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Japanese Journal of Clinical Oncology Pages 187-191

Immunohistochemical Analysis of PAI-2 (Plasminogen Activator Inhibitor Type 2) and p53 Protein in Early Gastric Cancer Patients with Recurrence: a Preliminary Report
Introduction
Patients and Methods
   Clinicopathological Study
   Immunohistochemical Staining
   Statistical Analysis
Results
   Clinicopathological Study
   Immunohistochemical Staining
Discussion
References
Immunohistochemical Analysis of PAI-2 (Plasminogen Activator Inhibitor Type 2) and p53 Protein in Early Gastric Cancer Patients with Recurrence: a Preliminary Report

Immunohistochemical Analysis of PAI-2 (Plasminogen Activator Inhibitor Type 2) and p53 Protein in Early Gastric Cancer Patients with Recurrence: a Preliminary Report

Makoto Kammori1, Michio Kaminishi1, Kaoru Kobayashi1, Takeshi Oohara1, Hisako Endo1, Kaiyo Takubo3 and Hajime Hashimoto4

1Department of Surgery, The University of Tokyo Branch Hospital, Tokyo, 2Department of Pathology, The University of Tokyo Branch Hospital, Tokyo, 3Department of Clinical Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo and 4Department of Surgery, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan

Background: High levels of urokinase-type plasminogen activator (u-PA) weredemonstrated in gastric carcinomas along with inhibitors of plasminogen activators (PAI-1 and PAI-2). They may influence the ability to invade and metastasize and therefore be of importance to the risk of recurrence of stomach neoplasms after curative operation. This also appears to be the case for p53 mutations and p53 protein overexpression.
Methods: Six patients, all differentiated cancer cases who developed recurrent disease 5-10 years after curative operations for early gastric cancers (recurrence group), were studied in comparison with 49 patients who had no recurrence more than 10 years after similar surgery (control group). The expression of u-PA, PAI-1, PAI-2 and p53 was compared immunohistochemically in the recurrence and control groups.
Results: The expression of PAI-2 was significantly more frequent in the recurrence group, being found in five (83.3%) patients vs eight (16.3%) in the control group. p53 was expressed in five (83.3%) patients in the recurrence group and in 15 (30.6%) in the control group; the rate was again significantly higher in the former.
Conclusion: The results suggest that PAI-2 and p53 expressed in differentiated early gastric cancers are possible indices of the risk of recurrence.

Key words: early gastric cancer - urokinase-type plasminogen activator - plasminogen activator inhibitor types 1 and 2 - p53 protein

INTRODUCTION

Plasminogen activators (PAs), serine proteases which degrade fibrin via the activation of plasmin, are divided into two types, tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) (1). It has been reported that adenocarcinomas of the large intestine, breast, lung and stomach have high u-PA activity, especially in association with highly invasive lesions or concomitant metastasis to lymph nodes or the liver (2-5). There are also two types of PA inhibitor, i.e. plasminogen activator inhibitor type 1 (PAI-1) and plasminogen activator inhibitor type 2 (PAI-2), reported to exert inhibitory effects on the growth and metastasis of cancers (6). In the present study we concentrated attention on the relevance of the PAs to gastric cancer recurrences. In the General Rules for Japanese Classification of Gastric Carcinoma (2nd English Edition) prescribed by the Japanese Research Society for Gastric Cancer, surgery involving dissection of regional lymph nodes of a greater group number than the actual positive regional lymph nodes dissected is defined as an absolute curative operation (7,8). Although early gastric cancer treated by an absolute curative operation has an excellent prognosis, there are some rare cases of recurrence. To cast light on the predictive potential of u-PA, PAI-1 and PAI-2 levels in the original tumors, we compared series of cases with and without recurrent disease 5-10 years after absolute curative operations for early gastric cancers. In addition, since p53 overexpression is associated with a poor prognosis in stomach cancer cases (7,8), this parameter was also investigated.

