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Clinical Cancer Research Vol. 10, 2738-2741, April 15, 2004
© 2004 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Plasma Level of Transforming Growth Factor ß1 Measured from the Azygos Vein Predicts Prognosis in Patients with Esophageal Cancer

Minoru Fukuchi, Tatsuya Miyazaki, Yasuyuki Fukai, Masanobu Nakajima, Makoto Sohda, Norihiro Masuda, Ryokuhei Manda, Katsuhiko Tsukada, Hiroyuki Kato and Hiroyuki Kuwano

Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Transforming growth factor (TGF)-ß regulates cell growth inhibition. When tumor cells lose their sensitivity to TGF-ß growth inhibition, the excess TGF-ß that results may act on tumor cells to facilitate tumor development. Previously, we have shown that an elevated systemic TGF-ß1 level is not related to tumor progression in esophageal cancer (Y. Fukai et al., Int J Cancer 2003;104:161–6). We considered that systemic inflammation or chronic disease, in addition to the tumor, may influence the plasma TGF-ß level. Therefore, we examined the hypothesis that the plasma TGF-ß level measured from the azygos vein would independently predict tumor progression and prognosis in patients with esophageal cancer.

Experimental Design: Fifty-seven plasma samples were obtained intraoperatively from the azygos vein in patients with esophageal cancer. ELISA was used to quantify the plasma TGF-ß1 levels, which were correlated with pathological features and patient survival.

Results: The mean plasma TGF-ß1 level measured from the azygos vein of esophageal cancer patients was 5.09 ± 0.48 ng/ml (mean ± SE). The survival rates of patients with a high TGF-ß1 level (defined as a level above the 4.6 ng/ml level of normal controls) in the azygos vein were significantly lower than those of patients with a low TGF-ß1 level (P = 0.0317). Moreover, the TGF-ß1 level in the azygos vein was an independent prognostic factor for overall survival (P = 0.0474).

Conclusions: The level of plasma TGF-ß1 measured from the azygos vein is an independent predictor in patients with esophageal cancer and may reflect tumor progression more specifically because the azygos vein is responsible for venous return from the esophagus.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Cytokines of the transforming growth factor (TGF)-ß superfamily are multifunctional proteins that regulate a variety of biological processes, including cell growth, differentiation, apoptosis, and morphogenesis (1 , 2) . TGF-ß strongly inhibits epithelial cell proliferation, and loss of the growth-inhibitory response to TGF-ß is found in many tumor cells (3 , 4) . When tumor cells lose their sensitivity to TGF-ß growth inhibition, the excess TGF-ß that results may act on tumor cells and stromal cells to facilitate invasion and metastasis (5) . In tumors, TGF-ß may have both negative and positive effects. It acts early in carcinogenesis as a tumor suppressor but later acts as a stimulator of tumor invasion by prompting extracellular matrix production and angiogenesis, stimulating tumor proliferation, and inhibiting host immune functions (6 , 7) .

Resistance to TGF-ß-induced growth inhibition as a result of the excess TGF-ß is associated with functional inactivation of TGF-ß-specific receptors or intracellular mediators, Smads, and their inactivating mutations have been reported in human cancers (8 , 9) . However, mutation of TGF-ß-specific receptors and Smad genes is rare in patients with esophageal cancer (10) . In previous immunohistological studies, lower expression of TGF-ß-specific receptors and Smads or higher local expression of TGF-ß1 was correlated with tumor progression in esophageal cancer (11, 12, 13) . We have also shown that the preoperative plasma TGF-ß1 level is elevated in esophageal cancer patients compared with normal controls (13) . Elevated systemic TGF-ß1 levels have been reported in patients with a variety of cancers and associated with tumor invasion, progression, and metastasis (14, 15, 16, 17, 18, 19) . However, our data suggested that an elevated systemic TGF-ß1 level is not related to tumor progression in esophageal cancer (13) . For this reason, we think that systemic inflammation or chronic disease, in addition to the tumor, may influence the plasma TGF-ß1 level.

In this study, we hypothesized that esophageal cancer patients who are at high risk for tumor development and prognosis would have an elevated level of plasma TGF-ß1 in venous blood obtained from the azygos vein instead of a peripheral vein. The azygos vein is mainly responsible for venous return from the esophagus (20, 21) , and its level of plasma TGF-ß1 may reflect tumor progression and condition more directly and accurately. Thus, we examined the correlation between pathological features and survival in patients with esophageal cancer who underwent potentially curative surgery and had their plasma TGF-ß1 levels measured from the azygos vein during surgery.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients.
Fifty-seven plasma samples were obtained intraoperatively from the azygos vein of patients (50 males and 7 females) with esophageal cancer who underwent potentially curative surgery without preoperative therapy at the Department of General Surgical Science, Gunma University Graduate School of Medicine, between 1999 and 2002. Moreover, the plasma samples were also obtained preoperatively from the peripheral vein of the same patients. The 57 esophageal cancer patients were histopathologically composed of 48 patients with squamous cell carcinoma, 5 patients with adenocarcinoma, and 4 patients with undifferentiated carcinoma. The age of the patients ranged from 36 to 79 years, with a mean age of 61.9 years. The mean follow-up period for the 57 patients was 20.8 months (range, 4.8–46 months). The mean plasma TGF-ß level measured from peripheral veins in 30 healthy volunteers was 4.6 ± 0.4 ng/ml (mean ± SE). In this study, this value was used as a normal control, as described previously (13) . Informed consent was obtained from all healthy volunteers and all patients.

