Distinct roles for cysteine cathepsin genes in multistage tumorigenesis Journal Article
| Authors: | Gocheva, V.; Zeng, W.; Ke, D.; Klimstra, D.; Reinheckel, T.; Peters, C.; Hanahan, D.; Joyce, J. A. |
| Article Title: | Distinct roles for cysteine cathepsin genes in multistage tumorigenesis |
| Abstract: | Multiple types of degradative enzymes, including cathepsins of the cysteine protease family, have been implicated in the regulation of angiogenesis and invasion during cancer progression. Several cysteine cathepsins are up-regulated in a mouse model of pancreatic islet cell carcinogenesis (RIP1-Tag2), and tumor progression is impaired following their collective pharmacologic inhibition. Using null mutations of four of the implicated cysteine cathepsins, we have now dissected their individual roles in cancer development. Mutants of cathepsins B or S impaired tumor formation and angiogenesis, while cathepsin B or L knockouts retarded cell proliferation and tumor growth. Absence of any one of these three genes impaired tumor invasion. In contrast, removal of cathepsin C had no effect on either tumor formation or progression. We have identified E-cadherin as a target substrate of cathepsins B, L, and S, but not cathepsin C, potentially explaining their differential effects on tumor invasion. Furthermore, we detected analogous increases in cathepsin expression in human pancreatic endocrine neoplasms, and a significant association between increased levels of cathepsins B and L and tumor malignancy. Thus individual cysteine cathepsin genes make distinctive contributions to tumorigenesis. © 2006 by Cold Spring Harbor Laboratory Press. |
| Keywords: | immunohistochemistry; controlled study; protein expression; gene mutation; mutation; disease course; cancer growth; nonhuman; pancreatic neoplasms; cell proliferation; mouse; animals; mice; mice, knockout; animal tissue; apoptosis; protein targeting; fluorescent dyes; animal model; enzyme activation; enzyme substrate; cysteine proteinase inhibitors; neovascularization, pathologic; uvomorulin; mice, inbred c57bl; carcinogenesis; animalia; cancer invasion; mice, inbred strains; tumor burden; pancreas tumor; recombinant proteins; neoplasms, experimental; malignant neoplastic disease; neoplasm invasiveness; cathepsin b; cathepsins; up-regulation; tumor growth; mouse models; indoles; tumor vascularization; cadherins; null allele; knockout gene; tumor microenvironment; crosses, genetic; mice, congenic; cathepsin l; cathepsin s; endocrine tumor; pancreatic endocrine cancer; proteases; cysteine cathepsins; cysteine proteinase; dipeptidyl peptidase i; fluorescein-5-isothiocyanate |
| Journal Title: | Genes and Development |
| Volume: | 20 |
| Issue: | 5 |
| ISSN: | 0890-9369 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 2006-01-01 |
| Start Page: | 543 |
| End Page: | 556 |
| Language: | English |
| DOI: | 10.1101/gad.1407406 |
| PUBMED: | 16481467 |
| PROVIDER: | scopus |
| PMCID: | PMC1410800 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 155" - "Export Date: 4 June 2012" - "CODEN: GEDEE" - "Source: Scopus" |
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