Prognostic relevance of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitors PAI-1 and PAI-2 in gastric cancer

Ito, Hiroki; Yonemura, Yutaka; Fujita, Hideto; Tsuchihara, Katsuo; Kawamura, Taiichi; Nojima, N; Fujimura, Takashi; Nose, Haruhiko; Endo, Yuichi; Sasaki, Takuma

doi:10.1007/bf00199509

Cited by 39 publications

(31 citation statements)

References 48 publications

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“…23,24 PAI-2 immunoreactivity in the metastases of stage III and IV ovarian cancer was predictive of a prolonged disease-free and overall survival, 35 whereas PAI-2 immunoreactivity in tumor tissue of gastric cancer was not associated with prognosis. 36 Our finding in endometrial cancer is thus in agreement with reports in colorectal cancer and with some studies of ovarian cancer. In contrast, several studies in breast cancer have indicated that high tumor tissue concentrations of PAI-2 are associated with better prognosis.…”

Section: Discussionsupporting

confidence: 93%

High tumor tissue concentration of plasminogen activator inhibitor 2 (PAI‐2) is an independent marker for shorter progression‐free survival in patients with early stage endometrial cancer

Nordengren

Lidebring

Bendahl

et al. 2001

Intl Journal of Cancer

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Previous studies including various tumor types have shown different associations between tumor tissue levels of plasminogen activator inhibitor 2 (PAI-2) and patient survival. High tumor tissue concentrations of PAI-2 have been associated with good prognosis in patients with breast cancer, small cell lung cancer and ovarian cancer, but with poor histologic differentiation and poor prognosis in patients with colorectal cancer. On the other hand, high tumor tissue concentrations of urokinase plasminogen activator (uPA), uPA receptor (R) and PAI-1 have more consistently been associated with poor histologic differentiation and poor prognosis. Our study quantified PAI-2 and uPAR using specific enzyme-linked immunosorbent assays in homogenates of 274 samples of endometrial cancer tissue. The prognostic power of each factor was analyzed in the subgroup of patients with early stage disease, i.e., International Federation of Gynecology and Oncology (FIGO) surgical stage I-II (n ‫؍‬ 188). This group had a median follow-up time of 6.8 years (range 0.7-9.9), and 23 progressions were observed. The 80 th percentile for PAI-2 and uPAR was used to dichotomize the material, and the results were analyzed for associations with clinical data including progression-free survival. The results were also compared with DNA ploidy status, S-phase fraction, uPA and PAI-1, which we reported in a previous study (Fredstorp Lidebring et al., Eur J Cancer 2001; in press). A high PAI-2 level was associated with shorter progression-free survival in univariate analysis and was an independent prognostic factor in bivariate analyses, which included PAI-1, uPA and DNA ploidy status. In contrast, a high level of uPAR had no association with prognosis in early stage endometrial cancer. The combination of high PAI-2 and PAI-1 levels in tumors revealed a small group of stage I-II patients with an accumulative progression rate of 50%.

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Section: Discussionsupporting

confidence: 93%

High tumor tissue concentration of plasminogen activator inhibitor 2 (PAI‐2) is an independent marker for shorter progression‐free survival in patients with early stage endometrial cancer

Nordengren

Lidebring

Bendahl

et al. 2001

Intl Journal of Cancer

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“…Some reports have indicated that PAI-2 expression in gastric tumors was associated with decreased metastasis (15) and was significantly higher in patients without lymph node involvement (43). In contrast, other reports have indicated either that PAI-2 expression was not related to prognosis (16) or was an indicator of recurrence (17). The reasons for these differences have been uncertain, and we now suggest that they reflect the balance between the effects of secreted and intracellular PAI-2.…”

Section: Discussionmentioning

confidence: 56%

“…Previous studies have established that uPA and the inhibitors PAI-1 and PAI-2 are expressed in gastric adenocarcinoma (15)(16)(17). In the present study, we asked whether H. pylori infection was associated with changes in gastric PAI-2 expression.…”

Section: Introductionmentioning

confidence: 87%

Helicobacter pyloriInduces Plasminogen Activator Inhibitor 2 in Gastric Epithelial Cells through Nuclear Factor-κB and RhoA

