Regression of Canine Cutaneous Histiocytoma is Associated with an Orchestrated Expression of Matrix Metalloproteinases

SummaryCanine cutaneous histiocytoma (CCH) is a common benign skin tumour originating from epidermal Langerhans cells. These tumours often display spontaneous regression and therefore represent a valuable animal model for investigation of tumour regression. Based on previous studies it was hypothesized that up-regulation of cytokines during CCH regression leads to up-regulation of matrix metalloproteinases (MMPs) favouring infiltration of lymphocytes and enhanced tumour regression. The expression of MMPs and their inhibitors (tissue inhibitors of metalloproteinases, TIMPs) was investigated immunohistochemically in 27 CCHs. The tumours were classified into four groups defined as having no regression (group 1), early regression (group 2), intermediate regression (group 3) or late regression (group 4). The distribution and expression intensity of MMP-1, -2, -3, -7, -9, -13 and -14 and TIMP-1 and -2 were determined in peripheral and central areas of each tumour. Group 3 and 4 CCHs showed up-regulation of expression of MMP-1, -9 and -14 at the periphery. Variable expression of MMP-2 and -3 was observed. Expression of the remaining MMPs and TIMPs showed no group-specific changes. Most MMPs and TIMPs displayed significantly higher expression at the tumour periphery compared with the centre, independently of the stage of regression and indicating more pronounced proteolysis in the peripheral areas. The results are consistent with cytokine-enhanced MMP expression, particularly of MMP-9, leading to enhanced lymphocyte recruitment in combination with elevated cleavage of extracellular matrix and basement membranes.