The expression and regulation of matrix metalloproteinases-12, -10 and -7 in epithelial cells and squamous cell cancer

Matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes which take part in the sophisticated coordination of extracellular matrix (ECM) synthesis and breakdown. Together they can cleave essentially all matrix proteins. Degradation of connective tissue is required both in normal physiologic processes and in pathologic tissue remodeling such as cancer. The aim of this study was to investigate the expression and regulation of metalloelastase (MMP-12), stromelysin-2 (MMP-10) and matrilysin (MMP-7) in epithelial cancers and to evaluate their role in the clinical behavior of tumors. Furthermore, we studied the role of MMP-12 during human development. Our results revealed a restricted expression of MMP-12 in hypertrophic chondrocytes in developing bone, beginning from the gestational age of 8 weeks, but not in other fetal tissues. Expression of MMP-12 mRNA could not be detected in normal adult cartilage or osteosarcomas but in chondrosarcomas in both macrophages and cancer cells. TNF-α induced MMP-12 transcription in chondrosarcoma-derived cells. MMP-12 was detected in basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) of the skin and vulva both in epithelial cancer cells and macrophages in vivo, as well as in various cultured SCC cell lines and transformed HaCaT cells, whereas pre-malignant tumors and primary skin keratinocytes were negative. MMP-7 and -12 proteins were also upregulated in areas of elastotic material in solar damage, including actinic keratosis, a condition that can develop into SCC. In vulvar SCCs, MMP-12 mRNA was expressed in cancer cells only in the histologically more aggressive grade II/III samples, thereby correlating with the dedifferentiation of the tumors. In contrast, macrophage-derived MMP-12 mRNA was most abundant in well-differentiated grade I tumors. The amount of signal for MMP-12, regardless of its origin, did not significantly correlate with metastases, the amount of blood vessels or patient survival. MMP-12 production was induced by transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) in cells derived from cutaneous SCC and epithelial MCF-10f cells, while only by TGF-β1 in HaCaTs. In SCCs of the vulva, MMP-7 mRNA was detected in 50 % of tumors mainly in epithelial tumor cells, the expression generally concentrating in more aggressive tumors. In HaCaTs it was upregulated by TNF-α. MMP-10 mRNA was expressed in SCCs and BCCs only in epithelial laminin-5 positive cancer cells with a pattern totally different from its close homologue stromelysin-1 (MMP-3). The production of MMP-10 was upregulated in cutaneous SCC cells by TGF-α and KGF, and by IFN-γ in combination with TGF-β1 and TNF-α, both in SCC and HaCaT cells. In conclusion, this study shows that MMP-12 can be expressed in vivo and in vitro by transformed epithelial cells. The level of cancer cell derived MMP-12 correlates with histological aggressiveness, while that of macrophages predicts less aggressive behavior of the tumors, suggesting a dual role for MMP-12 in cancer progression. According to the present results, there is a possibility that MMP-12 mRNA expression in m acrophages might serve as a new prognostic marker in patients with SCC. Furthermore, MMP-12 plays an important role in ECM remodeling during fetal bone development and is induced when chondrocytes undergo malignant transformation. In contrast, MMP-10 expression does not correlate with the invasive behavior of SCCs but may be induced by the wound healing and inflammatory matrix remodeling events associated with skin tumors.