Metalloelastase (MMP‐12) expression by tumour cells in squamous cell carcinoma of the vulva correlates with invasiveness, while that by macrophages predicts better outcome

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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‐β1 (TGF‐β1) and tumour necrosis factor‐α (TNF‐α) 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. Copyright © 2002 John Wiley & Sons, Ltd.
Funding Information
  • Helsinki University Central Hospital Research Foundation (EVO)
  • Turku University Central Hospital
  • Finnish Cultural Foundation
  • The Maud Kuistila Foundation
  • Academy of Finland
  • the Sigrid Jusélius Foundation
  • Finska Läkaresällskapet
  • Cancer Research Foundation of Finland