Collagenase Expression in Transgenic Mouse Skin Causes Hyperkeratosis and Acanthosis and Increases Susceptibility to Tumorigenesis

Abstract

In a series of transgenic mice, the human tissue collagenase gene was expressed in the suprabasal layer of the skin epidermis. Visually, the mice had dry and scaly skin which upon histological analysis revealed acanthosis, hyperkeratosis, and epidermal hyperplasia. At the ultrastructural level, intercellular granular materials were absent in the transgenic skin epidermis but contact was maintained through the intact desmosomes. Despite a diversity of underlying etiologies, similar morphological hyperproliferative changes in the epidermis are observed in the human skin diseases of lamellar ichthyosis, atopic dermatitis, and psoriasis. Subsequent experiments demonstrate that when the transgenic mouse skin was treated once with an initiator (7,12-dimethyl-benz[a]anthracene) and then twice weekly with a promoter (12-O-tetradecanoylphorbol-13-acetate), there was a marked increase in tumor incidence among transgenic mice compared with that among control littermates. These experiments demonstrate that by overexpressing the highly specific proteolytic enzyme collagenase, a cascade of events leading to profound morphological changes which augment the sensitivity of the skin towards carcinogenesis is initiated in the epidermis.

Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells

“…Previous studies with intravital video microscopy showed the importance of MMP for creating and maintaining an environment that supports the tumor formation and growth (Koop et al, 1994;Chambers and Matrisian, 1997). Collagenase-1 expression in the skin of transgenic mice led to earlier onset and increased numbers of papillomas arising after chemical initiation and promotion (D'Armiento et al, 1995). We overexpressed MMP-1 gene in the dominant-negative STAT3-expressing cells by retrovirus transduction, but were unable to rescue the tumor growth in nude mice (data not shown).…”

Matrix metalloproteinases and their tissue inhibitors direct cell fate during cancer development

“…Several chemical carcinogenesis models have been used to study MMPs in the early events of tumorigenesis. MMP-1 transgenics show increased susceptibility to skin carcinogens (D'Armiento et al, 1995), while MMP-9 null mice show decreased tumour incidence in another skin carcinogenesis model (Coussens et al, 2000). In the latter case, despite the deceased tumour incidence, tumours that do form are high-grade and more aggressive.…”

The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter

“…For example, mice that express a human collagenase-1 (MMP-1) transgene in squamous epithelium develop hyperproliferative skin lesions, and although they fail to form tumors spontaneously, they are more sensitive to chemical carcinogens than their non-transgenic littermates (D'Armiento et al, 1995). Conversely, mice that lack stromelysin-3 (MMP-11) form fewer and smaller DMBA-induced tumors than wild-type mice (Masson et al, 1998).…”