TY - JOUR T1 - Targeting cathepsins: a new glimmer of hope for pancreatic cancer therapy? JF - Gut JO - Gut SP - 790 LP - 791 DO - 10.1136/gutjnl-2011-301816 VL - 61 IS - 6 AU - Patrick Michl Y1 - 2012/06/01 UR - http://gut.bmj.com/content/61/6/790.abstract N2 - Recent whole-genome sequencing efforts have facilitated the detailed characterisation of the human degradome consisting of almost 600 proteases and homologues, which can be grouped into various classes including metalloproteinases, serine proteases and cysteine cathepsins.1 Whereas most proteases such as metalloproteinases and serine proteases are secreted and act extracellularly by modifying extracellular matrix or cell surface proteins, cathepsins are prototypical lysosomal cysteine proteases, which are predominantly located intracellularly in endolysosomal vesicles. In various types of malignancies, cathepsins have been associated with tumour progression and metastasis.2Cathepsin B is strongly expressed in pancreatic cancer, and high levels of this protease have been linked to reduced survival in patients after curative resection.3 The molecular basis for the elevated expression levels of cathepsin B in pancreatic cancer remains to be elucidated. In other cancers, however, genomic amplification, alternative splicing, as well as transcriptional and posttranscriptional upregulation have been reported.2 Interestingly, cathepsin B can be detected in both tumour cells and surrounding stromal cells such as tumour-associated macrophages and fibroblasts, indicating distinct roles of this protease during tumour progression in both the tumour microenvironment and the tumour cells themselves.2 Moreover, cathepsin B and several other cathepsins have been shown to function intracellularly as well as extracellularly, which puts them in a unique position and contrasts them with most other proteases such as metalloproteases or serine proteases.Extracellularly, cathepsins are secreted both as active enzymes and as inactive proforms, which are subsequently activated by interaction with extracellular matrix components and cell-surface proteins. Interestingly, cathepsin … ER -