Matrix Metalloproteinase-3 (MMP-3/Stromelysin-1) is upregulated in the epidermis during processes involving tissue remodeling. Mice that are null for MMP-3 have delayed closure of excisional wounds and, surprisingly, an increased susceptibility to squamous cell carcinoma (SCC). MMP-3 is widely expressed by a variety of cell types in the epidermis; however, keratinocyte expression of MMP-3 is restricted to the basal population during wound repair and during carcinogenesis upon conversion to an invasive phenotype. In order to examine the biological role of MMP-3 expression in keratinocytes, transgenic mice were generated with targeted expression of an autoactivated MMP-3 construct to basal keratinocytes under the control of keratin 5 and keratin 6 promoter regions. K5/6-MMP-3 mice displayed a modest but significantly accelerated time to excisional wound closure as compared to control animals. The responses of K5/6-MMP-3 mice and wildtype (WT) littermate controls to the classic two-stage DMBA/TPA chemically induced SCC were compared. Tumor onset and growth were similar; however, K5-MMP-3 mice developed fewer numbers of tumors per mouse than did WT controls. The decreased ability of keratinocytes expressing MMP-3 to form tumors was further explored using SP-1 murine papilloma cell lines generated to stably express MMP-3 (Sp-1/MMP-3). Sp-1/MMP-3 cell lines were unable to establish palpable tumors following orthotopic injection into immunocompromised mice (Rag-2-/-), in contrast to parental or Sp-1/Neo (vector control) cell lines. Epidermal biopsies were taken at 1-2 weeks following orthotopic injection of MMP-3 expressing and non expressing Sp-1 cell lines in order to investigate the lack of tumor establishment. At 2 weeks post-injection, histological (Gomori’s Trichrome) and immunohistochemical (α-smooth muscle actin) analysis revealed a more striking organized fibrotic response surrounding Sp-1/MMP-3 cells than parental or Sp-1/Neo cell lines. Although Sp-1/MMP-3 cell lines grew normally in vitro, these cell lines evidenced a diminished capacity to proliferate (BrdU incorporation) and showed areas of pronounced differentiation (i.e. fillagrin positive cells) following 1-2 weeks intradermal introduction as compared with parental or Sp-1/Neo cell lines. Interestingly, newly re-epithelialized epidermis of wounded K5-MMP-3 mice demonstrated expression of differentiation markers earlier than WT counterparts. These shared similarities between wounding and tumorigenic responses suggest that keratinocyte expression of MMP-3 promotes cellular differentiation. This allows for faster resolution of epidermis during reepithelialization, and impedes tumor establishment during carcinogenesis.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]