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Clinical Cancer Research Vol. 12, 117-122, January 2006
© 2006 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

Expression of Hepatoma-Derived Growth Factor Is Correlated with Lymph Node Metastasis and Prognosis of Gastric Carcinoma

Shinji Yamamoto1, Yasuhiko Tomita2, Yoshihiko Hoshida2, Shuji Takiguchi1, Yoshiyuki Fujiwara1, Takushi Yasuda1, Yuichiro Doki1, Kenya Yoshida3, Katsuyuki Aozasa2, Hideji Nakamura4 and Morito Monden1

Authors' Affiliations: Department of 1 Surgery and Clinical Oncology, 2 Pathology, and 3 Molecular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, and 4 Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan

Requests for reprints: Shinji Yamamoto, Department of Surgery and Clinical Oncology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-3251; Fax: 81-6-6879-3259; E-mail: shinjiyamamoto2005{at}yahoo.co.jp.


   Abstract
Top
 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Purpose: Hepatoma-derived growth factor (HDGF) is a unique nuclear/growth factor and might play an important role in the development and progression of carcinomas. In the present study, association of HDGF expression with recurrence and prognosis of gastric carcinoma was examined.

Patients and Methods: HDGF expression in 317 patients with gastric carcinoma (233 males and 84 females) with ages ranging from 26 to 81 years (median, 60 years) was analyzed by immunohistochemistry. Samples with >90% of tumor cells to express positive immunoreactivity similar to or stronger than that in endothelial cells both for nucleus and cytoplasm were regarded as HDGF index level 2, and others as HDGF index level 1.

Results: One hundred and eighty-two cases showed level 1 HDGF expression, whereas 135 cases showed level 2 HDGF expression. Patients with level 2 expression showed higher rates of proximal tumor location (P < 0.0001), large tumor size (P < 0.0001), infiltrative tumor growth (P < 0.0001), presence of vascular and lymphatic invasion (P < 0.0001 for both), presence of lymph node metastasis (P < 0.0001), deep tumor invasion (P < 0.0001), and poorer disease-free and overall survival (P < 0.0001 for both) compared to those with level 1 expression. Multivariate analysis revealed HDGF expression level as an independent prognosticator for disease-free and overall survival.

Conclusion: HDGF expression level was shown to be a prognostic factor for gastric carcinoma.

Gastric carcinoma is one of the main causes of cancer death worldwide, especially in East and Southeast Asia, including Japan (1, 2). The annual incidence rate of gastric carcinoma is ~40 per 100,000 population and its mortality is ranked second as a cause of cancer death in Japan (2) in spite of the recent advances in diagnostic techniques for early detection of the disease, and in spite of the progress in surgical procedures.

To date, a number of clinicopathologic characteristics such as depth of tumor invasion and lymph node metastasis have been identified to be prognosticators for recurrence and survival of patients with gastric carcinoma (3). The tumor-node-metastasis (TNM) staging system, which is composed of tumor invasion, lymph node metastasis, and distant metastasis, is regarded as the most important in predicting tumor recurrence and prognosis after potentially curative resection of gastric carcinoma (4). Although the prognoses for patients, even those with advanced disease (stages II and III), is heterogeneous, therefore, a strategy to establish appropriate therapeutic modalities for each patient is not formulated as yet.

Hepatoma-derived growth factor (HDGF) was one of the heparin-binding growth factors. It was originally purified from the conditioned medium of human hepatocellular carcinoma cell line HuH-7 that proliferates autonomously in a serum-free chemically defined medium (5, 6). HDGF is also highly expressed in several fetal tissues and may be involved in the development of organs such as lung, muscle, vessels, kidney, and liver (7–11). HDGF has a mitogenic function for various cells such as human hepatocellular carcinoma cells, fibroblasts, endothelial cells, vascular smooth muscle cells, and fetal hepatocytes (8, 9, 11–13). HDGF translocates to the nucleus and its nuclear targeting stimulates cell growth (8, 14). Following these reports, our hypothesis was that HDGF expression in human malignant tumors might also have an important functional role in the formation of metastasis and might consequently influence the prognosis of patients. In fact, there have been several reports showing the correlation of increased HDGF expression and poor prognosis in cancers (15–17). However, there have been no reports evaluating the correlation of HDGF expression with clinicopathologic features and prognosis in gastric carcinomas.