Table 1. Clincopathological data for the recurrence group
Case Gender Macroscopic type Histopathological type Tumor size (mm) Recurrence
Site Interval (years)
1 M IIc + III Tub1 22 × 3 Peritoneum* 7
2 M IIc Tub2 15 × 8 Liver[dagger] 10
3 M IIc Tub1 4 × 8 Peritoneum* 8
4 M IIc Tub2 65 × 65 Lung[dagger] 6
5 M IIa Tub1 20 × 18 Peritoneum* 6
6 M IIc + III Tub1 28 × 40 Peritoneum* 5
Tub1, well differentiated tubular adenocarcinoma. Tub2, moderately-differentiated tubular adenocarcinoma. *Carcinomatosa. [dagger]Metastasis.

Table 2. Clincopathological characteristics of the primary tumors in the recurrence and control groups
  Recurrence (n = 6) Control (n = 49)
Gender (male; female) 6; 0 23; 26
Average age (yr) (mean ± SD) 69 ± 6.54 70.9 ± 7.28
Cancer location
   C 0 (0%) 2 (4.1%)
   M 3 (50%) 23 (46.9%)
   A 3 (50%) 24 (49.0%)
Size (mm) (mean ± SD) 30 ± 30.5 31.4 ± 12.2
Stage of lymph node metastasis
   n0 4 (66.7%) 35 (71.4%)
   n1 1 (16.7%) 12 (24.5%)
   n2 1 (16.7%) 2 (4.1%)
Histological classification
   Papillary differentiated 0 (0%) 5 (10.2%)
   Well differentiated 4 (66.7%) 33 (67.3%)
   Moderately differentiated 2 (33.3%) 11 (22.5%)
Depth of invasion
   m 2 (33.3%) 17 (35.7%)
   sm 4 (66.7%) 32 (65.3%)
Lymphatic invasion
   ly0 2 (33.3%) 15 (30.6%)
   ly1 3 (50%) 30 (61.2%)
   ly2 1 (16.7%) 4 (8.2%)
Venous invasion
   v0 6 (100%) 47 (95.9%)
   v1 0 (0%) 2 (4.1%)
According to the Japanese Classification of Gastric Carcinoma (8). Recurrence: patients with recurrence of early gastric cancer 5-10 years after surgery. Control: patients with early gastric cancer who survived more than 10 years without recurrence.

PATIENTS AND METHODS

Of 298 patients with early gastric cancer who underwent absolute curative surgery at our Department between January 1980 and December 1990, six (2.01%) had recurrent early gastric cancer 5-10 years after surgery (recurrence group) (Table 1).

Clinicopathological Study

The six patients were studied clinicopathologically according to the General Rules for Japanese Classification of Gastric Carcinoma (2nd English Edition) (8). All six patients were men ranging in age from 60 to 80 years, with a mean age of 69 ± 6.54 years.

As a control, we selected 49 from the 90 patients who had no recurrence for more than 10 years after the same operation performed at our hospital during the same period. These 49 were obtained as the 8-times matched pair of the following clinicopathological features in the six recurrent cases: age at the operation, gender, macroscopic and histological types, depth of invasion, tumor size and location, stage of lymph node metastasis and the degree of permeation to the vessel (Table 2).

