Keratinocyte expression of MMP3 enhances differentiation and prevents tumor establishment.
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.
McCawley
Lisa J
LJ
Vanderbilt University, Department of Cancer Biology, Nashville, TN 37232-6840, USA. Lisa.McCawley@vanderbilt.edu
Wright
Jane
J
LaFleur
Bonnie J
BJ
Crawford
Howard C
HC
Matrisian
Lynn M
LM
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D002417:Cattle; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D004195:Disease Models, Animal; D004817:Epidermis / Q000201:enzymology / Q000473:pathology; D005260:Female; D018390:Gene Targeting; D053555:Keratin-5 / Q000378:metabolism; D015603:Keratinocytes / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000473:pathology; D051381:Rats; D017154:Stromal Cells / Q000473:pathology; D014184:Transplantation, Homologous
D053555:Keratin-5; D019278:Matrix Metalloproteinase 3