In the present study, the expression levels of HDGF in 317 patients with gastric carcinoma undergoing surgery, and the relation between the HDGF expression and clinicopathologic features and prognosis were analyzed.


   Patients and Methods
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 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Tissue specimens. Tumor tissue was collected from 317 patients with gastric carcinoma who underwent curative surgical resection between December 1993 and April 1999 at the Gastroenterological Surgery Division, Osaka University Hospital, Osaka, Japan. There were 233 male and 84 female patients with ages ranging from 26 to 81 years (median, 60 years). Informed consent for the use of the specimens were obtained from all the patients. The surgical procedures done included total gastrectomy in 96 patients, proximal gastrectomy in 23 patients, distal gastrectomy in 197 patients, and partial gastrectomy in 1 patient. The resected stomach was macroscopically examined to determine the location and size of the tumor. Location of tumors was as follows: upper-third in 85, middle third in 126, and lower-third in 109. The size of the main tumor ranged from 2 to 185 mm (mean, 43.8 mm). Samples obtained from the gastric lesions and dissected lymph nodes were fixed in 10% formalin and routinely processed for paraffin-embedding. Histologic sections cut at 4 µm were stained with H&E and immunoperoxidase procedures (avidin-biotin complex method). Histologic sections were reviewed by one of the authors (Y. Hoshida) to define the extent and mode of cancer invasion in the stomach, lymph node metastasis, and histologic subtype of gastric carcinoma based on the criteria of the Japanese Research Society for Gastric Cancer (18). Tumor stages were classified according to the pTNM classification (4).

After surgery, all patients received laboratory examination such as routine peripheral blood cell counts and serum carcinoembryonic antigen level at 1- to 6-month intervals, chest roentgenogram, ultrasonography of liver, computerized tomographic scan of abdomen, and endoscopic examination of the rest stomach at 6- to 12-month intervals. Adjuvant chemotherapy was done in 48 patients (preoperative in 9, during operation in 1, postoperative in 28, both pre- and postoperative in 5, and both during operation and postoperative period in 5) with high risk for tumor recurrence, i.e., presence of lymph node metastasis, huge size (diameter >10 cm) of the tumor, and tumor invasion to the serosa. Chemotherapeutic protocols were as follows: fluorouracil (5-FU) or its derivative alone in 7 patients; cisplatinum (CDDP) or its derivative alone in 4 patients; 5-FU and CDDP in 15 patients; 5-FU and mitomycin C (MMC) in 1 patient; CDDP and MMC in 1 patient; 5-FU, CDDP, and MMC in 2 patients; 5-FU, CDDP, and doxorubicin or its analogues in 2 patients; 5-FU, CDDP, and methotrexate in 4 patients; 5-FU, CDDP, doxorubicin, and MMC in 5 patients; 5-FU, CDDP, methotrexate, and epirubicin in 4 patients; 5-FU, CDDP, MMC, and epirubicin in 1 patient; and 5-FU, CDDP, doxorubicin, MMC, and epirubicin in 2 patients. Follow-up period for survivors ranged from 1 to 96 months (median, 52.0 months).

Immunohistochemical assays. Immunohistochemical studies were done by the avidin-biotin-peroxidase complex method. Antigen retrieval was done with heating the sections in 10 mmol/L citrate buffer for 5 minutes. In the primary antibody reaction step, the slides were incubated with the rabbit polyclonal antibody against COOH-terminal amino acids (amino acids 231-240) of the human HDGF sequence was used as the primary antibody at a dilution of 1:5,000. This specific anti-HDGF antibody was purified by COOH-terminal peptide-conjugated Sepharose column (11, 19). Nonimmunized rabbit IgG (Vector Labs, Burlingame, CA) was used as a substitute for the primary antibody to verify the possibility of false-positive responses from nonspecific binding of IgG or from the secondary antibody. Counterstaining was done with methyl green.

