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10.1245/s10434-007-9369-9
Annals of Surgical Oncology 14:2141-2149 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Expression Level of Hepatoma-Derived Growth Factor Correlates with Tumor Recurrence of Esophageal Carcinoma

Shinji Yamamoto, MD, PhD1, Yasuhiko Tomita, MD, PhD2, Yoshihiko Hoshida, MD, PhD2, Eiichi Morii, MD, PhD2, Takushi Yasuda, MD, PhD1, Yuichiro Doki, MD, PhD1, Katsuyuki Aozasa, MD, PhD2, Hirokazu Uyama, MD, PhD3, Hideji Nakamura, MD, PhD4 and Morito Monden, MD, PhD1

1 Department of Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, Japan 5650871
2 Department of Pathology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 5650871, Japan
3 Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, Japan 5650871
4 Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawacho, Nishinomiya, Hyogo, Japan 6638501

Correspondence: Address correspondence and reprint requests to: Shinji Yamamoto, MD, PhD; E-mail: shinjiyamamoto2005{at}yahoo.co.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Hepatoma-derived growth factor (HDGF) is thought to play an important role in the development and progression of carcinomas. In the present study, association of HDGF expression with recurrence and prognosis of esophageal carcinoma (EC) was examined.

Methods: HDGF expression in 111 patients with EC (101 men and 10 women) with ages ranging from 38 to 82 (median, 61) years was analyzed by immunohistochemistry. Samples in which >90% of tumor cells exhibited nuclear and cytoplasmic HDGF immunoreactivity at levels greater than or equal to what is observed in the endothelial cells were regarded as HDGF expression level 1, and others as HDGF expression level 0.

Results: Thirty-seven of 111 patients showed level 1 HDGF expression. There was no correlation between HDGF expression and other clinicopathologic factors. Patients with level 1 expression showed poorer disease-free and overall survival (P < .05 for both) compared with those with level 0 expression. HDGF expression was an independent prognostic factor for patients with early (pT1–2) stage of the disease, but not for those with advanced (pT3–4) stage.

Conclusions: HDGF expression level was shown to be a prognostic factor for EC.

Key Words: HDGF • Hepatoma-derived growth factor • Esophageal carcinoma • Immunohistochemistry


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hepatoma-derived growth factor (HDGF) is a heparin-binding protein that can be purified from the conditioned media of Huh-7 hepatoma cells, which proliferate autonomously in serum-free chemically defined medium.1,2 HDGF stimulates cell growth after translocation to the nucleus3,4 and has mitogenic activity for various cells, including hepatocellular carcinoma cells, fibroblasts, endothelial cells, vascular smooth muscle cells, and fetal hepatocytes.1–8 HDGF is highly expressed in fetal tissues, and its association with organ development, including the development of the cardiovascular system, the kidney, and the liver, has been proposed.1–10

HDGF has been reported to stimulate cell migration.11,12 Several findings suggest that HDGF expression correlates with the aggressive biological potential of cancer cells, such as proliferation, invasiveness, and metastasis.8,11 HDGF may therefore prove useful as one of prognosticators for patients with cancer. Recently, a high correlation between HDGF expression and the prognosis of patients with hepatic, gastric, and lung cancers has been reported.13–17 As for esophageal carcinoma (EC), increased expression of HDGF at the mRNA level in EC with a radioresistant phenotype was reported, implying that it plays a role in the progression and prognosis of EC.18

EC is a cancer with poor prognosis.19,20 For the management of patients with primary EC, surgical resection remains as the main mode of treatment.21 However, the prognosis is unsatisfactory, even in curatively resected patients where the 5-year survival rate is <50% after surgery.19,20 Moreover, with the exception of patients with early-stage disease, adjuvant therapeutic modalities such as chemotherapy, radiotherapy, or a combination of the two are necessary.

Several clinicopathologic factors, such as tumor size and lymph node invasion, were reported to be the main factors for tumor recurrence and for survival of patients with EC.19,22,23 These two factors were therefore included in the tumor, node, metastasis system (TNM) classification for the disease.24 The prognoses of patients are nonetheless unfavorable, even under conditions where the tumor sizes are small and lymph node invasion is unobserved at the microscopic level. Thus, new biological prognostic factors responsible for the recurrence of EC need to be investigated.

