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[Cancer Research 64, 3533-3537, May 15, 2004]
© 2004 American Association for Cancer Research

Regular Articles

Expression of Pigment Epithelium-Derived Factor Decreases Liver Metastasis and Correlates with Favorable Prognosis for Patients with Ductal Pancreatic Adenocarcinoma

Hirofumi Uehara1, Masaki Miyamoto1, Kentaro Kato1, Yuma Ebihara1, Hiroyuki Kaneko1, Hiroyuki Hashimoto1, Yoshihiro Murakami1, Ryunosuke Hase1, Ryo Takahashi1, Seiji Mega1, Toshiaki Shichinohe1, You Kawarada1, Tomoo Itoh2, Shunichi Okushiba1, Satoshi Kondo1 and Hiroyuki Katoh1

1 Department of Surgical Oncology, Division of Cancer Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, and 2 Department of Pathology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pigment epithelium-derived factor (PEDF) is expressed in several normal organs and identified as an inhibitor of neovascularization. In the present study, we screened the expression of PEDF immunohistochemically and investigated its correlation with clinicopathological features in patients who underwent surgery for ductal pancreatic adenocarcinoma. Of the 80 patients, 22 cases (27.5%) were positive for PEDF. A significant association was found between the PEDF expression and low microvessel density (P = 0.0003). No correlation was found between PEDF expression and age, gender, depth of invasion, tumor diameter, lymphatic invasion, venous, invasion or histopathological grading. The patients in pathological stage II had a significantly higher incidence of PEDF-positive expression than those in pathological stage III or IVA (P = 0.0418). PEDF immunoreactivity was inversely associated with liver metastasis (P = 0.0422). The survival of patients that were PEDF positive was significantly longer than that of those with negative expression (P = 0.0026). Multivariate analysis using the Cox regression model indicated that PEDF-positive expression was an independent favorable prognostic factor (risk ratio, 0.394; P = 0.0016). We conclude that PEDF expression suggests a more favorable prognosis than in patients whose carcinomas lack PEDF expression.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pancreatic cancer has a very poor prognosis and is one of the most common malignancies worldwide (1) . Tumor resection is performed in 9–36% of patients, and multivariate analyses have shown that curative resection is the clinical parameter related to favorable prognosis (2 , 3) . However, the 5-year survival rate of patients who have undergone resection is only 19–24% (4 , 5) . The prognosis of ductal pancreatic adenocarcinoma is correlated with the propensity of tumor cells to invade adjacent blood vessels and form hematogenous metastasis, as well as to infiltrate the surrounding anatomical structures in an early phase of the disease (6 , 7) .

Angiogenesis is essential for growth and nutrition of solid tumors (8) . Unorganized basement membrane of new capillary endothelial cells allows intravasation of tumor cells, and a high microvessel density (MVD) in tumors is associated with their expansion and invasiveness (9) . The tumor angiogenesis as reflected in the MVD has also been reported to have possible prognostic implications in a variety of tumors (9, 10, 11, 12, 13, 14, 15) . The liver is the most common and critical site of distant metastasis, which influences the prognosis of patients with ductal pancreatic carcinoma after resection (16) . There are still few clinical parameters that specifically predict liver metastasis. The identification of specific factors that regulate metastasis is of paramount importance for determining subgroups of high-risk patients after curative resection.

Pigment epithelium-derived factor (PEDF) was first identified in conditioned medium of cultured fetal retinal pigment epithelial cells (17) . PEDF is a Mr 50,000 secreted glycoprotein expressed in fetal and adult liver, adult testis, ovaries, placenta, brain, and pancreas (18) . PEDF resembles, in sequence and structure, members of the serine protease inhibitor (serpin) family but lacks protease inhibitor activity itself (19) . PEDF also inhibits endothelial cell migration and proliferation and has been shown to inhibit choroidal and retinal neovascularization (20, 21, 22, 23) . In an endothelial cell migration assay, PEDF was more potent than any of the other known inhibitors of angiogenesis, being more than twice as potent as angiostatin and more than seven times as potent as endostatin (20) .

