title: Metalloelastase (MMP-12) expression by tumour cells in squamous cell carcinoma of the vulva correlates with invasiveness, while that by macrophages predicts better outcome.
abstract: Human metalloelastase (MMP-12) has been implicated in elastin degradation and macrophage migration in many pathological conditions. It also generates angiostatin, thus having a potential to prevent tumour angiogenesis. It has previously been shown that transformed epithelial cells express MMP-12 in skin cancer. The aim of this study was further to elucidate the role of metalloelastase in squamous cell cancer (SCC) progression. By in situ hybridization, expression of MMP-12 mRNA was detected in 28/33 vulvar SCC samples in CD-68-positive macrophages, while 10 samples had positive cancer cells. By immunohistochemistry, MMP-12 protein was seen in the same area as the mRNA. MMP-12 mRNA expression in tumour cells correlated with more aggressive histology (p = 0.0099). In contrast, macrophage-derived MMP-12 mRNA was more abundant in well-differentiated grade I than grade III tumours (p = 0.01). However, the level of MMP-12 mRNA, regardless of its origin, did not correlate with metastasis or patient survival. No significant correlation was found between macrophage-derived MMP-12 mRNA and a low amount of blood vessels, as quantitated after von Willebrand staining. In agreement with vulvar SCCs in vivo, MMP-12 was expressed in cultured SCC cells by northern and western blot analysis. In HaCaTs and epithelial MCF-10f cells, MMP-12 mRNA was induced by transforming growth factor-beta1 (TGF-beta1) and tumour necrosis factor-alpha (TNF-alpha) as measured by quantitative RT-PCR (TaqMan). Two MMPs capable of generating angiostatin in vivo, matrilysin (MMP-7) and gelatinase B (MMP-9), were also examined in these tumours. MMP-7 mRNA was mainly expressed by epithelial tumour cells, particularly in less differentiated tumours. MMP-9 was usually expressed by neutrophils and macrophages; epithelial protein was predominantly found in grade II/III tumours. These results suggest a dual role for MMP-12 in tumour progression.
authors.affiliation: Department of Dermatology, Helsinki University Central Hospital and Biomedicum Helsinki, University of Helsinki, Meilahdentie 2, 00250 Helsinki, Finland.
authors.forename: Erja
authors.initials: E
authors.lastname: Kerkelä
authors.forename: Risto
authors.initials: R
authors.lastname: Ala-aho
authors.forename: Pekka
authors.initials: P
authors.lastname: Klemi
authors.forename: Seija
authors.initials: S
authors.lastname: Grénman
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kähäri
authors.forename: Ulpu
authors.initials: U
authors.lastname: Saarialho-Kere
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D017403:In Situ Hybridization; D008264:Macrophages / Q000201:enzymology*; D053508:Matrix Metalloproteinase 12; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000201:enzymology; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D014846:Vulvar Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D008666:Metalloendopeptidases; D020783:Matrix Metalloproteinase 7; D020780:Matrix Metalloproteinase 9; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12