Abstract
Human MMP-1 is a matrix metalloproteinase repeatedly associated with many pathological conditions, including cancer. Thus, MMP1 overexpression is a poor prognosis marker in a variety of advanced cancers, including colorectal, breast, and lung carcinomas. Moreover, MMP-1 plays a key role in the metastatic behavior of melanoma, breast, and prostate cancer cells. However, functional and mechanistic studies on the relevance of MMP-1 in cancer have been hampered by the absence of an in vivo model. In this work, we have generated mice deficient in Mmp1a, the murine ortholog of human MMP1. Mmp1a(-/-) mice are viable and fertile and do not exhibit obvious abnormalities, which has facilitated studies of cancer susceptibility. These studies have shown a decreased susceptibility to develop lung carcinomas induced by chemical carcinogens in Mmp1a(-/-) mice. Histopathological analysis indicated that tumors generated in Mmp1a(-/-) mice are smaller than those of wild-type mice, consistently with the idea that the absence of Mmp-1a hampers tumor progression. Proteomic analysis revealed decreased levels of chitinase-3-like 3 and accumulation of the receptor for advanced glycation end-products and its ligand S100A8 in lung samples from Mmp1a(-/-) mice compared with those from wild-type. These findings suggest that Mmp-1a could play a role in tumor progression by modulating the polarization of a Th1/Th2 inflammatory response to chemical carcinogens. On the basis of these results, we propose that Mmp1a knock-out mice provide an excellent in vivo model for the functional analysis of human MMP-1 in both physiological and pathological conditions.
Highlights
MMP1 is overexpressed in malignant tumors and its levels are associated with poor prognosis
Inflammatory Response Evaluation after Urethane-lung Carcinogenesis—Because the high levels of chitinase-3-like protein 3 (CHI3L3) in wildtype mice could be indicative of a Th2 protumoral inflammatory response [32, 33], and the increased levels of receptor for advanced glycation end-products (RAGE) and its ligand S100A8 in mutant mice could point to the occurrence of a Th1 anti-tumoral response [33, 34], we evaluated the levels of Th1 and Th2 cytokines in lungs from wild-type and Mmp1a knock-out mice
During the past few years, evidence has accumulated that matrix metalloproteinases (MMPs)-1 is associated with tumor progression and metastasis [16, 17, 19]
Summary
MMP1 is overexpressed in malignant tumors and its levels are associated with poor prognosis. Proteomic analysis revealed decreased levels of chitinase-3-like 3 and accumulation of the receptor for advanced glycation end-products and its ligand S100A8 in lung samples from Mmp1a؊/؊ mice compared with those from wild-type These findings suggest that Mmp-1a could play a role in tumor progression by modulating the polarization of a Th1/Th2 inflammatory response to chemical carcinogens. It is necessary to perform a detailed analysis of the specific role of each individual MMP in the multiple stages of tumor evolution This is the case for fibroblast or interstitial collagenase (MMP-1), the first member of the MMP family identified in human tissues and widely associated with cancer but whose functional relevance in the progression of the disease is still largely unknown [11, 12]. We propose that Mmp1aϪ/Ϫ mice represent a novel in vivo model to elucidate the functional relevance of human MMP-1 in the context of the large complexity and diversity of proteolytic enzymes
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