors.initials: F
authors.lastname: Dammacco
mesh_terms: D000368:Aged; D017364:Collagenases / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009182:Mycosis Fungoides / Q000201:enzymology / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D012878:Skin Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000473:pathology*; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9