Although it has been reported that PEDF is also expressed in normal pancreas cells (18) , the prognostic significance of its expression in pancreatic cancer has not been examined to date. To our knowledge, the current study is the first to investigate the expression of PEDF immunohistochemically in relation to the MVD, clinicopathological features, and survival in a large number of patients with ductal pancreatic adenocarcinoma.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Tissue Specimens.
Surgically resected specimens from 80 patients with ductal pancreatic adenocarcinomas were studied. All patients underwent surgical resection between 1992 and 1999 in the Second Department of Surgery at the Hokkaido University School of Medicine, Department of Surgery, Teinekeijinkai Hospital and Department of Surgery, Hokkaido Gastroenterology Hospital. Among the 80 patients with cancer, 61 patients underwent pancreaticoduodenectomy (Whipple operation), 14 patients underwent distal pancreatectomy, and 5 patients underwent total pancreatectomy, and all patients received extended radical lymphadenectomy. Of the 23 patients with positive portal vein invasion, 17 patients received portal vein resection. Pancreatic resection was not performed in patients presenting with distant site metastases. Any cases of mucinous cystadenocarcinoma or intraductal papillary-mucinous carcinoma were excluded from our study. None of these patients received either radiation or chemotherapy. Ductal pancreatic adenocarcinoma tissues were obtained from 45 men and 35 women with a mean age of 62 years (range, 31–83 years). Median duration of follow-up was 95.2 months (range, 50.0–141.7 months), and 71 patients (88.8%) died during the follow-up period. Sixty-five cases had recurrence and the types of recurrences were clarified in 48 of them. With regard the site of recurrence, hepatic metastasis occurred in 24 cases, peritoneal recurrence in 12 cases, local or lymph node recurrence in 10 cases, and there were other types of recurrence in 2 cases.

All specimens were fixed in 10% formalin and embedded in paraffin wax. Unstained 4-µm sections were then cut from paraffin blocks for immunohistochemical analysis. Histological classification of tumors was based on the WHO criteria. All tumors were staged according to the pathological Tumor-Node-Metastasis classification of the International Union against Cancer (24 , 25) . Seventeen of the tumors were classified as stage II, 37 as stage III, and 26 as stage IVA tumors. (Table 1)Citation .


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  		Table 1 Clinical characteristics of the patients with pancreatic adenocarcinoma

 
Determination of PEDF.
Immunohistochemical reactions were carried out using the streptavidin-biotin-peroxidase method. Each slide was deparaffined by xylene and rehydrated through a graded series of ethanol/water and treated with a pressure cooker for 10 min. The slides were immunostained using the Ventana ES automated immunohistochemistry system (Ventana Medical Systems Japan, Yokohama, Japan). The automated protocol is based on an indirect biotinavidin system and uses a universal biotinylated immunoglobulin secondary antibody and diaminobenzidine substrate and hematoxylin counterstain. Primary PEDF antibody (monoclonal mouse antihuman PEDF antibody; Chemicon International, Temecula, CA) was applied in a 1:200 dilution in PBS, and sections were incubated 32 min at 37°C. The anti-PEDF antibody was detected by adding biotinylated goat antimouse antibody, avidin-biotin complex, and 3,3'-diaminobenzidine (Ventana DAB Universal kit; Ventana-Bio Tek Solutions, Tucson, AZ). Sections then were counterstained in hematoxylin for 1 min and mounted in Permount (Microslides; Muto-Glass, Tokyo, Japan). As a positive control, the retinal pigment epithelial cells, which are known to react strongly to PEDF, were used. As negative controls, we used 10% normal mouse serum as the primary antibody.

Although qualitative differences in the staining intensity were observed, all positive cases showed strong unequivocal staining in the cytoplasm of some normal acinar cells, normal pancreas ductal cells and some ductal adenocarcinoma cells, at least focally.

In this study, we decided that the staining scores were categorized in only cancer cells as no staining, low staining (cytoplasmic staining in <10% of the cells), and high staining (cytoplasmic staining in >10% of the cells), respectively.

Patients were classified into two groups according to PEDF expression. High staining was classified as PEDF positive and the remainder as PEDF negative.

Microvessel Staining and Counting.
The staining process was similar to that used for PEDF. Intratumoral microvessels were detected using a monoclonal antibody against the CD34 antigen (monoclonal mouse antihuman CD34 antibody; Nitirei, Tokyo, Japan) was applied in a 1:100 dilution in PBS. After the area of highest neovascularization (hot spots) was located at a total magnification of x100 by light microscopy, the microvessel counts were determined at a total magnification of x200 using an eyepiece screen with an edge length of 10 mm/100 and an examination area of 0.785 mm2 (20) . In all samples, the mean value for the number of microvessels was calculated from four vascular hot spots. They were then assessed as the MVD for each case. Only the CD34 staining in the tumor area was reviewed, and any endothelial cell cluster consisting of two or more cells was considered to be a single, countable microvessel. Some immunopositive leukocytes were excluded on morphological grounds. All counts were performed by two independent observers without any knowledge of the corresponding clinicopathological data. Some cases that were differently interpreted by the two investigators were reexamined, and the larger count was selected.