Tumor stage was classified according to the fifth edition of the tumor-node-metastasis (TNM) classification of the International Union Against Cancer (22) . All of the distant metastatic lesions were in lymph nodes.

Plasma TGF-ß1 Quantification.
Venous blood samples from the azygos vein were drawn by syringe during surgery, as soon as possible after thoracotomy. Azygos veins were resected during the dissection for curative surgery in all patients.

For the ELISA used to measure plasma TGF-ß1, the blood samples were stored at 4°C after collection, and the platelet-poor plasma was obtained by centrifugation at 2000 x g for 20 min with the brake off; the plasma samples were kept frozen at –80°C until assayed. Before being assayed, all samples were activated with equal volumes of 2.5 N acetic acid/10 M urea, followed by 2.7 N NaOH/1 M HEPES, in accordance with the kit protocol. For quantitative measurements of plasma TGF-ß1 levels, we used a quantitative sandwich enzyme immunoassay (Quantikine human TGF-ß ELISA kit; R&D Systems, Minneapolis, MN). All samples were assayed in duplicate in a blinded fashion; the mean was used for data analysis (13) .

Statistical Analysis.
Statistical analysis was performed using the Mann-Whitney U test and the one-factor ANOVA test. The {chi}2 test and Fisher’s exact test were performed for qualitative analysis. Survival curves of the patients were calculated using the Kaplan-Meier method, and analysis was performed using the log-rank test. The prognostic factors were examined by univariate and multivariate analysis (proportional hazard regression model). Statistical significance in this study was set as P < 0.05.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Plasma TGF-ß1 Level Measured from the Azygos Vein in Patients with Esophageal Cancer.
The mean plasma TGF-ß1 level in the azygos vein and the peripheral vein of 57 esophageal cancer patients was 5.09 ± 0.48 ng/ml (mean ± SE) and 7.49 ± 0.86 ng/ml, respectively. The mean plasma TGF-ß1 level in the azygos vein was not significantly different from that measured in peripheral veins of healthy controls (P = 0.4767). However, the mean plasma TGF-ß1 level in the peripheral vein of esophageal cancer patients was significantly higher than that in the azygos vein (P = 0.0171) or that in the peripheral vein of healthy controls (P = 0.0185), as described previously (13) . The median concentration of TGF-ß1 in the azygos vein and peripheral vein was 4.55 ng/ml (range, 0.51–15.30 ng/ml) and 5.40 ng/ml (range, 0.57–26.63 ng/ml), respectively.

The correlations among the clinicopathological characteristics of patients with esophageal cancer and plasma TGF-ß1 levels measured from the azygos vein and peripheral vein in patients are summarized in Table 1Citation . There was a significant correlation between the TGF-ß1 level in the azygos vein and distant lymph node metastasis (M0, 4.70 ± 0.50 ng/ml; M1, 7.53 ± 1.36 ng/ml; P = 0.0396). However, there were no significant differences in the TGF-ß1 level in the azygos vein with histological grading (G1, 5.57 ± 1.24 ng/ml; G2, 5.56 ± 0.89 ng/ml; G3, 4.45 ± 0.53 ng/ml; P = 0.5270), primary tumor invasion (T1, 4.72 ± 0.89 ng/ml; T2, 5.46 ± 1.57 ng/ml; T3, 5.41 ± 0.69 ng/ml; T4, 4.69 ± 1.51 ng/ml; P = 0.9153), regional lymph node metastasis (N0, 4.34 ± 0.80 ng/ml; N1, 5.57 ± 0.60 ng/ml; P = 0.2138), or stage (stage I, 4.07 ± 1.07 ng/ml; stage II, 5.83 ± 0.93 ng/ml; stage III, 4.30 ± 0.65 ng/ml; stage IV, 6.98 ± 1.32 ng/ml; P = 0.1680). The TGF-ß1 level in the azygos vein did not correlate with patient age or sex or with tumor location. Although the plasma samples were obtained from 57 esophageal cancer patients (48 patients with squamous cell carcinoma, 5 patients with adenocarcinoma, and 4 patients with undifferentiated carcinoma), the TGF-ß levels in the azygos vein were not correlated with the histopathological differences (data not shown). Furthermore, there was no significant correlation between the clinicopathological characteristics of patients with esophageal cancer and the TGF-ß1 levels in the peripheral vein.