Specimen classification based on immunohistochemical results. All immunohistochemically stained sections were examined in a blinded manner without any knowledge of the clinicopathologic variables and patients' outcome. Staining in endothelial cells in the noncancerous areas in each specimen was used as an internal positive control. Constant HDGF expression in the endothelial cells has been reported (10). The HDGF expression pattern was independently evaluated for the nucleus and cytoplasm; cells showing staining intensity similar to or stronger than that in endothelial cells in the nucleus or cytoplasm were regarded as nucleus-positive or cytoplasm-positive, respectively. Samples with >90% of tumor cells to express positive immunoreactivity both for nucleus and cytoplasm were regarded as HDGF index level 2, and others as HDGF index level 1.

Statistical analysis. SAS software (Statistical Analysis System Institute, Cary, NC) was used for all statistical analyses. The {chi}2 test and Fisher's exact probability test were used to examine the relationship between HDGF expression and clinicopathologic variables of prognosis. The cumulative survival rate was calculated by the Kaplan-Meier method and statistical significance was examined by the log-rank test (20). Multivariate analysis of factors related to survival were analyzed by the Cox's proportional hazards regression model (21). Statistical significance was identified as P < 0.05.


   Results
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 Abstract
 Patients and Methods
 Results
Discussion
 References
 
Histologic findings. Histologically, 65 tumors were well-differentiated and 79 moderately differentiated adenocarcinomas, 2 papillary carcinomas, and 1 medullary carcinoma. They were categorized as differentiated carcinomas. The remaining were 125 cases with poorly differentiated adenocarcinomas, 37 with signet ring cell carcinomas, and 8 with mucinous carcinomas that were categorized as having undifferentiated carcinomas. Tumor cells invaded the mucosa or submucosa (pT1) in 165 patients, muscularis propria or subserosa (pT2) in 97, serosa (pT3) in 43, and adjacent organs (pT4) in 12. Two to 101 (median, 23) lymph nodes per patient were analyzed for the presence or absence of lymph node metastasis. Two hundred and six patients were node-negative (pN0), 65 had 1 to 6 positive nodes (pN1), 29 had 7 to 15 positive nodes (pN2), and 17 had >15 positive nodes (pN3).

Patients' outcome. Five-year disease-free and overall survival rate was 76.3% and 77.3%, respectively. Sixty-five patients died due to tumors and 72 showed tumor recurrence in the peritoneum in 37, lymph node in 24, liver in 12, and other organs in 5. Tumor recurrence in 12 patients was determined at the time of the patients' death. In the remaining 53 patients, tumor recurrence was detected from 12 days to 4 years (median, 133 days) before the patients' death.

Expression of HDGF in gastric carcinoma. HDGF expression was observed mainly in the nucleus in nonneoplastic gastric mucosa, where negative to faint immunostaining in the cytoplasm was observed. On the contrary, the staining pattern in the gastric carcinoma was diverse. One hundred and ninety-four cases (61.2%) showed strong staining in the nucleus of tumor cells in >90% of tumor cells, and were thus regarded as nucleus-positive, 188 cases (59.3%) with strong cytoplasmic staining in >90% of tumor cells were cytoplasm-positive. Among them, 138 cases (43.5%) indicating both nucleus- and cytoplasm-positivity, were regarded as HDGF index level 2. The remaining 179 cases (56.5%) were regarded as HDGF index level 1 (Fig. 1).



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  		Fig. 1. A and B, HDGF level 1 gastric carcinoma with well-differentiated subtype. Tumor cells exhibited weak HDGF staining both in the nucleus and cytoplasm. C and D, HDGF level 2 gastric carcinoma with well-differentiated subtype. Tumor cells exhibited strong HDGF staining both in the nucleus and cytoplasm (magnification, x50). E, endothelial cells exhibit HDGF-staining both in the nucleus and cytoplasm (magnification, x150).

 
The relationship between clinicopathologic features and HDGF expression in gastric carcinoma. Association between HDGF expression and clinical factors is listed in Table 1. In comparison to gastric carcinoma with HDGF index level 1, level 2 gastric carcinomas showed higher rates in the following categories: proximal location (16.5% in level 1, and 40.7% in level 2), large size (diameter >50 mm) (26.4% in level 1, and 54.1% in level 2), infiltrative growth (23.6% in level 1, 52.6% in level 2), presence of vascular invasion (15.4% in level 1, and 43.0% in level 2), presence of lymphatic invasion (37.9% in level 1, and 83.7% in level 2), presence of lymph node metastasis (17.5% in level 1, and 58.5% in level 2), and deep invasion (pT2-4 in 26.9% of level 1, and 76.3% in level 2).


