Expression of cathepsins B and S in the progression of prostate carcinoma

Fernández, Pedro; Farré, Xavier; Nadal, Alfons; Fernández, Eva; Peiró, Nerea; Sloane, Bonnie F.; Shi, Guo‐Ping; Chapman, Harold A.; Campo, Elı́as; Cardesa, Antonio

doi:10.1002/1097-0215(20010120)95:1<51::aid-ijc1009>3.0.co;2-j

Cited by 128 publications

(78 citation statements)

References 26 publications

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“…These findings indicate that Ctsb expressed by cells of tumour-associated stroma and/or inflammatory cells participates in the processes leading to induction of tumour cell proliferation, despite its function of proteolysis of extracellular matrix proteins. Increased Ctsb expression by stromal cells at the invasive front of the tumour node has been reported (McKerrow et al, 2000;Fernandez et al, 2001). In addition, there is growing evidence supporting the regulation of tumour cell proliferation by different stromal cells (for example stromal fibroblasts, myeloid cells) through secretion of mitogenic and growth factors (van Roozendaal et al, 1996;Loffek et al, 2006).…”

Section: Discussionmentioning

confidence: 94%

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Reduced tumour cell proliferation and delayed development of high-grade mammary carcinomas in cathepsin B-deficient mice

et al. 2008

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Section: Discussionmentioning

confidence: 94%

“…These cell types are reckoned to contribute to the tumour-promoting effects of the stroma. In particular, macrophages strongly upregulate Ctsb expression on recruitment to a tumour (McKerrow et al, 2000;Fernandez et al, 2001;Vasiljeva et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Reduced tumour cell proliferation and delayed development of high-grade mammary carcinomas in cathepsin B-deficient mice

et al. 2008

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“…CatS expression was associated with poor prognosis and local recurrence. Fernandez et al 34 demonstrated CatS expression at all stages of prostatic carcinoma progression with no correlation between expression levels and tumor grade. In a study of lung cancer, Kos et al 35 Interpretation of CatS expression data from tumor lysates is problematic because of the cellular complexity of the tumor environment, which contains host normal and inflammatory cells in addition to tumor cells.…”

Section: Discussionmentioning

confidence: 99%

The Clinical Significance of Cathepsin S Expression in Human Astrocytomas

Flannery¹,

Gibson²,

Mirakhur³

et al. 2003

The American Journal of Pathology

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Early local invasion by astrocytoma cells results in tumor recurrence even after apparent total surgical resection, leading to the poor prognosis associated with malignant astrocytomas. Proteolytic enzymes have been implicated in facilitating tumor cell invasion and the current study was designed to characterize the expression of the cysteine proteinase cathepsin S (CatS) in astrocytomas and examine its potential role in invasion. Immunohistochemical analysis of biopsies demonstrated that CatS was expressed in astrocytoma cells but absent from normal astrocytes, oligodendrocytes, neurones and endothelial cells. Microglial cells and macrophages were also positive. Assays of specific activity in 59 astrocytoma biopsies confirmed CatS expression and in addition demonstrated that the highest levels of activity were expressed in grade IV tumors. CatS activity was also present in astrocytoma cells in vitro and the extracellular levels of activity were highest in cultures derived from grade IV tumors. In vitro invasion assays were carried out using the U251MG cell line and the invasion rate was reduced by up to 61% in the presence of the selective CatS inhibitor 4-Morpholineurea-LeuHomoPhe-vinylsulphone. We conclude that CatS expression is up-regulated in astrocytoma cells and provide evidence for a potential role for CatS in invasion. Astrocytomas are the commonest primary brain tumors and within this group the malignant grade III and IV tumors predominate (anaplastic astrocytomas and glioblastomas). Despite their non-metastatic nature, prognosis is poor because tumor infiltration of surrounding brain leads to recurrence even after apparently radical surgery. Multiple stereotactic biopsies of astrocytomas have demonstrated isolated tumor cells at considerable distances from the main tumor mass, 1 and recent investigations 2 have shown that tumor cells may be cultured from histologically normal brain at a distance greater than 4 cm from the gross tumor. Astrocytoma invasion is an active process that involves interactions with the host extracellular matrix (ECM), proteolytic modification of the ECM, and migration of the tumor cells into the modified matrix. 3 Members of the metalloproteinase, serine proteinase, and cysteine proteinase superfamilies have been linked to glioma invasion. 4 The cysteine proteinase cathepsin B (CatB) is expressed in gliomas in vitro 5 and immunohistochemical studies have demonstrated its presence in astrocytomas and glioblastomas in contrast to its absence from astrocytes in normal brain. 6,7 The expression and activity of CatB is higher in anaplastic astrocytomas and glioblastomas compared with low-grade tumors and normal brain 8 and high levels of CatB are positively correlated with poor survival. 9 Human glioblastoma cell lines also exhibit higher levels of CatB expression than lower grade astrocytomas 10 and the functional relevance of the enzyme is confirmed by a marked reduction in in vitro invasiveness of a glioblastoma cell line transfected with antisense CatB cDNA. 11 There is evide...

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“…Despite the cathepsins' general localization in the endosomal/lysosomal compartment, changes in distribution during neoplasia formation result in secretion and extracellular effects (14,15). Various human malignancies show overexpression of some cysteine cathepsins and accumulation at the invasive tumor front of solid cancers (16,17). This increased expression and proteolytic activity correlates with poor prognosis in several human cancers, including breast cancer (18).…”

mentioning

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.

149

122

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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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Expression of cathepsins B and S in the progression of prostate carcinoma

Cited by 128 publications

References 26 publications

Reduced tumour cell proliferation and delayed development of high-grade mammary carcinomas in cathepsin B-deficient mice

Reduced tumour cell proliferation and delayed development of high-grade mammary carcinomas in cathepsin B-deficient mice

The Clinical Significance of Cathepsin S Expression in Human Astrocytomas

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

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