Pancreatic trypsinogen and cathepsin B in human pancreatic carcinomas and associated metastatic lesions

Abstract

Summary Expression of pancreatic trypsinogen and cathepsin B in 23 surgically resected pancreatic ductal adenocarcinomas was evaluated immunohistochemically, using a monoclonal antibody against human pancreatic trypsinogen and a polyclonal antibody against human cathepsin B. Fifteen of 20 invasive tubular adenocarcinomas (75%) expressed pancreatic trypsinogen in a coarse granular pattern located in the supranuclear cytoplasm of the carcinoma cells. In addition, metastatic lesions, including those in peripancreatic lymph nodes and neural plexuses, expressed pancreatic trypsinogen. In contrast, three intraductal (noninvasive) papillary adenocarcinomas did not express pancreatic trypsinogen. Cathepsin B expression was recognised in 14 of 20 invasive tubular adenocarcinomas (70%) in a fine granular pattern located diffusely in the cytoplasm of the carcinoma cells, while none of the three intraductal papillary adenocarcinomas had detectable cathepsin B. These findings suggest that pancreatic invasive ductal adenocarcinomas express pancreatic trypsinogen and cathepsin B immunoreactive peptides, raising the possibility that pancreatic trypsinogen and cathepsin B may act independently of each other in the process of carcinoma invasion and metastasis, like other different classes of proteases involved in the proteolytic modification of the matrix barrier.Pancreatic trypsinogen is one of the proteolytic enzymes produced by pancreatic acinar cells. A recent study (Miszczuk-Jamska et al., 1991) has shown that a new human pancreatic adenocarcinoma cell line (CFPAC-1) and a previously established human pancreatic carcinoma cell line (CAPAN-1) produce human pancreatic trypsinogen. This enzyme is a target protease for pancreatic secretory trypsin inhibitor (PSTI). Tumour-associated trypsinogen is also known to be a serine protease produced by malignant tumour cells, and is believed to play an essential role in cancer invasion and metastasis by degrading trypsin-sensitive extracellular matrix components (Tryggvason et al., 1987;Koivunen et al., 1991a). Tumour-associated trypsinogen has been identified as a target protease for a tumour-associated trypsin inhibitor (TATI), also referred to as PSTI (Huhtala et al., 1982;Halila et al., 1988;Stenman et al., 1988). A recent study (Koivunen et al., 1989) has shown that tumourassociated trypsinogen and pancreatic trypsinogen are similar with respect to amino-terminal sequence, molecular weight and immunoreactivity, but that significant differences exist with respect to isoelectrophoretic mobility and stability. Therefore, it is possible that pancreatic trypsinogen may also take part in the protease cascade associated with tumour invasion and metastasis. It is currently not known whether the differences between tumour-associated trypsinogen and pancreatic trypsinogen are a result of tissue-specific trypsinogen modification or distinct genes.We have therefore evaluated the presence or absence of pancreatic trypsinogen immunohistochemically in 23 surgically resected pancreatic ductal adeno...

Expression of Trypsinogen-1, Trypsinogen-2, and Tumor-Associated Trypsin Inhibitor in Ovarian Cancer

“…It degrades a wide spectrum of extracellular matrix proteins (12) and activates proforms of other proteinases, including MMPs 1, 2, 8, 9, and 13 (13)(14)(15)(16). Tumor-associated trypsinogen-1 and trypsinogen-2 are strongly expressed in most ovarian cancers (17)(18)(19) and in several other cancers, e.g., pancreatic (20), gastric (21,22) and colorectal cancer (23,24), cholangiocarcinoma (25), and in esophageal squamous cell carcinoma (26). In ovarian cancer, expression of trypsinogen is associated with tumor aggressiveness (17,19), and in esophageal squamous cell carcinoma, it is strongly associated with recurrence and poor prognosis (26).…”

Identification of pancreatic juice proteins as biomarkers of pancreatic cancer

“…PRSS2 may play a key role in tumor invasion by degrading a wide spectrum of extracellular matrix proteins (14) and activating other proteinases, including MMPs 1, 2, 8, 9 and 13 (15,16). PRSS2 has been reported to be highly expressed in several cancers, e.g., pancreatic (17), gastric (18), colorectal cancer (19), cholangiocarcinoma (20) and esophageal squamous cell carcinoma (21). The serum concentration of the inactive PRSS2 preproprotein was significantly higher in ovarian cancer patients with high stage compared to those with a low stage (22).…”

Risk Factors for Pancreatic Cancer: Underlying Mechanisms and Potential Targets

“…Metastatic peripancreatic neural plexuses and lymph nodes also stained intensely positive for trypsinogen. In addition, they stained positive for cathepsin B, but only weak to moderate (Ohta et al, 1994). In a more recent paper it has been shown that knockout of cathepsin B is associated with slowed PDAC progression, extended survival and decreased liver metastasis in a mouse model (Gopinathan et al, 2012).…”