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Loss of collagenase-2 confers increased skin tumor susceptibility to male mice

Abstract

Matrix metalloproteinases (MMPs) have fundamental roles in tumor progression1,2, but most clinical trials with MMP inhibitors have not shown improvements in individuals with cancer3. This may be partly because broad-range inhibitors also reduce host-protective antitumor properties of individual MMPs. We generated mice deficient in collagenase-2 (Mmp8), an MMP mainly produced by neutrophils in inflammatory reactions and detected in some malignant tumors1,4. Loss of Mmp8 did not cause abnormalities during embryonic development or in adult mice. Contrary to previous studies with MMP-deficient mice, however, the absence of Mmp8 strongly increased the incidence of skin tumors in male Mmp8−/−mice. Female Mmp8−/−mice whose ovaries were removed or were treated with tamoxifen were also more susceptible to tumors compared with wild-type mice. Bone marrow transplantation experiments confirmed that Mmp8 supplied by neutrophils was sufficient to restore the natural protection against tumor development mediated by this protease in male mice. Histopathological analysis showed that mutant mice had abnormalities in the inflammatory response induced by carcinogens. Our study identifies a paradoxical protective role for Mmp8 in cancer and provides a genetic model to evaluate the molecular basis of gender differences in cancer susceptibility.

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Figure 1: Generation of Mmp8−/− mice.
Figure 2: Skin tumorigenesis in wild-type (WT) and Mmp8−/− (KO) mice.
Figure 3: Skin carcinogenesis in Mmp8−/− mice transplanted with bone marrow from wild-type mice.
Figure 4: Histopathological analysis of MCA-treated skin from wild-type and Mmp8−/− mice.

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Acknowledgements

We thank M. Aracil and A. Bernad for advice on bone marrow transplantation studies; J.M. López for help with histopathological analysis; A. Noël, A. A. Ferrando, E. Campo, L. Boscá, J. P. Freije, L. M. Sánchez and G. Velasco for comments; T. Sánchez for help in animal care facilities; and S. Alvarez, M. Fernández, F. Rodríguez and M. S. Pitiot for technical assistance. This work was supported by grants from Comisión Interministerial de Ciencia y Tecnología, Gobierno del Principado de Asturias, Fundación “La Caixa” and European Union. C.M.O. is supported by a Canada Research Chair in Metalloproteinase Biology. The Instituto Universitario de Oncología is supported by Obra Social Cajastur-Asturias, Spain. S.D.S. is supported by a grant from the US National Heart, Lung, and Blood Institute.

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Correspondence to Carlos López-Otín.

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Balbín, M., Fueyo, A., Tester, A. et al. Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nat Genet 35, 252–257 (2003). https://doi.org/10.1038/ng1249

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