Expression of tumor-associated trypsinogens (TAT-1 and TAT-2) in prostate cancer

Department of Urology, Malmö University Hospital, Lund University, Malmö, Sweden.
The Prostate (Impact Factor: 3.57). 06/2005; 64(1):29-39. DOI: 10.1002/pros.20236
Source: PubMed


Trypsinogens are pancreatic serine proteinases and expressed in several cancers as tumor-associated trypsinogens (TAT). Trypsin mediates activation of pro-uPA and pro-MMPs, thus promoting angiogenesis and tumor invasion. Recently, we described expression of TAT in the human male genital tract and now we studied TAT in relation to PSA in PCa.
TAT expression was studied by immunohistochemistry, in situ hybridization, RT-PCR, DNA-sequencing and IFMA. LNCaP cells were used to study secretion of TAT and PSA after androgen stimulation.
Immunoreactive TAT was localized in all prostatic tumors (n = 109), lymph node (n = 16), and bone metastases (n = 17). Immunostaining intensity increased with higher Gleason's grade, whereas PSA immunostaining decreased significantly. PSA and TAT were not identically distributed in benign and malignant cells. Androgen stimulation of LNCaP cells decreased secretion of TAT and increased that of PSA. TAT mRNA was demonstrated in tissue sections and identified as TAT-1 and -2 by RT-PCR and DNA-sequencing.
Expression of TAT is better preserved than PSA in high-grade PCa. Expression of TAT and PSA is regulated by different mechanisms as demonstrated in tissue sections and in vitro. Locally produced TAT may act in a paracrine mode to promote angiogenesis and tumor invasion in PCa by both activating and degrading of other proteinases. Further studies on the role of TAT in invasive PCa and on the mechanisms involved in the regulation of TAT expression are warranted.

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    • "as pseudotrypsin is theoretically capable of cleaving at position Cys49–Gly50 of NDRG1. In fact, since tumour-associated trypsinogens are present in the DU145, PC3 and LNCaP prostate cancer cell lines [39], it is plausible that pseudotrypsin could cleave off NDRG1. Tumour-associated trypsin is expressed in a multitude of human cancers [40–44]. "
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    Bioscience Reports 05/2013; 33(3). DOI:10.1042/BSR20130042 · 2.64 Impact Factor
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    • "Lastly, the antiproteinase mediator pancreatic secretory trypsin inhibitor (PSTI) protects from premature activity. An imbalance in this ‘proteinase–antiproteinase-system’ plays a pathophysiological role in the development of pancreatitis and seems to present an increased risk for developing pancreatic adenocarcinoma (29–31) PSTI is excreted by the mucosa of the normal gastrointestinal tract, where it serves to protect the cells from proteolytic breakdown. The same peptide is secreted by tumour cells, and is often referred to as ‘tumour associated trypsin inhibitor’ (TATI), which is identical to PSTI. "
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    Gastroenterology and hepatology from bed to bench 03/2011; 444(2):43-5243.
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    • "SPINK1 levels are strongly elevated during inflammation and pancreatitis (Paju and Stenman, 2006). Like the pancreas, the prostate gland also secretes a variety of serine proteases, most notably the kallikrein enzyme prostate specific antigen (PSA), but also trypsin, the expression of which is increased in prostate cancer (Bjartell et al., 2005). Thus, SPINK1 outlier expression may have a role in modulating the activity of cancer-related proteases. "
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    ABSTRACT: ETS gene fusions have been characterized in a majority of prostate cancers; however, the key molecular alterations in ETS-negative cancers are unclear. Here we used an outlier meta-analysis (meta-COPA) to identify SPINK1 outlier expression exclusively in a subset of ETS rearrangement-negative cancers ( approximately 10% of total cases). We validated the mutual exclusivity of SPINK1 expression and ETS fusion status, demonstrated that SPINK1 outlier expression can be detected noninvasively in urine, and observed that SPINK1 outlier expression is an independent predictor of biochemical recurrence after resection. We identified the aggressive 22RV1 cell line as a SPINK1 outlier expression model and demonstrate that SPINK1 knockdown in 22RV1 attenuates invasion, suggesting a functional role in ETS rearrangement-negative prostate cancers.
    Cancer cell 07/2008; 13(6):519-28. DOI:10.1016/j.ccr.2008.04.016 · 23.52 Impact Factor
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