Intracellular and extracellular cathepsin B facilitate invasion of MCF-10A neoT cells through reconstituted extracellular matrix in vitro

Premzl, Aleš; Zavašnik-Bergant, Valentina; Türk, Vito; Kos, Janko

doi:10.1016/s0014-4827(02)00055-1

Cited by 129 publications

(116 citation statements)

References 32 publications

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“…As reported for tumor cells [23,31], we observed that Mfs carry out extracellular and intracellular proteolysis of ECM components when they invade through Matrigel by the mesenchymal mode. We developed two quantitative cell tests enabling the separate analysis of extracellular and intracellular collagenolysis by using fluorescently labeled collagen IV.…”

Section: Discussionsupporting

confidence: 79%

Three‐dimensional invasion of macrophages is mediated by cysteine cathepsins in protrusive podosomes

et al. 2012

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IntroductionThe ability of macrophages (Mfs) to progress to specific tissues, increase matrix remodeling, and induce angiogenesis is essential for their normal physiological function [1,2]. In addition, tissue infiltration of Mfs is also involved in pathological processes such as chronic inflammation, atherosclerosis, neurodegenerative disorders, and cancer progression [3]. The presence of Mfs Correspondence: Dr. Bojana Mirković e-mail: bojana.mirkovic@ffa.uni-lj.si within tumors is generally a marker of poor prognosis since they enhance angiogenesis and metastasis [4]. Furthermore, tumorassociated Mfs are emerging as essential matrix-remodeling cells during tumor-cell invasion. They have been reported to be present at high frequency at the invasive front of the tumor, where the breakdown of extracellular matrix (ECM) occurs [5]. Therefore, there is a great need to specifically control tissue infiltration of Mfs by targeting Mf migration-related molecules [6]. * These authors contributed equally to the present work. Eur. J. Immunol. 2012. 42: 3429-3441 Mf migration has been studied extensively in two dimensions (2D) on artificial substrates; however, in vivo Mfs migrate through physiological and pathological tissue and interact with the surrounding three-dimensional (3D) ECM, including basement membrane, collagen-rich interstitial matrices, and dense tissues such as tumors. Cells of different origins and/or at different differentiation stages use distinct mechanisms of cell motility in the 3D environment. In the mesenchymal mode, cells wider than the matrix pore size degrade the matrix via proteolytic and force-based matrix remodeling, thus migrating in a "path-generating" manner, while amoeboid cells squeeze through pre-existing pores in a proteaseindependent fashion in a "path-finding" mode [7,8]. The first 3D migration studies performed on cells of the immune system suggested that these cells migrate in a protease-independent fashion [7,9]. In contrast, a recent study demonstrated that Mfs adapt their migration strategy depending on the architecture of the 3D environment. In this study, Mfs were found to use the amoeboid migration mode in fibrillar collagen I and the mesenchymal migration mode in dense substrates, such as Matrigel and gelled collagen I [10].The invasion of cancer cells is facilitated by ECM-degrading invadopodia [11]. Podosomes are structures functionally similar to the invadopodia that are found in Mfs, osteoclasts, and DCs [12,13]. During migration on 2D surfaces [14], dot or ringlike podosomes form at the ventral surface of the migrating cells where they establish direct contact with the substratum and are also involved in matrix degradation [11]. Structurally, podosomes comprise a concentrated core of F-actin and actin-regulatory proteins [14]. Surrounding the core is a ring region that contains scaffolding-, signaling-, and integrin-binding proteins, including the typical focal adhesion proteins vinculin, talin, paxillin, and FAK [15]. When Mfs migrate in a 3D environment (i.e., migra...