In the present study, HDGF expression was analyzed in 111 patients with EC and its correlation with clinicopathologic features and patients’ prognosis was evaluated to determine whether HDGF expression level could be used for the prediction of recurrence and prognosis in patients with EC.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Tumor Specimens
One hundred eleven patients receiving surgery for EC (without preoperative chemotherapy or radiotherapy) at the Gastroenterological Surgery Division, Osaka University Hospital, Osaka, Japan, were selected for the present study over the period of July 1989 to February 2002. The patient pool consisted of 101 men and 10 women with ages ranging from 38 to 82 years (median, 61 years).

Patients underwent preoperative diagnostic examinations that included endoscopy, esophagography, computed tomography, and endoscopic ultrasonography for the evaluation of clinical staging. Histological diagnosis of EC was confirmed with biopsy specimens obtained before surgery. All patients underwent an attempted curative operation, with the surgeries that were performed were as follows: subtotal esophagectomy in 106 patients, partial esophagectomy in 3 patients, and endoscopic mucosal resection in 2 patients. Resected esophagus specimens were evaluated macroscopically to determine the location and size of the tumor. Tumors were located in cervical esophagus in 3 patients, the upper thoracic esophagus in 6, the mid thoracic in 60, the lower thoracic in 35, and abdominal esophagus in 7. The length of the main tumors ranged from 2 to 100 mm (median, 45 mm).

Specimens of esophageal lesions were fixed in 10% formalin and processed for paraffin embedding. Histologic sections cut at 4 µm were stained with hematoxylin and eosin and were used for immunoperoxidase staining (avidin-biotin complex method). Histologic sections were reviewed by one of the authors (Y.H.) to determine the extent and mode of cancer invasion in the esophagus, lymph node metastasis, and the histologic subtype of EC on the basis of the criteria of the Japanese Research Society for Esophageal Cancer.25 Tumor stage evaluations were based on the International Union Against Cancer pTNM classification.24 Histological examination showed that 42 tumors were well-differentiated squamous cell carcinomas, 35 were moderately differentiated squamous cell carcinomas, and 34 were poorly differentiated squamous cell carcinomas. Tumor cells invaded the mucosa or submocosa (pT1) in 34 patients, muscularis propria or subserosa (pT2) in 22, serosa (pT3) in 50, and adjacent organs (pT4) in 5.

After surgery, all patients had standardized follow-up examinations, including such laboratory examinations as routine peripheral blood cell counts and serum squamous cell carcinoma antigen level measurements at 1- to 6-month intervals. The following examinations were performed at 6- to 12-month intervals: chest roentgenogram, ultrasonogram of the liver, computerized tomographic scan of the thorax and abdomen, and endoscopic examination of the rest of the esophagus. Adjuvant therapies (chemotherapy or radiotherapy) were performed in four patients (postoperative chemotherapy alone in one patient; postoperative radiotherapy alone in one patient; postoperative chemoradiation in two patients). Radiation doses ranged from 40 to 60 Gy. The chemotherapeutic agents used were 5-fluorouracil and cisplatinum. Follow-up period for survivors ranged from 1 to 107 months (median, 46 months). Five-year disease-free and overall survival rates were 43.0% and 47.3%, respectively. Fifty-six patients showed tumor recurrence: local recurrence occurred in 9 patients, lymph node recurrence in 24, liver recurrence in 10, and recurrence in other organs in 13. Forty-nine patients died from disease.

Immunohistochemistry
The immunoperoxidase procedure (avidin-biotin complex method) for detection of HDGF was performed on paraffin-embedded sections. Briefly, antigen retrieval was performed by heating the sections in 10 mM citrate buffer for 5 minutes. Rabbit polyclonal antibody against the C-terminal amino acids (amino acids 231–240) of the human HDGF sequence was used as the primary antibody at a dilution of 1:5000. This HDGF-specific antibody was purified by C-terminal peptide-conjugated Sepharose column.6,7 Sections were lightly counterstained with methyl green. Positive staining in endothelial cells was used as an internal positive control. For negative controls, immunohistochemistry without primary antibody was performed; this gave uniformly negative results.