Statistical Analysis.
The correlation of PEDF immunoreactivity with patients’ clinicopathological variables was analyzed by the {chi}2 test or Fisher’s exact test. The Kaplan-Meier method was used to estimate overall survival. Survival differences according to PEDF expression were analyzed by the log-rank test. The influence of variables on survival was assessed using Cox univariate and multivariate regression analysis. The risk ratio and its 95% confidence interval were recorded for each marker. Ps of <0.05 were considered statistically significant in all of the analyses. All analyses were performed with statistical software (StatView version 5.0; SAS Institute, Inc., Cary, NC).


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Immunohistochemical Pattern of PEDF Expression in Normal Tissue and Carcinoma.
PEDF was detected in the cytoplasm of some normal acinar and ductal cells (Fig. 1A)Citation . In normal tissues, >10% of acinar cells in 53 of 80 cases (66.3%) and >10% of normal ductal cells in 29 of 80 cases (36.3%) had PEDF reactivity. In this study, we decided that the staining scores were categorized in only cancer cells. Among 80 ductal pancreatic adenocarcinoma specimens, 22 cases (27.5%) were classified as high staining for PEDF (Fig. 1B)Citation , 6 cases (7.5%) were low staining, and 52 cases (65.0%) were no staining (Fig. 1C)Citation . In our procedure, high staining was classified as PEDF positive (n = 22) and the remainder as PEDF negative (n = 58). PEDF positives were found in 8 of 17 cases (47.0%) of stage II, 8 of 37 (21.6%) of stage III, and 6 of 26 (23.1%) of stage IVA.



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  		Fig. 1. Pigment epithelium-derived factor was detected in the cytoplasm of some normal acinar (yellow arrows) and ductal cells (blue arrows; A), ductal adenocarcinoma cells in a positive specimen (B), and pigment epithelium-derived factor in a negative specimen (C). Immunohistochemical staining of anti-CD34 antibody. Endothelial cells of blood vessels (red arrows) show a strong immunoreaction. A tumor area with high vessel density is demonstrated (D).

 
MVD.
CD34 antigen was located in the cytoplasm and cellular membrane of vascular endothelial cells (x200) in the representative field of ductal pancreatic adenocarcinoma. The MVD ranged from 5 to 59, with a mean of 27.7 (Fig. 1D)Citation .

Correlation between the PEDF Expression and MVD.
A significant association was found between the PEDF expression and MVD by the Mann-Whitney U test (P = 0.0003; Fig. 2Citation ). The median value of MVD in PEDF-positive specimens was 19.3, and PEDF-negative specimens was 31.1.



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  		Fig. 2. Correlation between pigment epithelium-derived factor (PEDF) expression and microvessel density (MVD). A significant association was found between them (P = 0.0003). The median value of MVD in a PEDF-negative specimen was 31.1 and a PEDF-positive specimen was 19.3.

 
Correlations between PEDF Expression and Various Clinicopathological Features.
Correlations between PEDF expression and various clinicopathological features are summarized in Table 2Citation . No significant correlation was found between PEDF expression and age, gender, depth of invasion, tumor diameter, surgical margin, lymphatic invasion, venous invasion, or histopathological grading. PEDF expression, however, demonstrates a close association with the pathological Tumor-Node-Metastasis stage. The patients in stage II had a significantly higher incidence (8 of 17, 47.1%) of PEDF-positive expression than those (14 of 63, 22.2%) in stage III or IVA (P = 0.0418). Concerning liver metastasis, the patients with pancreatic cancers that were PEDF positive had a significantly lower incidence (3 of 17, 17.6%) of liver metastasis than those (21 of 46, 45.6%) that were PEDF negative (P = 0.0422).


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  		Table 2 Association between pigment epithelium-derived factor expression and clinicopathological variables

 
Kaplan-Meier Survival Analysis.
Survival curves constructed according to the Kaplan-Meier method are shown in (Fig. 3, A and B)Citation . In 80 patients with ductal pancreatic adenocarcinoma, the survival rates for the patients that were PEDF positive were significantly higher than those who were PEDF negative (log-rank test, P = 0.0026; Fig. 3ACitation ). In cases with stage III and IVA disease (n = 63), the survival rates for patients with PEDF-positive expression were significantly higher than those that were PEDF negative (log-rank test, P = 0.0107; Fig. 3BCitation ).



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  		Fig. 3. Kaplan-Meier analysis for overall survival according to pigment epithelium-derived factor (PEDF) expression in patients with ductal pancreatic adenocarcinoma (log-rank test, P = 0.0026; A). Kaplan-Meier analysis in patients with stage III and IV patients (log-rank test, P = 0.0107; B).

