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Originally published online as doi:10.2353/ajpath.2008.080132 on October 2, 2008

Published online before print October 2, 2008
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(American Journal of Pathology. 2008;173:1528-1539.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080132

Keratinocyte Expression of MMP3 Enhances Differentiation and Prevents Tumor Establishment

Lisa J. McCawley*, Jane Wright{dagger}, Bonnie J. LaFleur{ddagger}, Howard C. Crawford* and Lynn M. Matrisian*

From the Department of Cancer Biology,* Department of Pharmacology,{dagger} and Department of Biostatistics,{ddagger} Vanderbilt University, Nashville, Tennessee

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.






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Copyright © 2008 by the American Society for Investigative Pathology.