Trypsinogen expression in human ovarian carcinomas

Hirahara, Fumiki; Miyagi, Yohei; Miyagi, Etsuko; Yasumitsu, Hidetaro; Koshikawa, Naohiko; Nagashima, Yoji; Kitamura, Hitoshi; Minaguchi, Hiroshi; Umeda, Makoto; Miyazaki, Kaoru

doi:10.1002/ijc.2910630205

Intl Journal of Cancer

1995

DOI: 10.1002/ijc.2910630205

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Trypsinogen expression in human ovarian carcinomas

Fumiki Hirahara

Yohei Miyagi

Etsuko Miyagi

et al.

Abstract: Increased secretion of matrix metalloproteinases and serine proteinases is well known to be associated with cancer invasion and metastasis. We aimed to elucidate the implication of trypsin, a serine proteinase and a representative digestive enzyme in invasion and metastasis of human carcinomas. Northern blot, RT-PCR and Western blot analyses and immunohistochemical studies were performed to detect and analyze trypsinogen expression in 5 ovarian carcinoma cell lines and 10 human ovarian carcinoma tissues using … Show more

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Cited by 65 publications

(40 citation statements)

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“…This may be related to the poorer prognosis of serous than mucinous ovarian carcinomas at an early stage of the disease (Vergote et al, 1993). By immunohistochemistry, we detected trypsinogen-2 and TATI in the secretory epithelium of ovarian carcinomas as has been earlier described (Ueda et al, 1989;Hirahara et al, 1995). Trypsinogen-2 and TATI immunoreactivity was detected more frequently in mucinous than in serous tumours and in agreement with this, the trypsinogen and TATI concentrations were found to be significantly higher in mucinous than in serous cyst fluids.…”

supporting

confidence: 85%

“…Two variants of the trypsinogen isoenzymes trypsinogen-1 (cationic) and trypsinogen-2 (anionic), called tumour-associated trypsinogen-1 and -2, have been shown to occur in ovarian tumour cyst fluid (Koivunen et al, 1989). Recently, extrapancreatic expression of trypsinogen has been observed in several human malignancies such as ovarian (Koivunen et al, 1989;Hirahara et al, 1995) and gastric cancer (Fujimura et al, 1998) and in cholangiocarcinoma (Terada et al, 1995). Several tumour cell lines also express trypsinogen (Koivunen et al, 1991b;Koshikawa et al, 1994).…”

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confidence: 99%

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The levels of trypsinogen isoenzymes in ovarian tumour cyst fluids are associated with promatrix metalloproteinase-9 but not promatrix metalloproteinase-2 activation