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  		Table 1 The correlation between clinicopathological characteristics and plasma TGF-ß1a levels measured from the azygos vein and the peripheral vein

 
Prognostic Significance of Plasma TGF-ß Level in the Azygos Vein.
We determined the cutoff value as 4.6 ng/ml, which was the mean TGF-ß1 level measured from peripheral veins in the 30 healthy controls, to assess the prognostic value of the TGF-ß1 level measured from the azygos vein (13) . There was no significant difference in age and sex between esophageal cancer patients with a high TGF-ß1 level in the azygos vein (a level above the cutoff value; n = 33) and those with a low TGF-ß1 level (a level below the cutoff value; n = 24). The survival rates of patients with a high TGF-ß1 level in the azygos vein were significantly lower than those of patients with a low TGF-ß1 level (P = 0.0317; Fig. 1Citation ). However, there was no significant difference in the survival rates between patients with a high TGF-ß1 level and those with a low level in the peripheral vein (data not shown). The 3-year survival rate of patients with a high TGF-ß1 level in the azygos vein was 25%, and that of patients with a low level was 83%. Moreover, according to multivariate analysis using a Cox proportional hazards model, the TGF-ß1 level in the azygos vein was an independent prognostic factor of overall survival (P = 0.0474; hazard ratio, 4.151; Table 2Citation ).



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  		Fig. 1. Survival curves according to the plasma transforming growth factor (TGF)-ß1 level measured from the azygos vein in patients with esophageal cancer. Patients with high TGF-ß1 levels (levels above the cutoff value; n = 33) had a significantly more unfavorable prognosis than those with low TGF-ß1 levels (levels below the cutoff value; n = 24). P was determined using the log-rank test.

 

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  		Table 2 Multivariate analysis of risk factors affecting survival rate

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
TGF-ß is a multifunctional cytokine that plays an important role in the inhibition of epithelial cell proliferation (2) . However, loss or resistance of this inhibitory effect to TGF-ß has been reported in many tumor cells (3 , 4) . When tumors acquire resistance to TGF-ß growth inhibition, the excess TGF-ß may facilitate tumor progression by angiogenesis, extracellular matrix production, and immune suppression (5, 6, 7) . Thus, elevated systemic TGF-ß1 levels have been reported in patients with various cancers (14, 15, 16, 17, 18, 19) , and increased local TGF-ß1 has also been observed in many cancer cells (12 , 13 , 23 , 24) . In a previous study, local expression of TGF-ß1 was related to tumor progression in esophageal cancer, in contrast to systemic TGF-ß1 level (13) . The plasma TGF-ß1 level may be influenced by systemic inflammation or a chronic disease, and TGF-ß1 may be secreted from normal tissues as well as tumors.

In this study, the plasma TGF-ß1 level in venous blood obtained from the azygos vein instead of a peripheral vein was measured and correlated with pathological findings and survival of patients with esophageal cancer. The azygos vein is chiefly responsible for venous return from the esophagus, and the level of plasma TGF-ß1 in the azygos vein may therefore reflect tumor progression and condition more directly and accurately than the TGF-ß1 level in other veins (20) . Plasma for normal controls could not be obtained from the azygos vein of healthy volunteers, so we used the mean value measured from peripheral veins, as described previously (13) . We observed a significant correlation between the TGF-ß1 level measured from the azygos vein and metastasis to distant lymph nodes in esophageal cancer (P = 0.0396). These data suggest that elevated TGF-ß1 exhibits the effects of angiogenesis, extracellular matrix production, and immune suppression, and contributes to tumor development, including metastasis to distant lymph nodes (25) .

The survival rates of patients with high TGF-ß1 levels (levels above the mean value of healthy controls) were significantly lower than those of patients with low TGF-ß1 levels (P = 0.0317). Moreover, the TGF-ß1 level measured from the azygos vein was an independent prognostic factor of overall survival (P = 0.0474). According to these results, the TGF-ß1 level in the azygos vein may reflect tumor condition and viability more appropriately than local expression does. Furthermore, high TGF-ß1 levels predict poor prognosis in patients who would eventually have cancer recurrence in lymph nodes or other organs. Therefore, we would be able to start early discussion about modifying adjuvant therapy for these patients (26 , 27) .

An elevated TGF-ß level in the azygos vein might be a result of excess secretion from tumor cells or para-tumor cells, if the tumor cells have acquired resistance to TGF-ß growth inhibition. This resistance is associated with inactivating mutations in various human cancers (3 , 4) , but mutation of the genes encoding TGF-ß signaling mediators is rare in patients with esophageal cancer (10) . In previous studies, abnormal expression of TGF-ß receptors and Smads was shown to be correlated with tumor progression in esophageal cancer and appeared to cause partial resistance to TGF-ß growth inhibition (11, 12, 13) . However, expression of TGF-ß receptors and Smads was not identified as an independent prognostic marker.

In conclusion, the level of plasma TGF-ß1 measured from the azygos vein, which is responsible for venous return from the esophagus, is a useful prognostic marker in patients with esophageal cancer. In the future, we will need to study TGF-ß1 levels in the azygos vein in more patients with esophageal cancer and follow-up those patients for longer periods.


   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: Minoru Fukuchi, Department of General Surgical Science, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma, 371-8511, Japan. Phone: 81-27-220-8224; Fax: 81-27-220-8230; E-mail: mfukuchi{at}med.gunma-u.ac.jp

Received 7/15/03; revised 12/ 4/03; accepted 1/22/04.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
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