Stained sections were evaluated in a blinded manner without prior knowledge of the clinical information. HDGF expression in the nucleus and in the cytoplasm was independently evaluated. Tumor cells showing nuclear staining that was equal to or stronger than the staining intensity in endothelial cells were considered nuclear positive. The same process was followed for cytoplasmic staining. Cases with >90% of tumor cells showing nuclear positive staining and >90% of tumor cells showing cytoplasmic positive staining were categorized as level 1 HDGF staining, and the remaining cases as level 0 HDGF staining.13,14

Statistical Analysis
JMP software (SAS Institute, Cary, NC) was used for statistical analysis. The correlation between HDGF expression (as determined by immunohistochemistry) and the clinicopathologic features of EC was analyzed with the {chi}2 test and the Fisher exact probability test. Survival rates and differences in survival curves were calculated by Kaplan-Meier methods and by the log rank test.26 Independent prognostic factors were analyzed by the Cox proportional hazard regression model in a stepwise manner.27 The difference was considered to be significant when P values were less than .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
HDGF Expression in EC
One hundred eleven specimens of EC were evaluated for HDGF expression. Both nuclear and cytoplasmic staining for HDGF were analyzed in EC cells by immunohistochemical analysis. Seventy-four cases (66.7%) showed partial HDGF staining (<90% of positive cells in either the nuclear or cytoplasmic staining) or no HDGF staining at all and were thus categorized as HDGF level 0 staining (Fig. 1aGo). Thirty-seven cases (33.3%) showed >90% positive staining both in the nucleus and cytoplasm and were thus considered HDGF level 1 staining (Fig. 1bGo). Nontumorous esophageal mucosa showed HDGF level 0 staining.


Figure 1
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  		FIG. 1. (a, b) Esophageal carcinoma with hepatoma-derived growth factor (HDGF) expression level 0. Tumor cells exhibited weak HDGF staining in the cytoplasm. (c, d) Esophageal carcinoma with HDGF expression level 1. Tumor cells exhibited strong nuclear and cytoplasmic HDGF staining.

 
Uni- and Multivariate Analysis of Prognostic Factors in EC
There was no correlation between HDGF expression level and other clinicopathologic factors (Table 1Go). Patients with level 0 expression EC showed better disease-free and overall 5-year survival rates than those with HDGF level 1 EC (P < .05) (Table 2Go, Fig. 2Go). Univariate analysis revealed that the depth of tumor invasion, vascular invasion, lymphatic invasion, and lymph node metastasis were significant factors for both disease-free and overall survival rates, whereas tumor size was only a significant factor for overall survival (Table 2Go). Multivariate analysis with factors proven to be significant in the univariate analysis revealed that depth of tumor invasion and lymph node metastasis were independent prognostic factors for both disease-free and overall survival, whereas vascular invasion was important only for overall survival (Table 3Go). On the other hand, HDGF expression, tumor size, and lymphatic invasion were not shown to be independent prognostic factors (Table 3Go).


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  		TABLE 1. Relationship between HDGF expression and clinicopathologic factors in 111 patients with esophageal squamous cell carcinoma
 

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  		TABLE 2. Univariate analysis of clinicopathologic factors for disease-free and overall survival in patients with esophageal carcinoma
 

Figure 2
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  		FIG. 2. Disease-free (A) and overall (B) survival of patients with esophageal carcinoma exhibiting hepatoma-derived growth factor (HDGF) expression level 0 and level 1. Significant difference was observed between the 2 groups.

 

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  		TABLE 3. Multivariate analysis of clinicopathological factors for disease-free and overall survival of 111 patients with esophageal squamous cell carcinoma
 
Prognostic Significance of HDGF Expression in pT1–2 Disease
Prognostic significance of HDGF expression was analyzed in patients with EC according to the pTNM classification.24 HDGF expression was a prognosticator among patients with pT1–2 stage disease (Fig. 3Go); however, HDGF expression was not prognostically significant in those with pT3–4 disease (data not shown). HDGF expression proved to be an independent prognosticator for both disease-free and overall survival among patients in the stage pT1–2 group (Table 4Go).