et al. 2001

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Summary Proteolysis mediated by matrix metalloproteinases (MMPs) and serine proteinases is associated with cancer invasion and metastasis. Activation of latent proMMPs, and especially the proforms of the type IV collagen degrading gelatinases A and B (proMMP-2 and proMMP-9), is thought to be a critical step in this process. We have recently found that human tumour-associated trypsin-2 is a potent activator of proMMP-9 and it also activates proMMP-2 in vitro. Trypsinogen, MMP-2, and MMP-9 are expressed in ovarian cancer. To elucidate the function of trypsin in vivo, we studied whether high concentrations of trypsinogen-1, trypsinogen-2, their α 1 -proteinase inhibitor (API) complexes, and tumour-associated trypsin inhibitor (TATI) are associated with proMMP-2 and proMMP-9 activation in ovarian tumour cyst fluids. Zymography and immunofluorometric analysis of 61 cyst fluids showed a significant association between high trypsin concentrations and the activation of MMP-9 (P = 0.003-0.05). In contrast, the trypsin concentrations were inversely associated with the activation of MMP-2 (P = 0.01-0.02). Immunohistochemical analysis of ovarian tumour tissue demonstrated expression of trypsinogen-2 and TATI in the secretory epithelium. MMP-2 was detected both in stromal and epithelial cells whereas MMP-9 was detected in neutrophils and macrophage-like cells in stromal and epithelial areas. These results suggest that trypsin may play a role in the regulation of the MMP-dependent proteolysis associated with invasion and metastasis of ovarian cancer. 1363-1371 © 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2001.1806, available online at http://www.idealibrary.com on http://www.bjcancer.com aminoterminal domain for the expression of activity (Tryggvason et al, 1987). The urokinase type plasminogen activator (uPA) -plasmin system (Mazzieri et al, 1997) and membrane type MMP-1 (MT1-MMP, MMP-14) (Sato et al, 1994;Tokuraku et al, 1995) have been suggested to represent physiological mechanisms for the control of MMP-2 and MMP-9 activity. Recent studies have shown that human trypsin-2 is more potent than plasmin and other serine proteinases in activating several MMPs, including MMP-2 and MMP-9 (Sorsa et al, 1997), and that downregulation of trypsin-2 expression and activity in colon cancer cells is associated with decreased proMMP-9 activation (Lukkonen et al, 2000).In the present study we investigated the involvement of trypsin in the activation of MMP-2 and MMP-9 in vivo by studying whether the concentrations of trypsins, trypsin-API-complexes, and TATI are associated with activation of proMMP-2 and proMMP-9 in ovarian tumour cyst fluid. Furthermore, we studied the immunohistochemical expression and localization of trypsinogen-2, TATI, MMP-2, and MMP-9 in ovarian tumours. MATERIALS AND METHODS Clinical specimensCyst fluid samples (n = 61) were obtained from 58 patients (age range 13-79 years) undergoing surgery for removal of the tumour during 1986-1998 at Helsinki University Central Hospital. Of the tumours, 41 were benign...

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supporting

confidence: 85%

mentioning

confidence: 99%

The levels of trypsinogen isoenzymes in ovarian tumour cyst fluids are associated with promatrix metalloproteinase-9 but not promatrix metalloproteinase-2 activation

et al. 2001

View full text Add to dashboard Cite

show abstract

“…Extra-pancreatic production of trypsin was shown in ovarian (Hirahara et al, 1995), lung (Kawano et al, 1997), gastric and colonic tumours (Bernard-Perrone et al, 1998;Miyata et al, 1999); 2. The trypsinogen gene is significantly expressed in vascular endothelial cells around gastric tumours ; 3.…”

mentioning

confidence: 99%

Initiation of human colon cancer cell proliferation by trypsin acting at protease-activated receptor-2

et al. 2001

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SummaryThe protease-activated receptor-2 (PAR-2) is a G protein-coupled receptor that is cleaved and activated by trypsin. We investigated the expression of PAR-2 and the role of trypsin in cell proliferation in human colon cancer cell lines. A total of 10 cell lines were tested for expression of PAR-2 mRNA by Northern blot and RT-PCR. PAR-2 protein was detected by immunofluorescence. Trypsin and the peptide agonist SLIGKV (AP2) were tested for their ability to induce calcium mobilization and to promote cell proliferation on serum-deprived cells. PAR-2 mRNA was detected by Northern blot analysis in 6 out of 10 cell lines Cl.19A, SW480,. Other cell lines expressed low levels of transcripts, which were detected only by RT-PCR. Further results were obtained with HT-29 cells: (1) PAR-2 protein is expressed at the cell surface; (2) an increase in intracellular calcium concentration was observed upon trypsin (1-100 nM) or AP2 (10-100 µM) challenges; (3) cells grown in serum-deprived media supplemented with trypsin (0.1-1 nM) or AP2 (1-300 µM) exhibited important mitogenic responses (3-fold increase of cell number). Proliferative effects of trypsin or AP2 were also observed in other cell lines expressing PAR-2. These data show that subnanomolar concentrations of trypsin, acting at PAR-2, promoted the proliferation of human colon cancer cells. The results of this study indicate that trypsin could be considered as a growth factor and unravel a new mechanism whereby serine proteases control colon tumours.

