Gelatinase B (MMP-9), but not its inhibitor (TIMP-1), dictates the growth rate of experimental thymic lymphoma

Centre de Recherche en Santé Humaine, INRS-Institut Armand-Frappier, Université du Québec, Laval, Canada.
International Journal of Cancer (Impact Factor: 5.09). 09/1999; 82(5):743-7.
Source: PubMed

ABSTRACT Dysregulation of metalloproteinase production at tumor sites contributes to the modification of local stromal tissue necessary for tumor development. Gelatinase B (matrix metalloproteinase-9, MMP-9) is one of the key enzymes that have been associated with the progression of several tumors. Paradoxically, MMP-9 expression by tumor cells, most notably by lymphoma cells, is concomitant with the expression of its physiological inhibitor, TIMP-1. Not only are both genes often co-expressed in the most aggressive forms of lymphomas but also both are up-regulated upon contact with stromal cells. Since TIMP-1 is known to regulate growth in several cell types and some aggressive lymphoma cells express TIMP-1 constitutively without MMP-9, it is unclear whether the over-expression of MMP-9 is counterbalanced by TIMP-1 and whether TIMP-1 expression alone could favor the development of lymphoma. To gain further insight into the respective roles of MMP-9 and TIMP-1 in lymphoma, we generated lymphoma cell lines expressing constitutively high levels of MMP-9 or TIMP-1 and compared these cells for the ability to form thymic lymphoma in vivo. Moreover, we generated lymphoma cell lines expressing constitutively high levels of both MMP-9 and TIMP-1 to reproduce the net physiological balance resulting from the expression of both genes simultaneously and to determine which gene overrides the other. Our results show that mice injected with lymphoma cells expressing MMP-9 constitutively developed thymic lymphoma more rapidly than those injected with control lymphoma cells. Over-expression of TIMP-1 alone did not significantly influence tumor progression of lymphoma nor did it delay the capacity of MMP-9 to accelerate the development of thymic lymphoma.

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    • "e l s e v i e r . c o m / l o c a t e / y c i m m the largest and most complex member of MMPs family [19], and a potential regulatory function of MMPs on intrathymic, ECMmediated interactions has recently been suggested [11] [20]. However, roles of these MMPs and TIMPS on thymic atrophy observed during infection have not been characterized clearly. "
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    ABSTRACT: The thymus plays a crucial role in the generation of T-cells, and so our laboratory has been interested in the study of the intrathymic events that occur during infection diseases and may cause disruption in its functions. Previously, we showed that thymus from experimentally Plasmodium berghei-infected mice present histological alterations with high levels of apoptosis, changes in cell migration-related molecules, and premature egress of immature thymocytes to periphery. In addition, parasites were found inside the thymus. In this work we investigated alterations in the expression pattern and activity of matrix metalloproteinases MMP-2 and -9, and their tissue inhibitors, TIMP-1 and TIMP-2. Our results show enhanced expression and widespread distribution of these molecules in thymus from infected animals. Also, the presence of active MMP-2 was detected. These data are suggestive of MMPs and TIMPs importance in the earlier observed changes in the extracellular matrix during thymic alterations after plasmodium infection.
    Cellular Immunology 10/2012; 279(1):53-59. DOI:10.1016/j.cellimm.2012.09.006 · 1.92 Impact Factor
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    • "The enzymatic activity of MMPs is regulated by tissue inhibitors of metalloproteinases (TIMPs), the endogenous inhibitors with a higher affi nity for specifi c MMPs (Aoudjit et al., 1999; Lukes et al., 1999). For example, TIMP-1 inhibits MMP- 9 activity by forming a specifi c complex with MMP-9, whereas MMP-2 is bound by TIMP-2 (Aoudjit et al., 1999; Wang et al., 2000; Giannelli et al., 2002; Sellner and Leib, 2006). Therefore , a favorable balance of MMPs/TIMPs system plays a pivotal role in maintaining normal homeostasis in the CNS which is essential for preventing neurological disorders (Gardner and Ghorpade, 2003; Kim and Joh, 2012). "
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    ABSTRACT: Radiation therapy, the most commonly used for the treatment of brain tumors, has been shown to be of major significance in tu-mor control and survival rate of brain tumor patients. About 200,000 patients with brain tumor are treated with either partial large field or whole brain radiation every year in the United States. The use of radiation therapy for treatment of brain tumors, however, may lead to devastating functional deficits in brain several months to years after treatment. In particular, whole brain radiation therapy results in a significant reduction in learning and memory in brain tumor patients as long-term consequences of treatment. Although a number of in vitro and in vivo studies have demonstrated the pathogenesis of radiation-mediated brain injury, the cel-lular and molecular mechanisms by which radiation induces damage to normal tissue in brain remain largely unknown. Therefore, this review focuses on the pathophysiological mechanisms of whole brain radiation-induced cognitive impairment and the iden-tification of novel therapeutic targets. Specifically, we review the current knowledge about the effects of whole brain radiation on pro-oxidative and pro-inflammatory pathways, matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) system and extracellular matrix (ECM), and physiological angiogenesis in brain. These studies may provide a foundation for defin-ing a new cellular and molecular basis related to the etiology of cognitive impairment that occurs among patients in response to whole brain radiation therapy. It may also lead to new opportunities for therapeutic interventions for brain tumor patients who are undergoing whole brain radiation therapy.
    Biomolecules and Therapeutics 07/2012; 20(4):357-370. DOI:10.4062/biomolther.2012.20.4.357 · 1.73 Impact Factor
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    • "However, owing to the detected protein sizes in zymogram gels, only the pro-form of MMP-9 and not the activated protease was present in the samples. Similarly, other groups could show functional effects, although no active form of MMP-9 could be detected (Aoudjit et al., 1999; Liu et al., 2000; Nold et al., 2003). This observation might be explained by the lack of activating agents, like MMP-3 (Ogata et al., 1992), MMP-2 (Fridman et al., 1995), MMP-7 (von Bredow et al., 1998), and MMP-13 (Knauper et al., 1997), which usually cleave MMP-9 to its active form or other nonfavorable conditions during culture (Fridman et al., 2003). "
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    ABSTRACT: Skin inflammation and the migration of cells at the site of the immune response play an important role in allergic skin diseases. It has already been described that matrix metalloproteinase 9 (MMP-9) influences tissue remodeling and facilitates cell migration by proteolytic degradation of basal membrane components. The aim of this study was to investigate MMP-9 expression on human primary keratinocytes (KCs) upon stimulation with histamine, a potent mediator in allergic responses. With ELISA and zymography, we could show that histamine induced dose-dependent upregulation of MMP-9 in cultured KCs and in punch biopsies of human skin. The histamine H(1) receptor (H(1)R) agonist beta-histine-but not agonists for H(2)R, H(3)R, and H(4)R-induced MMP-9, whereas the H(1)R antagonist clemastine blocked the effect in a dose-dependent manner. Immunohistological staining showed that histamine-induced MMP-9 led to destruction of type IV collagen at the basement membrane in healthy skin. In a coculture system of KCs and T cells, migration of T cells through an artificial basement membrane was increased after histamine stimulation of KCs. Our findings demonstrate enhanced MMP-9 production and cell migration after histamine stimulation and may represent a new mechanism by which KCs contribute to the pathology of skin diseases.
    Journal of Investigative Dermatology 07/2008; 128(12):2783-91. DOI:10.1038/jid.2008.153 · 7.22 Impact Factor
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