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      Effects of radiation therapy on tissue and serum concentrations of tumour associated trypsin inhibitor and their prognostic significance in rectal cancer patients

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          Abstract

          Background

          We have previously demonstrated that elevated concentrations of tumour-associated trypsin inhibitor (TATI) in both tumour tissue (t-TATI) and in serum (s-TATI) are associated with a poor prognosis in colorectal cancer patients. It was also found that s-TATI concentrations were lower in patients with rectal cancer compared to patients with colon cancer. In this study, we investigated the effects of neoadjuvant radiotherapy (RT) on concentrations of t-TATI and s-TATI in patients with rectal cancer.

          Methods

          TATI was analysed in serum, normal mucosa and tumour tissue collected at various time points in 53 rectal cancer patients enrolled in a case-control study where 12 patients received surgery alone, 20 patients 5 × 5 Gy (short-term) preoperative RT and 21 patients 25 × 2 Gy (long-term) preoperative RT. T-TATI was analysed by immunohistochemistry and s-TATI was determined by an immunofluorometric assay. Mann-Whitney U test and Wilcoxon Z (Z) test were used to assess t-TATI and s-TATI concentrations in relation to RT. Spearman's correlation (R) test was used to explore the associations between t-TATI, s-TATI and clinicopathological parameters. Overall survival (OS) according to high and low t-TATI and s-TATI concentrations was estimated by classification and regression tree analysis, Kaplan-Meier analysis and the log rank test.

          Results

          RT did not affect concentrations of t-TATI or s-TATI. In patients receiving short-term but not long-term RT, s-TATI concentrations were significantly higher 4 weeks post surgery than in serum drawn prior to surgery (Z = -3.366, P < 0.001). T-TATI expression correlated with male gender (R = 0.406, P = 0.008). High t-TATI expression in surgical specimens was associated with a significantly shorter OS (P = 0.045). S-TATI concentrations in serum drawn at all time points were associated with an impaired OS (P = 0.035 before RT, P = 0.001 prior to surgery, P = 0.043 post surgery). At all time points, s-TATI correlated with higher age (P < 0.001-0.021) and with increased s-creatinine concentrations assessed prior to surgery (P = 0.041).

          Conclusions

          The results presented here further validate the utility of t-TATI and s-TATI as prognostic biomarkers in patients with rectal cancer, independent of neoadjuvant RT.

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          Most cited references14

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          Association of trypsin expression with tumour progression and matrilysin expression in human colorectal cancer.

          Overexpression of the matrix serine protease (MSP) trypsin has been implicated in tumour growth, invasion, and metastasis. The objective of this study was to clarify the clinicopathological and prognostic significance of trypsin expression in colorectal cancer. This study analysed the association between immunohistochemically detected trypsin expression in colorectal cancer and clinicopathological characteristics, and investigated whether trypsin is a predictor of recurrence and/or survival. Trypsin immunoreactivity was more intense at the invasive front than in the superficial part of the tumour. Sections with immunostaining signals in more than 30% of carcinoma cells at the invasive front, which were observed in 48 cases (48%), were judged to be positive for trypsin. Trypsin positivity was significantly correlated with depth of invasion, lymphatic and venous invasion, lymph node and distant metastasis, advanced pathological tumour-node-metastasis (TNM) stage, and recurrence. Patients with trypsin-positive carcinoma had significantly shorter overall and disease-free survival periods than did those with trypsin-negative carcinoma. Trypsin retained its significant predictive value for overall and disease-free survival in multivariate analysis that included conventional clinicopathological factors. It is well known that trypsin activates matrilysin (matrix metalloproteinase-7), which plays an important role in colorectal cancer progression. Patients with concordant overexpression of trypsin and matrilysin at the invasive front, in which they were often co-localized, had the worst prognosis. Trypsinogen-1-transfected HCT116 colon cancer cells showed not only trypsin activity, but also active matrilysin activity and were more invasive in vitro than mock-transfected HCT116 cells. These results suggest that trypsin plays a key role in the progression of colorectal cancer. Detection of trypsin expression as well as matrilysin is useful for the prediction of recurrence in and poor prognosis of colorectal cancer patients. Copyright 2003 John Wiley & Sons, Ltd.
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            High expression of tumour-associated trypsin inhibitor correlates with liver metastasis and poor prognosis in colorectal cancer

