Expression of matrix metalloproteinase (MMP)-7 and MMP-13 and loss of MMP-19 and p16 are associated with malignant progression in chronic wounds.
BACKGROUND
The risk of squamous cell carcinoma (SCC) is significantly increased in chronic leg ulcers. Very little is known about the molecular pathogenesis of these tumours, which are often undiagnosed for a long time. As matrix metalloproteinases (MMPs) are implicated at all stages of tumorigenesis, we investigated whether the pattern of epithelial MMP expression can predict development of SCC from pseudoepitheliomatous hyperplasia of chronic wounds.


METHODS
Samples from nine patients with SCCs that had arisen in chronic wounds and 31 with venous leg ulcers were studied using immunohistochemistry for MMP-7, MMP-8, MMP-9, MMP-13, MMP-19 and the tumour suppressor p16. In situ hybridization was performed for MMP-1, MMP-3, MMP-7, MMP-12 and MMP-13.


RESULTS
MMP-7 was expressed by malignantly transformed epithelium, while it was absent from chronic wounds. MMP-9 was detected in the epithelium in both SCCs and chronic wounds. Epithelial MMP-13 expression was strong in SCC, but was absent in chronic wounds. MMP-12 was expressed in the epithelium in two SCCs, while macrophages were positive in chronic wounds. MMP-19 was induced in proliferating epithelium of wounds, but was absent from invasive areas of SCC. p16 was expressed by keratinocytes in half of the chronic wounds and at superficial margins of SCCs, while invasive areas were negative.


CONCLUSIONS
Our results suggest that epithelial expression of MMP-7, MMP-12 and MMP-13, but not that of MMP-1, MMP-3, MMP-8, MMP-9 and MMP-10, in chronic wounds provides a diagnostic clue for distinguishing SCCs from nonmalignant wounds. The loss of MMP-19 and p16 from the epithelium could aid in making the differential diagnosis between well-differentiated SCCs and nonmalignant chronic wounds.
Impola
U
U
Department of Dermatology, Helsinki University Central Hospital and Biomedicum Helsinki Meilahdentie 2, 00250 Helsinki, Finland.
Jeskanen
L
L
Ravanti
L
L
Syrjänen
S
S
Baldursson
B
B
Kähäri
V-M
VM
Saarialho-Kere
U
U
D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000378:metabolism*; D002908:Chronic Disease; D017364:Collagenases / Q000032:analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis*; D003937:Diagnosis, Differential; D018093:Gelatinases / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D007871:Leg Ulcer / Q000175:diagnosis / Q000378:metabolism*; D053508:Matrix Metalloproteinase 12; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3 / Q000032:analysis; D020783:Matrix Metalloproteinase 7 / Q000032:analysis; D020784:Matrix Metalloproteinase 8 / Q000032:analysis; D020782:Matrix Metalloproteinases / Q000032:analysis*; D053505:Matrix Metalloproteinases, Secreted; D008666:Metalloendopeptidases / Q000032:analysis; D012878:Skin Neoplasms / Q000201:enzymology / Q000378:metabolism*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D017364:Collagenases; D018093:Gelatinases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D053505:Matrix Metalloproteinases, Secreted; D008666:Metalloendopeptidases; C108362:matrix metalloproteinase 19; D019278:Matrix Metalloproteinase 3; D020783:Matrix Metalloproteinase 7; D020784:Matrix Metalloproteinase 8; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12