Pre‐operative serum level of tumour‐associated trypsin inhibitor and residual turnour size as prognostic indicators in Stage III epithelial ovarian cancer

Venesmaa, Pekka; Stenman, Ulf‐Hǎkan; Forss, M.; Leminen, Arto; Lehtovirta, Pentti; Vartiainen, Juhani

doi:10.1111/j.1471-0528.1998.tb10150.x

Cited by 31 publications

(28 citation statements)

References 15 publications

(20 reference statements)

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“…We have earlier shown that elevated preoperative serum TATI concentrations predict adverse prognosis in patients with stage III and IV epithelial ovarian cancer (3,31). The results of the present study confirm these findings, and they additionally show that immunohistochemical expression of TATI also is a strong prognostic factor independent of tumor stage, grade, and histological type.…”

Section: Discussionsupporting

confidence: 81%

“…The strong prognostic value of TATI expression in ovarian cancer tissue appears to explain our earlier findings showing that serum TATI predicts adverse survival in epithelial ovarian cancer (3,30,31). Serum TATI correlated with prognosis in advanced ovarian cancer also in this study, but an elevated serum concentration of trypsin-2-API was a prognostic factor both among all patients and those with advanced disease.…”

Section: Discussionsupporting

confidence: 39%

“…TATI is expressed together with trypsin in several tumors and cancer cell lines (29), and elevated serum concentrations are common in several malignant diseases (29). TATI is a useful serum marker for diagnosis of mucinous ovarian cancer and a prognostic factor for ovarian (30,31) and renal cell cancer (32).…”

Section: Introductionmentioning

confidence: 99%

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

Paju¹,

Vartiainen

Haglund

et al. 2004

Clinical Cancer Research

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Purpose:The purpose is to study the prognostic significance of tissue expression of trypsinogen-1, trypsinogen-2, and tumor-associated trypsin inhibitor (TATI) and serum concentration of trypsinogen-2, trypsin-2-API (complex of trypsin-2 with ␣-1-proteinase inhibitor), and TATI in epithelial ovarian cancer.Experimental Design: Expression of trypsinogen-1, trypsinogen-2, and TATI was determined by immunohistochemistry with monoclonal antibodies in tissue sections of tumors from 119 patients with untreated primary epithelial ovarian cancer. Preoperative serum concentrations of trypsinogen-2, trypsin-2-API and TATI were analyzed using specific immunoassays.Results: Fifty-four percent of the tumors expressed trypsinogen-1, 45% expressed trypsinogen-2, and 30% expressed TATI. In patients with stage III and IV disease, TATI tissue expression (P ‫؍‬ 0.002) and elevated TATI concentration in serum (P ‫؍‬ 0.048) were associated with adverse cancer-specific and progression-free survival in univariate analysis. In multivariate analysis, TATI tissue expression (P ‫؍‬ 0.005), tumor grade (P ‫؍‬ 0.0001), histological type (P ‫؍‬ 0.02), and stage (P ‫؍‬ 0.0005) were independent prognostic factors for adverse cancer-specific survival and TATI tissue expression (P ‫؍‬ 0.006) and grade (P ‫؍‬ 0.0003) for progression-free survival. In multivariate analysis of all patients and those with advanced disease, serum trypsin-2-API concentration was an adverse prognostic factor for cancer-specific and progression-free survival, and it was independent of stage and histological type of the tumor (P < 0.01).Conclusions: Tissue expression of TATI and an elevated preoperative serum concentration of trypsin-2-API are strong independent prognostic factors in advanced epithelial ovarian cancer. These results suggest that trypsin expression plays a role in the progression of ovarian cancer. TATI and trypsin-2-API are of potential use as an aid for stratification of randomized studies and for selecting treatment strategies.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 39%

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

Paju¹,

Vartiainen

Haglund

et al. 2004

Clinical Cancer Research

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“…Early studies showed that SPINK1 in urine is a promising marker for diagnosis of ovarian cancer (13,14 ). As a diagnostic marker for ovarian cancer, serum SPINK1 was shown to be inferior to cancer antigen 125 (CA125) but superior as a prognostic marker (15 ). CA125 is the most widely studied marker for ovarian cancer.…”

Section: Ovarian Cancermentioning

confidence: 99%

Emerging Roles of SPINK1 in Cancer

et al. 2016

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BACKGROUND Tumor-associated trypsin inhibitor (TATI) was originally isolated from the urine of a patient with ovarian cancer. It was later shown to be produced by many other tumors and several normal tissues. It had earlier been isolated from the pancreas and was hence called pancreatic secretory trypsin inhibitor (PSTI). It belongs to a family of protease inhibitors presently called serine peptidase inhibitor Kazal type (SPINK). In the SPINK family TATI/PSTI is SPINK1, which is the name used in this review. CONTENT In addition to being a protease inhibitor, SPINK1 also acts as an acute-phase reactant and a growth factor. Furthermore, it has been shown to modulate apoptosis. Overexpression of SPINK1 predicts an unfavorable outcome in several cancers and determination of SPINK1 in serum can be used to identify patients at increased risk of aggressive disease. Thus serum SPINK1 can be used as a prognostic tumor marker. Because SPINK1 acts as a growth factor and an inhibitor of apoptosis in some cancers, it has also been suggested that it can be a therapeutic target in cancer. However, because SPINK1 is the major physiological inhibitor of trypsin, inhibition of SPINK1 may increase the risk of pancreatitis. SUMMARY Taking into account the many functions of SPINK1, assessing the role of SPINK1 in cancer has several potentially important clinical applications ranging from a biomarker to a potential new target for cancer therapy.

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“…TATI is expressed together with trypsinogen by several tumours and cancer cell lines (Stenman et al, 1991). TATI in serum has been used as a tumour marker for mucinous ovarian cancer and it is a prognostic factor in stage III epithelial ovarian cancer (Venesmaa et al, 1998).…”

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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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Pre‐operative serum level of tumour‐associated trypsin inhibitor and residual turnour size as prognostic indicators in Stage III epithelial ovarian cancer

Cited by 31 publications

References 15 publications

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

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

Emerging Roles of SPINK1 in Cancer

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

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