Immunohistochemical Staining

All resected specimens were fixed in 10% formalin (pH 7.0), embedded in paraffin and cut into 4 µm sections for staining immunohistochemically with the avidin-biotin complex (ABC) method. To block non-specific binding they were reacted with normal serum (mouse IgG) for 5 min at room temperature. Subsequently, the tissue sections were exposed in a refrigerator overnight to 1/100 dilutions of MUK-4, MAI-21 and MAI-11 (all from Biopool, CA, Sweden) as primary mouse monoclonal antibodies to human agonist u-PA, PAI-2 and PAI-1, respectively. An antibody agonist p53 protein, PAb1801, was used. PAb1801(Oncogene Science, Manhasset, NY), is mouse monoclonal antibody agonist human p53, recognizing a denaturation-resistant epitope between amino acids 32 and 79 and has been shown to recognize both the wild-type and mutant forms of p53 protein. They were then reacted with biotinylated anti-mouse antibody for 10 min and with ABC for another 10 min, with intervening washes. Diaminobenzidine (DAB) was used for color development and Mayer's hematoxylin technique for nuclear staining. To examine the specificity of immunostaining, the primary antibodies were replaced by mouse normal IgG at a 1:100 dilution in Tris-buffered saline. Control slides were invariably negative for immunostaining. To confirm constant immunohistochemical findings, control slides of a positive gastric carcinoma were stained at the same time. Cases with stained cancer cells accounting for [ge]30% of the whole cancer area were defined as positive and those with values <30% as negative.

Statistical Analysis

The significance of differences were analyzed by the Mann-Whitney test and Wilcoxon's rank sum test with P < 0.05 considered significant.

RESULTS

Clinicopathological Study

In the recurrence group, the macroscopic classification was depressed-type lesions in five patients and the protruded type in one (Table1). The depth of invasion was judged to be m (mucosa) in two patients and sm (submucosa) in four. The mode of recurrence was peritoneal dissemination in four patients, liver metastasis in one and lung metastasis in one. All lesions were histologically classified as differentiated adenocarcinomas, comprising four well differentiated and two moderately differentiated adenocarcinomas. Metastasis to group 1 lymph nodes was found in one patient and to group 2 lymph nodes in another, while the other four patients were negative for lymph node metastasis.

Immunohistochemical Staining

Expression of u-PA, PAI-1 and PAI-2


Figure 1. Immunohistochemical staining of u-PA in a well differentiated adenocarcinoma in a recurrence case (×400). High-level immunoreactivity. More than 30% of cells show cytoplasm staining.

The high immunoreactivity of u-PA was demonstrated in the cytoplasm, and also the plasma membrane, of cancer cells especially in the advancing fronts of invading gastric cancers. u-PA was positive in four (66.7%) cases in the recurrence group and in 33 (67.3%) in the control group, with no significant difference between the two. In normal tissue, binding was found in some vascular endothelial cells and fibroblast-like interstitial cells and sometimes foveolar epithelial cells (Fig. 1). Immunoreactivity for PAI-1 was found in the cytoplasm and plasma membrane of cancer cells, again particularly in the advancing fronts. In normal tissue, binding could be demonstrated in some vascular endothelial cells (Fig. 2). There were four (66.7%) lesions positive for PAI-1 in the recurrence group, while 31 of the control group cancers demonstrated binding (63.3%). PAI-2 demonstrated a granular appearance in the cytoplasm of cancer cells in the advancing fronts. It was found in the Golgi fields of some pyloric glands and in the intestinal metaplastic epithelium in background tissue. PAI-2 was positive in five (83.3%) cases in the recurrence group and in eight (16.3%) in the control group, with a statistically significant difference (P < 0.05) (Fig. 3).


Figure 2. Immunohistochemical staining of PAI-1 in a moderately differentiated adenocarcinoma in a recurrence case (×400). High-level immunoreactivity. More than 30% of cells show cytoplasm staining.


Figure 3. Immunohistochemical staining of PAI-2 in a well differentiated adenocarcinoma in a recurrence case (×400). High-level immunoreactivity. More than 30% of cells show cytoplasm and plasma membrane staining.


Figure 4. p53 expression inan early gastric cancer in a recurrence case (×400). High-level immunoreactivity. More than 30% of cells show intense nuclear staining.

Expression of p53 Protein

Immunoreactivity indicative of p53 protein overexpression was found in the nuclei of gastric cancer cells, but not in the cytoplasm or plasma membranes (Fig. 4). Five cases were positive in p53 staining in the recurrence group (83.3%), whereas 6 cases in the control group (31.6%); the positive rate was significantly higher in the former (p < 0.05) (Fig. 5). In the p53-positive tumors in the recurrence group, the positive areas accounted for 50% or more of the total cancer areas.


