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      Emerging roles of proteases in tumour suppression

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      Nature Reviews Cancer

      Springer Science and Business Media LLC

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          Abstract

          Proteases have long been associated with cancer progression because of their ability to degrade extracellular matrices, which facilitates invasion and metastasis. However, recent studies have shown that these enzymes target a diversity of substrates and favour all steps of tumour evolution. Unexpectedly, the post-trial studies have also revealed proteases with tumour-suppressive effects. These effects are associated with more than 30 different enzymes that belong to three distinct protease classes. What are the clinical implications of these findings?

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          Most cited references 78

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          MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis.

          The matrix metalloproteinase MMP-9/gelatinase B is upregulated in angiogenic dysplasias and invasive cancers of the epidermis in a mouse model of multi-stage tumorigenesis elicited by HPV16 oncogenes. Transgenic mice lacking MMP-9 show reduced keratinocyte hyperproliferation at all neoplastic stages and a decreased incidence of invasive tumors. Yet those carcinomas that do arise in the absence of MMP-9 exhibit a greater loss of keratinocyte differentiation, indicative of a more aggressive and higher grade tumor. Notably, MMP-9 is predominantly expressed in neutrophils, macrophages, and mast cells, rather than in oncogene-positive neoplastic cells. Chimeric mice expressing MMP-9 only in cells of hematopoietic origin, produced by bone marrow transplantation, reconstitute the MMP-9-dependent contributions to squamous carcinogenesis. Thus, inflammatory cells can be coconspirators in carcinogenesis.
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            Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy.

            The matrix metalloproteinases (MMPs) mediate homeostasis of the extracellular environment. They have multiple signalling activities that are commonly altered during tumorigenesis and that might serve as intervention points for anticancer drugs. However, there are many criteria to consider in validating MMPs as drug targets and for the development of MMP inhibitors. The inhibition of some MMPs could have pro-tumorigenic effects (making them anti-targets), counterbalancing the benefits of target inhibition. These effects might partially account for the failure of MMP inhibitors in clinical trials. What are the major challenges in MMP target validation and MMP-inhibitor-drug development?
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              Cell biology: autophagy and cancer.

               Beth Levine (2007)
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                Author and article information

                Journal
                Nature Reviews Cancer
                Nat Rev Cancer
                Springer Science and Business Media LLC
                1474-175X
                1474-1768
                October 2007
                October 2007
                : 7
                : 10
                : 800-808
                Article
                10.1038/nrc2228
                17851543
                © 2007

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