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“…24 Trypsin can stimulate fibroblasts to secrete procollagen, stimulate mast cells to degranulate, and is secreted by numerous tumor cell lines that are correlated with the stage and histological type of carcinoma. 4,[25][26][27] Some of the actions of trypsin are mediated by a second protease-activated receptor known as PAR-2. 8,28 -30 PAR-2 has been described in human tissues and tumor cell lines 20,29 -33 as well as in human mast cells.…”

mentioning

confidence: 99%

Differential Expression of Protease-Activated Receptors-1 and -2 in Stromal Fibroblasts of Normal, Benign, and Malignant Human Tissues

D’Andrea¹,

Derian²,

Santulli³

et al. 2001

The American Journal of Pathology

131

102

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The serine proteases thrombin and trypsin are among many factors that malignant cells secrete into the extracellular space to mediate metastatic processes such as cellular invasion, extracellular matrix degradation, angiogenesis, and tissue remodeling. Malignant cells solicit the help of other cell types, such as stromal fibroblasts, mast cells, monocytes, and vascular cells, to facilitate their invasion into the surrounding tissue 1 because unrestrained growth of the tumor, by itself, does not result in invasion and metastasis. 2 The interface between the invading malignant cells and the hosting stromal cells, referred to as the tumor microenvironment (TME), 3 possesses a vast array of well-orchestrated cell signaling molecules which function to facilitate the ability of the proliferating tumor front to invade the stroma, as well as to degrade and remodel the extracellular matrix. 1 Of the many factors secreted by tumor cells, the two proteolytic enzymes, thrombin and trypsin, have been correlated to the stage and type of carcinoma and are associated with cell invasion and extracellular matrix degradation. 4,5 Furthermore, the ratio of proteases to their inhibitors in the TME can favor capillary sprout elongation and lumen formation during angiogenesis. 2 Thrombin is known to influence the behavior of all of the cells identified within the TME. For instance, thrombin activates platelets to adhere to other cells or extracellular matrix, increases vascular permeability and expression of adhesion molecules, attracts monocytes, stimulates mitogenic activity of endothelial cells and fibroblasts, and degranulates mast cells. 6 -9 Thrombin also influences the rate of deposition of connective tissue proteins and the development of tissue fibrosis during normal wound healing; a process similar to cellular metastasis. 10,11 Many of thrombin's effects are mediated through the seven transmembrane G-protein coupled receptors, protease-activated receptor (PAR)-1, via proteolytic cleavage of the amino-terminal extension unveiling a new amino terminus that activates the receptor through a tethered peptide ligand mechanism. 12 In vitro studies have demonstrated increased tumor cell adhesion to endothelium, extracellular matrix and platelets, enhanced metastatic capacity of tumor cells, and activated cell growth and stimulation of angiogenesis in response to thrombin and PAR-1 agonist peptides. 13-18 PAR-1 has been localized in smooth muscle cells, 19 pancreas tumor cells, 20 -21 carcinoma and melanoma cell lines 16 and recently in human mast cells. 22 In breast carcinoma cells, the level of PAR-1 expression has been correlated to the degree of invasiveness. 23 Furthermore, B16F10 melanoma cells, transfected with PAR-1, enhanced thrombin-treated tumor cell adhesion to fibronectin 2.5-fold in vitro and pulmonary metastasis as high as 39-fold in vivo compared to the control thrombin-treated tumor cells. 24 Trypsin can stimulate fibroblasts to secrete procollagen, stimulate mast cells to degranulate, and is secreted

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Trypsinogen expression in human ovarian carcinomas

Cited by 65 publications

References 25 publications

The levels of trypsinogen isoenzymes in ovarian tumour cyst fluids are associated with promatrix metalloproteinase-9 but not promatrix metalloproteinase-2 activation

The levels of trypsinogen isoenzymes in ovarian tumour cyst fluids are associated with promatrix metalloproteinase-9 but not promatrix metalloproteinase-2 activation

Initiation of human colon cancer cell proliferation by trypsin acting at protease-activated receptor-2

Differential Expression of Protease-Activated Receptors-1 and -2 in Stromal Fibroblasts of Normal, Benign, and Malignant Human Tissues

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