Figure 5. A statistically significant difference (P < 0.05) between the recurrence group and the control group was shown in PAI-2 and p53 staining; not shown in u-PA and PAI-1 staining.

DISCUSSION

In the present study, the first author had transferred from the University of Tokyo Branch Hospital to Tokyo Metropolitan Geriatric Hospital, but we selected the control group from the patients in the former hospital. It is now coming to be recognized that the early gastric cancer was operated on with good curability. For such patients operated on for early gastric cancer, there seems to be little difference between our hospital and others. It is generally inferred that u-PA secreted from tumor cells of the large intestine, breast, lung and stomach is intimately involved in their invasion and metastasis, by contributing to proteolysis of the extracellular matrix and basement membrane through activation of plasmin and type IC collagenase (9-13). Although much remains to be clarified regarding the role of u-PA in cancer invasion and metastasis, it has been speculated that u-PA receptors are expressed on the surfaces of cancer cells and this causes secreted u-PA to collect where it can promote invasion (14-16). In a study on the relationship between the expression of u-PA in colorectal cancer cells and interstitial cells, Mulcahy et al. (17) found that the expression of u-PA in cancer cells alone was related to recurrence.

With regard to the relationship between gastric cancer and the expression of u-PA, Katai et al. (18) reported that the intensity of staining for u-PA was significantly higher in intestinal-type than in diffuse-type adenocarcinomas. Wang et al. (5) also stated that the expression of u-PA was frequent among gastric cancer patients with lymph node metastasis. In the present study, the u-PA positive rate was high in both the recurrence group (four cases, 66.7%) and the control group (33 cases, 67.3%), with no significant inter-group difference. In addition, no definite relationship with lymph node metastasis was found. However, since the study included only six patients with recurrence, all of whom had differentiated adenocarcinoma, they might not have represented a complete view.

PAI-1, the main inhibitor of plasminogen activator, is present in the blood of healthy humans (6). In the present study, there was no significant difference in PAI-1 expression between the recurrence group and the control group cases. According to Ganesh et al. (19), the activity of PAI-1 is higher in metastatic foci in the liver than in primary colorectal cancer. The recurrence site was only detected by computed tomography.

Unlike PAI-1, PAI-2 is virtually absent in the blood of healthy humans. However, evidence of its secretion from some cancer cells has suggested that it plays some role in their growth, invasion and metastasis (11,12,20). However, there are two conflicting views; one is that PAI-2 inhibits u-PA to interfere with invasion and metastasis of cancer (20) and the other is that PAI-2 exerts a promoting effect on such invasion and metastasis (11,12). The present study, with expression of PAI-2 more frequent in the recurrence group, provided support for the latter. In the recurrence group, three (50%) patients were positive for both u-PA and PAI-2, two (33.3%) were negative for u-PA and positive for PAI-2 and one (16.75%) was positive for u-PA and negative for PAI-2, providing no evidence of an inhibitory effect of PAI-2 on the expression of u-PA.

It has been reported that there is a correlation between the expression of p53 protein and biological malignancy of cancers of the breast, large intestine, urinary bladder and head and neck (25-33). The positive rate of p53 protein is reportedly 40-60% in patients with gastric cancer (23) and its potential as a prognostic factor has been stressed (28,29). In our study, the expression of p53 protein was significantly more frequent in the recurrence group (five cases, 83.3%) than in the control group (15 cases, 30.6%) (P < 0.05).

The results suggest that PAI-2 and/or p53 expressed in primary differentiated early gastric cancers are possible indices of the risk of recurrence.

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Received September 24, 1998; accepted January 21, 1999
For reprints and all correspondence: Makoto Kammori, The University of Tokyo Branch Hospital. 3-28-6, Mejirodai, Bunkyoku, Tokyo 112-8688, Japan. E-mail: kammori-dis@h.u-tokyo.ac.jp

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