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Section: Discussionsupporting

confidence: 79%

Three‐dimensional invasion of macrophages is mediated by cysteine cathepsins in protrusive podosomes

et al. 2012

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“…Ctsb also is known to initiate proteolytic cascades through activation of other tumor-promoting proteases, including matrix metalloproteinases and urokinase-type plasminogen activator (35). Accordingly, inhibition of Ctsb by inhibitors or neutralizing antibodies or knockdown by antisense RNA results in reduced invasion through ECM in vitro (36,37), whereas overexpression of Ctsb facilitates invasion and metastasis (38,39).…”

Section: Discussionmentioning

confidence: 99%

Synergistic antitumor effects of combined cathepsin B and cathepsin Z deficiencies on breast cancer progression and metastasis in mice

Sevenich

Schurigt

Sachse

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

153

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The lysosomal cysteine proteases cathepsin B (Ctsb) and cathepsin Z (Ctsz, also called cathepsin X/P) have been implicated in cancer pathogenesis. Compensation of Ctsb by Ctsz in Ctsb −/− mice has been suggested. To further define the functional interplay of these proteases in the context of cancer, we generated Ctsz null mice, crossed them with Ctsb-deficient mice harboring a transgene for the mammary duct–specific expression of polyoma middle T oncogene (PymT), and analyzed the effects of single and combined Ctsb and Ctsz deficiencies on breast cancer progression. Single Ctsb deficiency resulted in delayed detection of first tumors and reduced tumor burden, whereas Ctsz-deficient mice had only a prolonged tumor-free period. However, only a trend toward reduced metastatic burden without statistical significance was detected in both single mutants. Strikingly, combined loss of Ctsb and Ctsz led to additive effects, resulting in significant and prominent delay of early and advanced tumor development, improved histopathologic tumor grading, as well as a 70% reduction in the number of lung metastases and an 80% reduction in the size of these metastases. We conclude that the double deficiency of Ctsb and Ctsz exerts significant synergistic anticancer effects, whereas the single deficiencies demonstrate at least partial reciprocal compensation.

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“…Intracellular and extracellular cathepsin B activity contributes to the in vitro invasiveness of MCF10AT cells (Premzl et al, 2003). Synthetic cysteine proteinase inhibitors, selective for cathepsin B, have been shown to significantly reduce the invasiveness of MCF10AT cells (Bervar et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of cathepsin B and MMP-9 gene expression in glioblastoma cell line via RNA interference reduces tumor cell invasion, tumor growth and angiogenesis

et al. 2004

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Extracellular proteases have been shown to cooperatively influence matrix degradation and tumor cell invasion through proteolytic cascades, with individual proteases having distinct roles in tumor growth, invasion, migration and angiogenesis. Matrix metalloproteases (MMP)-9 and cathepsin B have been shown to participate in the processes of tumor growth, vascularization and invasion of gliomas. In the present study, we used a cytomegalovirus promoter-driven DNA template approach to induce hairpin RNA (hpRNA)-triggered RNA interference (RNAi) to block MMP-9 and cathepsin B gene expression with a single construct. Transfection of a plasmid vectorexpressing double-stranded RNA (dsRNA) for MMP-9 and cathepsin B significantly inhibited MMP-9 and cathepsin B expression and reduced the invasive behavior of SNB19, glioblastoma cell line in Matrigel and spheroid invasion models. Downregulation of MMP-9 and cathepsin B using RNAi in SNB19 cells reduced cell-cell interaction of human microvascular endothelial cells, resulting in the disruption of capillary network formation in both in vitro and in vivo models. Direct intratumoral injections of plasmid DNA expressing hpRNA for MMP-9 and cathepsin B significantly inhibited established glioma tumor growth and invasion in intracranial tumors in vivo. Further intraperitoneal (ip) injections of plasmid DNA expressing hpRNA for MMP-9 and cathepsin B completely regressed pre-established tumors for a long time (4 months) without any indication of these tumor cells. For the first time, these observations demonstrate that the simultaneous RNAi-mediated targeting of MMP-9 and cathepsin B has potential application for the treatment of human gliomas.

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Intracellular and extracellular cathepsin B facilitate invasion of MCF-10A neoT cells through reconstituted extracellular matrix in vitro

Cited by 129 publications

References 32 publications

Three‐dimensional invasion of macrophages is mediated by cysteine cathepsins in protrusive podosomes

Three‐dimensional invasion of macrophages is mediated by cysteine cathepsins in protrusive podosomes

Synergistic antitumor effects of combined cathepsin B and cathepsin Z deficiencies on breast cancer progression and metastasis in mice

Inhibition of cathepsin B and MMP-9 gene expression in glioblastoma cell line via RNA interference reduces tumor cell invasion, tumor growth and angiogenesis

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