Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01034 (cystatin C)
 3,397 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cathepsin B is a matrix protease that may be associated with colorectal carcinoma invasion and progression. In this study, we investigated the localization of cathepsin B in cancerous and noncancerous tissues of 80 patients with colorectal cancer including 25 cases with liver metastasis. In addition, the expression of cystatin C, one of several cathepsin B inhibitors, was compared with that of cathepsin B in the same samples to reveal one of the regulation mechanisms of cathepsin B. The cancer cells in the advancing edge of the tumors often exhibited the strongest immunostaining of cathepsin B, and stromal cells and normal epithelial cells adjacent to the tumors were also positive for cathepsin B. The percentage of cathepsin B-positive cases was significantly larger in the group with liver metastases than in the group without liver metastases. In the group without liver metastases, the cancer cells and stromal cells more frequently exhibited cathepsin B immunoreactivity in Dukes' A cases than in Dukes' B and C cases. In situ hybridization and reverse transcription-polymerase chain reaction (RT-PCR) confirmed cathepsin B synthesis in the cancer and proximal epithelial cells. There was an average 3.7-fold increase in cathepsin B mRNA levels in the cancerous tissues compared with that of noncancerous tissues, and Dukes' A tumors exhibited the highest expression level. Conversely, cystatin C mRNA levels were similar in all samples, and tended to show an inverse correlation with the cathepsin B levels. In conclusion, cathepsin B expression by human colorectal cancers and surrounding noncancerous cell components may contribute to both local invasion at the early stage and remote metastasis without influence of cystatin C.
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PMID:Expression of cathepsin B and cystatin C in human colorectal cancer. 1037 77

Tumor cell invasion and metastasis are associated with degradation of components of the extracellular matrix by different proteinases. Among those, papain-like cysteine proteases, such as cathepsin B, seem to play an important role, as they are associated with poor clinical outcome in different cancers. In this study, we tested whether cystatin C, a natural extracellular inhibitor of papain-like cysteine proteases, can inhibit metastasis when overexpressed at the tumor-host interface. Local overexpression of cystatin C in liver and lungs of CD1 nu/nu mice was achieved by gene transfer with a novel adenoviral construct, which also led to the presence of 60 ng/mL of cystatin C in the serum. Three days after gene transfer, these mice were challenged by i.v. inoculation of lacZ-tagged human fibrosarcoma cells (HT1080lacZ-K15), leading to the formation of experimental lung and liver metastases. In this model, formation of experimental metastatic foci correlated with expression of cathepsin B in lungs, whereas there was no correlation with metastasis to the liver. In mice overexpressing cystatin C, the number of lung metastases was significantly reduced by 92%, as compared with mice receiving control adenovirus. The efficacy of extravasation of HT1080lacZ-K15 cells into the liver was not affected, indicating the independence of this process from the activity of cysteine-cathepsins. The present report is the first evidence of successful reduction of metastasis by inhibition of cysteine-cathepsins by cystatin C overexpression in the host microenvironment. Furthermore, organ-specific protease expression during tumor-host cell interactions could affect the success of antiproteolytic intervention against metastasis.
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PMID:Reduction of experimental human fibrosarcoma lung metastasis in mice by adenovirus-mediated cystatin C overexpression in the host. 1620 25

Formation of multiple and scattered metastases in target organs, leading to disruption of organ functional integrity, is the death-determining step for most lethal cancers. In the clinic, elevated expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) is often associated with increased aggressiveness of cancer. We demonstrated that elevated host expression of TIMP-1 leads to the promotion of scattered liver metastases in mice, associated with increased activity of cysteine proteases (CPs). This study aimed for reduction of TIMP-1-promoted experimental liver metastases of lacZ-tagged human fibrosarcoma cells by overexpression of cystatin C, a natural inhibitor of CPs, in the murine host. Although CP inhibition reduced TIMP-induced proteolytic activity, the TIMP-1-induced increase in total tumor cell burden in livers was not significantly reduced. However, overexpression of cystatin C in livers with elevated TIMP-1 led to the formation of large multicellular metastatic foci in 42% of the mice. This formation was associated with increased expression of plasminogen activators (PAs). Additional overexpression of plasminogen activator inhibitor-2 prevented the formation of macrometastatic foci as well as the TIMP-1-induced increase in total tumor cell burden. This demonstrates that PAs are crucial for the prometastatic activity of TIMP-1 and led to the assumption that patients with elevated TIMP-1 expression may benefit from an antiproteolytic treatment directed against PAs.
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PMID:Plasminogen activator inhibitor-2, but not cystatin C, inhibits the prometastatic activity of tissue inhibitor of metalloproteinases-1 in the liver. 1868 31