Strongin, A. Y. Mislocalization and unconventional functions of cellular MMPs in cancer. Cancer Metastasis Rev. 25, 87-98

The Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Cancer and metastasis reviews (Impact Factor: 7.23). 04/2006; 25(1):87-98. DOI: 10.1007/s10555-006-7892-y
Source: PubMed


MMPs are multifunctional enzymes capable of targeting the extracellular matrix, growth factors, cytokines and cell surface-associated adhesion and signaling receptors. The cellular localization and the activity of MMPs are tightly controlled at both the transcriptional and the post-transcriptional levels. Mislocalization and presentation in unconventional cellular compartments provide MMPs with an opportunity to cleave previously unidentified proteins. This review is focused on two, entirely different MMPs, one of which is membrane-tethered and another of which is soluble (MT1-MMP and MMP-26, respectively) from twenty four known human MMPs. Our recent studies determined that both of these enzymes functioned at unexpected cellular compartments and it was resulted in the identification of novel proteolytic pathways, whose significance we only partially comprehend as of this writing. It is reasonable, however, to hypothesize from these data that many individual MMPs perform in a similar manner and display a much broader range of functions compared to what we earlier thought.

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    • "Blocking MMPs by Marimastat, although with smaller impact compared to the effect of actin cytoskeleton disruption, also showed significant alteration on the degree of collagen compaction. In fact, MMPs have been associated to tumor stroma and fibrosis in vivo [26] [27]. A recent research conducted by tracking bead displacement to assess ECM remodeling also showed the treatment of MMP inhibitor reduced the magnitude of ECM deformation [28], supporting our evaluation by spatial correlation method. "
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    ABSTRACT: Extracellular matrix (ECM) remodeling is a critical step of many biological and pathological processes. However, most of the studies to date lack a quantitative method to measure ECM remodeling at a scale comparable to cell size. Here, we applied image spatial correlation to collagen second harmonic generation (SHG) images to quantitatively evaluate the degree of collagen remodeling by cells. We propose a simple statistical method based on spatial correlation functions to determine the size of high collagen density area around cells. We applied our method to measure collagen remodeling by two breast cancer cell lines (MDA-MB-231 and MCF-7), which display different degrees of invasiveness, and a fibroblast cell line (NIH/3T3). We found distinct collagen compaction levels of these three cell lines by applying the spatial correlation method, indicating different collagen remodeling ability. Furthermore, we quantitatively measured the effect of Latrunculin B and Marimastat on MDA-MB-231 cell line collagen remodeling ability and showed that significant collagen compaction level decreases with these treatments.
    Journal of Biophysics 07/2013; 2013:532030. DOI:10.1155/2013/532030
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    • "In these cancers, claudin 1 mislocalization was shown to increase the invasiveness of the cancer cells [11,16-18,35]. This observation leads us to speculate that it is possible that cytoplasmic claudin 1 may have a different function from membranous claudin 1, as mislocalization of a number of membrane and subcellular proteins to the cytoplasm in some studies has been shown to impart tumorigenicity [36-40]. "
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    ABSTRACT: Background Defects in tight junctions, gate-keepers of the integrity of the epidermal barrier function, are known to contribute to cancer development. As such, enhancing our understanding of how the expression of proteins involved in these junctions is regulated in cancer, remains a priority. Although the expression of one of these proteins, claudin 1, is down regulated in most invasive human breast cancers (HBC), we have recently shown that high levels of claudin 1, characterized tumors belonging to the very aggressive basal-like breast cancer (BLBC) subtype. In these tumors, the claudin 1 protein, usually localized in the cell membrane, is often mislocalized to the cytoplasm. Methods To examine the clinical relevance of this observation, we have generated and analyzed an invasive HBC tissue microarray consisting of 151 breast tumor samples; 79 of which presented a basal-like phenotype (i.e. ER-ve, PR-ve HER2-ve, CK5/6 or EGFR+ve). We also interrogated the outcome of claudin 1 knockdown in a human BLBC cell line, BT-20. Results Immunohistochemical analysis of this patient cohort revealed a significant association between high claudin 1 expression and BLBCs in women 55 years of age and older. Interestingly, no significant association was found between claudin 1 and nodal involvement, tumor grade or tumor size. Regression analysis however, showed a significant positive association between claudin 1 and claudin 4, even though claudin 4 did not significantly correlate with patient age. Claudin 1 knockdown in BT-20 cells resulted in decreased cell migration. It also significantly altered the expression of several genes involved in epithelial-mesenchymal-transition (EMT); in particular, SERPINE 1 (PAI1) and SSP1 (osteopontin), known to inhibit EMT and cancer cell migration. Conversely, genes known to maintain EMT through their interaction, SNAIL2, TCF4 and FOXC2 were significantly down regulated. Conclusions The association of high claudin 1 protein levels observed in tumors derived from older women with BLBC, suggests that claudin 1 has the potential to serve as a marker which can identify a specific subgroup of patients within the BLBC subtype and thus, further contribute to the characterization of these ill-defined breast cancers. More importantly, our studies strongly suggest that claudin 1 directly participates in promoting breast cancer progression, possibly through the alteration of expression of EMT genes.
    BMC Cancer 05/2013; 13(1):268. DOI:10.1186/1471-2407-13-268 · 3.36 Impact Factor
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    • "MMP-26 upregulation is described for different tumor entities, for example, colon cancer and HNSCCs 42. It is described as epithelial-cell derived enzyme that is largely stored within the cellular compartment and only secreted in small fractions into the extracellular milieu 43. MMP-26 is capable of cleaving collagen-4, fibronectin, fibrinogen, and gelatin, and can further process proMMP-9 to the final active form 28. In vitro, MMP-26 is expressed by migrating human mucosal keratinocytes and inhibition resulted in aberrant migration and proliferation 44. "
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    ABSTRACT: Granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes tumor progression in different tumor models in an autocrine and paracrine manner. However, at the same time GM-CSF is used in cancer therapies to ameliorate neutropenia. We have previously shown in GM-CSF and G-CSF expressing or negative skin or head and neck squamous cell carcinoma that GM-CSF expression is associated with a highly angiogenic and invasive tumor phenotype. To determine the functional contribution of GM-CSF to tumor invasion, we stably transfected a GM-CSF negative colon adenocarcinoma cell line HT-29 with GM-CSF or treated the same cell line with exogenous GM-CSF. While GM-CSF overexpression and treatment reduced tumor cell proliferation and tumor growth in vitro and in vivo, respectively, it contributed to tumor progression. Together with an enhanced migratory capacity in vitro, we observed a striking increase in tumor cell invasion into the surrounding tissue concomitant with the induction of an activated tumor stroma in GM-CSF overexpressing or GM-CSF treated tumors. In a complex 3D in vitro model, enhanced GM-CSF expression was associated with a discontinued basement membrane deposition that might be mediated by the increased expression and activation of MMP-2, -9, and -26. Treatment with GM-CSF blocking antibodies reversed this effect. The increased presence and activity of these tumor cell derived proteases was confirmed in vivo. Here, expression of MMP-26 protein was predominantly located in pre- and early-invasive areas suggesting MMP-26 expression as an early event in promoting GM-CSF dependent tumor invasion.
    Cancer Medicine 04/2013; 2(2):117-29. DOI:10.1002/cam4.20 · 2.50 Impact Factor
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