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  		Table 1. Correlation between HDGF expression and clinicopathologic factors of 317 patients with gastric carcinoma

 
Univariate and multivariate analysis for prognosis of patients with gastric carcinoma. Patients with HDGF index level 1 gastric carcinoma showed better 5-year survival rates than those with level 2 gastric carcinoma (disease-free, 91.4% versus 56.9%; P < 0.0001; overall, 92.4% versus 56.0%; P < 0.0001; Table 2; Fig. 2). Univariate analysis revealed that location and size of tumor, histologic differentiation, depth of tumor invasion, pattern of tumor growth, vascular invasion, lymphatic invasion, and lymph node metastasis were significant factors for both disease-free and overall survival (Table 2). The age of patients significantly affected overall survival but not disease-free survival.


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  		Table 2. Univariate analysis of clinicopathologic factors for disease-free and overall survival of 317 patients with gastric carcinoma

 


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  		Fig. 2. Disease-free (A) and overall (B) survival of patients with HDGF expression level 1 and 2 gastric carcinoma. Significant differences were observed between the two groups.

 
Multivariate analysis with factors proven to be significant in the univariate analysis revealed that HDGF index, tumor size, depth of tumor invasion, pattern of tumor growth, and lymph node metastasis were independent prognostic factors for disease-free and overall survival. Age of patients was an independent prognosticator for overall but not for disease-free survival (Table 3).


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  		Table 3. Multivariate analysis of clinicopathologic factors for disease-free and overall survival of 317 patients with gastric carcinoma

 

   Discussion
Top
 Abstract
 Patients and Methods
 Results
 Discussion
References
 
In the present study, cases with HDGF index level 2 showed the higher frequency in deep tumor invasion, presence of lymph node metastasis, lymphatic invasion, venous invasion, and tumor stage compared with cases with level 1, all of which are well-reported pathologic factors of tumor progression in gastric carcinoma. In addition, patients with HDGF index level 2 gastric carcinoma showed a higher rate in disease recurrence and, eventually, with decreased disease-free and overall survival. Previous studies in cell biology have addressed that HDGF has a range of biological functions, such as DNA synthesis, proliferation, growth-stimulating activity, and vascular development (8, 9, 11–13). The present study clearly shows that HDGF is also involved in gastric carcinoma progression in vivo.

Proximally located gastric carcinomas showed the highest rate of HDGF level 2 and deep tumor invasion. However, there was no significant difference as for the rate of HDGF level 2 among the groups according to tumor location when cases of the same depth (pT) were compared. Increased frequency of HDGF level 2 cases in proximally located gastric carcinomas might be due to the higher frequencies of advanced tumor in this group.

Adjuvant chemotherapy was done for patients with a high risk for tumor recurrence, i.e., deep tumor invasion or metastasis to the lymph nodes and other organs. Gastric carcinomas obtained from patients receiving chemotherapy showed a higher rate of HDGF level 2 compared with those treated with surgery alone, however, there was no significant difference as for the rate of HDGF level 2 between patients receiving preoperative chemotherapy and postoperative chemotherapy. Therefore, the effect of chemotherapy on HDGF expression in the tumors could not be shown in the present study.

The present univariate and multivariate analyses revealed the HDGF expression level to be an independent prognosticator for gastric carcinoma recurrence and patients' survival. Analysis of HDGF index, together with other independent prognosticators such as tumor size, pattern of tumor growth, lymph node metastasis, and depth of tumor invasion, might be a useful tool in predicting prognosis and in the decision-making for choosing the appropriate therapeutic modalities for patients with gastric carcinoma.

In conclusion, HDGF expression, as determined by immunohistochemistry, could be used as a new prognosticator for gastric carcinoma. Although further study is still needed to determine the precise role of HDGF in the malignant behavior of gastric carcinoma, the results of the present study imply that HDGF might be a potential target for anticancer drug design.


   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.

Received 6/21/05; revised 9/ 5/05; accepted 10/26/05.


   References
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 Patients and Methods
 Results
 Discussion
 References
 

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