Figure 3
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  		FIG. 3. Disease-free (A) and overall (B) survival of patients with stage pT1–2 esophageal carcinoma exhibiting hepatoma-derived growth factor (HDGF) expression level 0 and level 1. Significant difference was observed between the 2 groups.

 

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  		TABLE 4. Multivariate analysis of clinicopathologic factors for disease-free and overall survival of 56 patients with early esophageal squamous cell carcinoma (pT1–2)
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Patient characteristics such as sex, age, primary lesion site, and 5-year survival rates in the present study were similar to those in previous reports from Japan and other Asian countries where squamous cell carcinoma is the main histologic subtype.22,28 In addition, univariate and multivariate analyses showed the prognostic significance of clinicopathologic factors, such as the size and depth of the tumor, lymphatic and vascular invasion, and lymph node metastasis, as reported previously from Western countries19,23 and Japan.28 These findings indicate that the results obtained from the present cases are applicable to EC in other counties.

The conventional TNM staging classification system for esophageal squamous cell carcinoma provides useful information for predicting tumor recurrence and patient survival.24 However, recent advances in therapeutic modalities for EC present new problems that need to be addressed. For example, recently introduced reduction surgeries, such as endoscopic mucosal resection and transhiatal esophagectomy, enable tumor excision without greatly affecting the patient’s general condition.21,29,30 However, given that lymph node metastasis is observed at relatively high frequency even in early EC,28 the introduction of these techniques carries a risk. The introduction of adjuvant chemotherapy and radiotherapy has improved the prognosis of patients with EC, especially those with a high potential for lymph node metastasis.31,32 Under these circumstances, preoperative assessment for the presence of lymph node metastasis and for the metastatic potential of EC is essential for therapeutic decision making.

Previous studies in cellular biology have shown that HDGF, a member of the heparin-binding growth factor family, has a wide range of biological functions, including mitogenic activity and vascular development.3,4,5,8,10 Increased HDGF expression in tumor tissue as compared with an adjacent nontumorous area has been reported in an animal model33 as well as in several human cancers.13–17 Furthermore, the prognostic use of HDGF in these cancers has been clearly demonstrated. As for EC, correlation between increased HDGF mRNA expression and radioresistance has been shown,18 but the prognostic use of HDGF expression has not yet been reported. The present study therefore investigated whether HDGF plays a role in the recurrence and prognosis of EC.

The prognostic significance of HDGF staining in the nucleus, the cytoplasm, or both has been evaluated.13,14 The prognostic value was most important when cases that showed high HDGF expression in both the nucleus and the cytoplasm were compared with others. This categorization was therefore chosen for the present study. Prominent nuclear translocation of HDGF has been reported to be essential for the increased DNA synthesis and proliferation as well as growth-stimulating activity.3,4 Recently, the existence of a plasma membrane–located HDGF receptor has been reported.34 Further investigation is necessary to clarify the biological effect of HDGF that is localized to the cytoplasm.

HDGF expression was an independent prognosticator for EC at the pT1–2 stage, but not for EC at the pT3–4 stage. The main cause for the poor prognosis of EC is metastasis to the lymph node.19,28,35 Pleiotropic HDGF activities such as antiapoptotic effects, proliferation, and angiogenesis may help cancer cells to invade lymphatic vessels and form metastatic foci in the lymph nodes. Analysis of HDGF expression in EC at the early stage might be a useful tool in predicting prognosis and for the decision making involved in choosing appropriate therapeutic modalities for patients.

In summary, HDGF expression, as determined by immunohistochemistry, could be offered as a new prognostic marker for EC. The present study indicated that classification of patients according to conventional TNM staging and HDGF expression level provides a valuable tool for predicting tumor recurrence in and prognosis of patients with EC. This system may also provide a new way to explore effective treatment modalities for EC.

Received for publication June 13, 2006. Accepted for publication January 8, 2007.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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