Keratinocyte expression of MMP3 enhances differentiation and prevents tumor establishment.

McCawley LJ, Wright J, LaFleur BJ, Crawford HC, Matrisian LM
Am J Pathol. 2008 173 (5): 1528-39

PMID: 18832569 · PMCID: PMC2570142 · DOI:10.2353/ajpath.2008.080132

Matrix metalloproteinase (MMP)-3 is induced by multiple cell types in the skin during processes involved in both normal and pathological tissue remodeling. We previously demonstrated that MMP3-null animals have an increased sensitivity to the development of squamous cell carcinoma, suggesting that overall, MMP3 has a protective role in squamous cell carcinoma. However, not all cellular responses affected by a loss of MMP3 are tumor-protective, and tumor expression of MMP3 is co-incident with an invasive tumor phenotype. Transgenic mice were generated with MMP3 targeted to keratinocytes to examine the biological role of tumor-produced MMP3. Overexpression of MMP3 reduced tumor multiplicity in response to chemically induced squamous cell carcinoma. Vascular density was increased with MMP3 overexpression; however, other cellular processes, including tumor growth and leukocyte infiltration, were unaffected. In accordance with the change in tumor multiplicity, SP-1 murine papilloma cell lines that were generated to stably express MMP3 lost the capacity to establish palpable tumors following orthotopic injection into immunocompromised mice. Analysis of epidermal biopsies taken at 1 to 2 weeks postinjection revealed that these MMP3-expressing Sp-1 lines had reduced levels of proliferation and pronounced differentiation. These same cells demonstrated an increased ability to differentiate in vitro, an effect that was inhibited by broad-spectrum MMP and selective MMP3 inhibition. These studies suggest that keratinocyte expression of MMP3 promotes cellular differentiation, impeding tumor establishment during tumorigenesis.

MeSH Terms (22)

Animals Carcinoma, Squamous Cell Cattle Cell Differentiation Cell Line, Tumor Cell Movement Cell Proliferation Cell Survival Disease Models, Animal Epidermis Female Gene Targeting Keratin-5 Keratinocytes Male Matrix Metalloproteinase 3 Mice Mice, Transgenic Neutrophils Rats Stromal Cells Transplantation, Homologous

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