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


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.
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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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    • "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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