 
Univariate and Multivariate Analyses of PEDF Expression and Clinicopathological Variables.
Univariate analysis for overall survival using Cox regression analysis identified PEDF-positive expression (P = 0.0034), lymph node metastasis (P = 0.0003), tumor diameter (P = 0.0131), and venous invasion (P = 0.0059) as significant prognostic predictors. Age, gender, depth of invasion, lymphatic invasion, and histopathological grading had no prognostic value. Multivariate analysis of the same set of patients was performed for PEDF expression and pathological predictors for survival time using the Cox regression model. The results indicated that PEDF-positive expression was an independent favorable prognostic factor (risk ratio, 0.394; P = 0.0016). Positive lymph node metastasis (risk ratio, 2.553; P = 0.0017), positive venous invasion (risk ratio, 1.801; P = 0.0212), and tumor diameter (risk ratio, 1.704; P = 0.0414) also had an independent prognostic value (Table 3)Citation .


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  		Table 3 Prognostic factors in Cox proportional hazards model

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Angiogenesis is the complex biological process involved in the development and formation of new blood vessels, which is known to play a critical role in tumor growth and metastasis (26) . To accommodate their continued proliferation, primary tumors release angiogenic factors, including vascular endothelial growth factor, platelet-derived growth factor, and acidic-/basic-fibroblast growth factors. In contrast, tumors also produce angiogenic inhibitors, including angiostatin, thrombospondin, and endostatin (27, 28, 29) . In this study for PEDF, we found that 35% (28 of 80 cases) of ductal pancreatic adenocarcinoma showed positive staining by immunohistochemically. These results indicate that angiogenesis is regulated by a net balance between these positive and negative factors of angiogenesis produced by tumors and other cells.

Interestingly, in PEDF-deficient mice, stromal vessels were increased and associated with epithelial cell hyperplasia in pancreas (30) . Then, PEDF was identified as a key inhibitor of stromal vasculature and epithelial tissue growth in mouse prostate and pancreas. In the in vivo gene transfer model of PEDF, the ability of PEDF gene transfer to inhibit angiogenesis was evaluated by immunohistochemical analysis of MVD. With this model, MVD was significantly less dense in tumors treated with PEDF when compared with controls (31 , 32) . In the present study, PEDF expression significantly correlates with the MVD, pathological stage, liver metastasis, and prognosis of patients. Our findings in this study are understandable based on previous reports in which the extent of tumor angiogenesis has been implicated as a critical factor in determining metastatic potential (33) . In solid tumors such as breast cancer (8 , 9) , non-small cell lung cancer (10) , ovarian carcinoma (11) , malignant melanoma (12) , nasopharyngeal carcinoma (13) , gastric carcinoma (14) , and pancreas carcinoma (15) , the high MVD is a predictor of increased risk of metastasis and of shorter survival. We carried out this investigation to confirm whether or not the PEDF expression in pancreatic tumor tissue may lead to a low MVD, which correlates with liver metastasis and the prognosis. In our study, staining of PEDF significantly correlated with MVD and liver metastasis. As it is known that vascular endothelial growth factor expression is closely correlated with MVD and liver metastasis in ductal pancreatic adenocarcinoma (15) , these results may indicate that liver metastasis and MVD are regulated by a net balance between PEDF and vascular endothelial growth factor.

Initially, patients were classified by staining grade into three groups: no staining; low staining; and high staining. Subsequently, survival curves of these three groups were assessed. The survival rate for the high staining group was better than the low staining and the no staining group (log-rank test, P = 0.0056; figure not shown), and the survival rate for the PEDF low staining group was as poor as that for the PEDF no staining group (log-rank test, P = 0.3463; figure not shown). These data suggest that low staining group should belong to negative group.

In conclusion, we have demonstrated that PEDF expression is associated with increased risk of hepatic metastasis and short survival.


   ACKNOWLEDGMENTS
 
We thank Hiraku Shida, Rika Osanai, and Jun Moriya for immunohistochemical technical support. We also thank the many physicians, especially Drs. Nobuichi Kasimura (Teinekeijinkai Hospital) and Takayuki Morita (Hokkaido Gastroenterology Hospital), who cared for these patients at the affiliated hospitals’ Department of Surgical Oncology.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Hirofumi Uehara, Department of Surgical Oncology, Division of Cancer Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, Hokkaido, 060-8638 Japan. Phone: 81-11-706-7714; Fax: 011-81-11-706-7158; E-mail: h-uehara{at}qd5.so-net.ne.jp

Received 11/30/03. Revised 3/ 9/04. Accepted 3/15/04.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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S. Halin, P. Wikstrom, S. H. Rudolfsson, P. Stattin, J. A. Doll, S. E. Crawford, and A. Bergh
Decreased Pigment Epithelium-Derived Factor Is Associated with Metastatic Phenotype in Human and Rat Prostate Tumors
Cancer Res., August 15, 2004; 64(16): 5664 - 5671.
[Abstract] [Full Text] [PDF]

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