Varró

Noble²,

Pritchard³

et al. 2004

Cancer Research

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The gastric pathogen Helicobacter pylori is associated with a progression to gastric cancer. The specific targets of H. pylori that might influence this progression are still unclear. Previous studies indicated that the gastric hormone gastrin, which may be increased in H. pylori infection, stimulates gastric expression of plasminogen activator inhibitor (PAI)-2, which is an inhibitor of the urokinase plasminogen activator and has previously been shown to be increased in gastric adenocarcinoma. Here, we report that H. pylori also increases PAI-2 expression. In gastric biopsies of H. pylori-positive subjects there was increased PAI-2, including subjects with plasma gastrin concentrations in the normal range. PAI-2 was expressed mainly in chief and mucous cells. In a gastric cancer cell line (AGS), H. pylori increased PAI-2 expression, which was associated with inhibition of H. pylori-stimulated cell invasion and apoptosis. The induction of PAI-2 by H. pylori was mediated by release of interleukin-8 and activation of cyclooxygenase-2, and interestingly, gastrin stimulated PAI-2 expression by similar paracrine pathways. The activation of NFB was required for interleukin-8 and cyclooxygenase-2 activation but did not occur in cells responding to these paracrine mediators. The data suggest that induction of PAI-2 is a specific target in H. pylori infection, mediated at least partly by paracrine factors; induction of PAI-2 inhibits cell invasion and apoptosis and is a candidate for influencing the progression to gastric cancer.

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“…Clinical results reveal that a lower level of SERPINB2 expression is associated with poor prognosis and outcome in gastric (8,9), breast (10) and lung cancers (11 to completely inhibit soluble and cell-surface bound plasminogen activator activity, resulting in the suppression of the metastasis of melanoma cells in SCID mice (12). SERPINB5 (MASPIN) has been well studied and was confirmed to be a tumor-suppressor gene, which suppresses tumor growth, invasion and metastasis in different types of cancers, and has potential therapeutic perspectives (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Suppression of the invasion and migration of cancer cells by SERPINB family genes and their derived peptides

et al. 2011

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Abstract.Apart from SERPINB2 and SERPINB5, the roles of the remaining 13 members of the human SERPINB family in cancer metastasis are still unknown. In the present study, we demonstrated that most of these genes are differentially expressed in tumor tissues compared to matched normal tissues from lung or breast cancer patients. Overexpression of each SERPINB gene effectively suppressed the invasiveness and motility of malignant cancer cells. Among all of the genes, the SERPINB1, SERPINB5 and SERPINB7 genes were more potent, and the inhibitory effect was further enhanced by co-expression of any two of them. In addition, single treatment of the synthetic peptides corresponding to the P5-P5' sequences of the reactive center loop (RCL) of SERPINB1, SERPINB5 or SERPINB7 markedly suppressed the invasive and migratory properties of the cancer cells in a dose-dependent manner. More significantly, combination treatment of these peptides in cancer cells further improved the suppressive effect by 20-40%. Here, we determined the expression of all SERPINB family members in lung and breast cancer patients, and identified those members with potent inhibitory ability toward invasion and migration, and designed RCL-derived peptides to suppress the malignancy of cancer cells. Forced re-expression of these anti-invasive SERPINB genes or application of the SERPINB RCL-peptides may provide a reasonable strategy against lethal cancer metastasis. IntroductionCancer metastasis is the leading cause of morbidity and mortality in cancer patients. It is a highly complex process, including cell detachment, migration, invasion, circulation in blood vessels, adhesion, colonization at other sites and formation of secondary tumors (1). Prior to tumor cell detachment from the primary site, which leads to cell migration and invasion in the metastasis process, the extracellular matrix (ECM) microenvironment must be degraded by proteases, such as urokinase plasminogen activator (uPA), uPA receptor (uPAR) and the plasmin network (2,3) and matrix metalloproteinases (MMPs) (4). On the other hand, protease inhibitors negatively regulate the proteolysis process in cancer metastasis, e.g. plasminogen activator inhibitors (PAIs), PAI-1 (SERPINE1) and PAI-2 (SERPINB2) against uPA/uPAR/plasmin network and the tissue inhibitor of matrix metalloproteinases (TIMPs), TIMP-1 to TIMP-4 against MMPs.Serine protease inhibitors (serpins) regulate many physiological processes, such as blood coagulation, fibrinolysis, inflammation, complement activation and cell migration (5). Based on their phylogenic relationships, the superfamily is divided into 16 different clades (A-P), in which human serpins are the first 9 clades (A-I) (6). The clade B serpins (SERPINB family) is the largest one within the human serpin superfamily. It contains 13 genes located on chromosome 6p25 (SERPINB1, SERPINB6 and SERPINB9) and 18q21 (the remaining members of the family). Unlike circulating serpins, the SERPINB family genes lack the N and C terminus extension regions common to other serpin...

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Prognostic relevance of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitors PAI-1 and PAI-2 in gastric cancer

Cited by 39 publications

References 48 publications

High tumor tissue concentration of plasminogen activator inhibitor 2 (PAI‐2) is an independent marker for shorter progression‐free survival in patients with early stage endometrial cancer

High tumor tissue concentration of plasminogen activator inhibitor 2 (PAI‐2) is an independent marker for shorter progression‐free survival in patients with early stage endometrial cancer

Helicobacter pyloriInduces Plasminogen Activator Inhibitor 2 in Gastric Epithelial Cells through Nuclear Factor-κB and RhoA

Suppression of the invasion and migration of cancer cells by SERPINB family genes and their derived peptides

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