            Increased expression of tumour-associated trypsin inhibitor (TATI) in tumour tissue and/or serum has been associated with poor survival in various cancer forms. Moreover, a proinvasive function of TATI has been shown in colon cancer cell lines. In this study, we have examined the prognostic significance of tumour-specific TATI expression in colorectal cancer, assessed by immunohistochemistry (IHC) on tissue microarrays (TMAs) with tumour specimens from two independent patient cohorts. Kaplan–Meier analysis and Cox proportional hazards modelling were used to estimate time to recurrence, disease-free survival and overall survival. In both cohorts, a high (>50% of tumour cells) TATI expression was an independent predictor of a significantly shorter overall survival. In cohort II, in multivariate analysis including age, gender, disease stage, differentiation grade, vascular invasion and carcinoembryonal antigen (CEA), high TATI expression was associated with a significantly decreased overall survival (HR=1.82; 95% CI=1.19–2.79) and disease-free survival (HR=1.56; 95% CI=1.05–2.32) in curatively treated patients. Moreover, there was an increased risk for liver metastasis in both cohorts that remained significant in multivariate analysis in cohort II (HR=2.85; 95% CI=1.43–5.66). In conclusion, high TATI expression is associated with liver metastasis and is an independent predictor of poor prognosis in patients with colorectal cancer.
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              Autocrine induction of invasion and metastasis by tumor-associated trypsin inhibitor in human colon cancer cells.

              From the conditioned medium of the human colon carcinoma cells, HT-29 5M21 (CM-5M21), expressing a spontaneous invasive phenotype, tumor-associated trypsin inhibitor (TATI) was identified and characterized by proteomics, cDNA microarray approaches and functional analyses. Both CM-5M21 and recombinant TATI, but not the K18Y-TATI mutant at the protease inhibitor site, trigger collagen type I invasion by several human adenoma and carcinoma cells of the colon and breast, through phosphoinositide-3-kinase, protein kinase C and Rho-GTPases/Rho kinase-dependent pathways. Conversely, the proinvasive action of TATI in parental HT29 cells was alleviated by the TATI antibody PSKAN2 and the K18Y-TATI mutant. Stable expression of K18Y-TATI in HT-29 5M21 cells downregulated tumor growth, angiogenesis and the expression of several metastasis-related genes, including CSPG4 (13.8-fold), BMP-7 (9.7-fold), the BMP antagonist CHORDIN (5.2-fold), IGFBP-2 and IGF2 (9.6- and 4.6-fold). Accordingly, ectopic expression of KY-TATI inhibited the development of lung metastases from HT-29 5M21 tumor xenografts in immunodeficient mice. These findings identify TATI as an autocrine transforming factor potentially involved in early and late events of colon cancer progression, including local invasion of the primary tumor and its metastatic spread. Targeting TATI, its molecular partners and effectors may bring novel therapeutic applications for high-grade human solid tumors in the digestive and urogenital systems.
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                Author and article information

                Journal
                Radiat Oncol
                Radiation Oncology (London, England)
                BioMed Central
                1748-717X
                2011
                24 August 2011
                : 6
                : 100
                Affiliations
                [1 ]Department of Clinical Sciences, Division of Pathology, Lund University, Skåne University Hospital, Lund, Sweden
                [2 ]Department of Clinical Sciences, Division of Colorectal Surgery, Lund University, Skåne University Hospital, Malmö, Sweden
                [3 ]Department of Clinical Chemistry, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
                [4 ]Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, Skåne University Hospital, Malmö, Sweden
                [5 ]Department of Clinical Sciences, Division of Urological Cancers, Lund University, Skåne University Hospital, Malmö, Sweden
                Article
                1748-717X-6-100
                10.1186/1748-717X-6-100
                3173337
                21864386
                4c419598-1d77-433f-90e6-2f2cd2897b53
                Copyright ©2011 Gaber et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 3 May 2011
                : 24 August 2011
                Categories
                Research

                Oncology & Radiotherapy
                biomarker,prognosis,rectal cancer,tissue micro array,tati,radio therapy
                Oncology & Radiotherapy
                biomarker, prognosis, rectal cancer, tissue micro array, tati, radio therapy

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