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Clinical Cancer Research Vol. 7, 277-282, February 2001
© 2001 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Preserved Smad4 Expression in the Transforming Growth Factor ß Signaling Pathway Is a Favorable Prognostic Factor in Patients with Advanced Gastric Cancer1

Che Xiangming, Shoji Natsugoe, Sonshin Takao, Shuichi Hokita, Sumiya Ishigami, Gen Tanabe, Masamichi Baba, Kazunao Kuroshima and Takashi Aikou2

First Department of Surgery, School of Medicine, Kagoshima University, Kagoshima 890-8520, Japan [C. X., S. N., S. T., S. H., S. I., G. T., M. B., T. A.], and Department of Surgery, Terada Hospital, Kagoshima 895-25, Japan [K. K.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The signals of the transforming growth factor ß (TGF-ß) superfamily are conveyed through cell surface serine/threonine kinase receptors to the intracellular mediators known as Smads. Activation of Smads causes their translocation from the cytoplasm to the nucleus, where they function to control gene expression. The present study analyzed the expression of Smad4 and TGF-ß1 to determine their prognostic significance in advanced gastric cancer. Of 249 cases of advanced gastric cancer, 41 had invaded the muscular layer, 114 had invaded the subserosal layer, and 94 had invaded the serosa. Anti-Smad4 and TGF-ß1 antibodies were used for immunohistochemical staining. Reduced expression of Smad4 was 75.1%, whereas positive expression of TGF-ß1 was 39.6% in gastric cancer. Smad4 expression was related to the depth of tumor invasion (P < 0.05), and TGF-ß1 expression correlated with tumor gross type (P < 0.05). Postoperative survival analysis indicated that patients who had a tumor with reduced Smad4 expression had a poorer clinical outcome than those with preserved expression (P < 0.05). Furthermore, in patients with TGF-ß1-positive tumors, survival rate was significantly better in patients with preserved Smad4 expression than in those with reduced Smad4 expression (P < 0.05). According to multivariate analysis, Smad4 expression acted as an independent prognostic factor. Smad4 expression, particularly in the TGF-ß pathway, is an effective predictor of outcome for patients with advanced gastric cancer.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The TGF3 -ß superfamily is a group of related multifunctional polypeptide factors (1 , 2) . The members of this superfamily elicit their biological effects through a family of transmembrane serine/threonine kinase receptors classified as type I or type II receptors (3 , 4) . The type II receptors, after being dimerized upon binding to the TGF-ß ligand, phosphorylate the type I receptors, which then transmit the TGF-ß signal to a set of intracellular mediators, known as the Smad proteins (5) .

The Smads, named after the founder members Sma and Mad (6) , are a family of intracellular signal transducers that act downstream of the receptors for TGF-ß family members (3) . Structurally and functionally, the Smads are divided into three classes: the receptor-regulated Smads (R-Smads: Smad1, 2, 3, 5, and 8) are phosphorylated and activated by different activated type I receptors for TGF-ß family ligands; Smad4 is distinct from the R-Smads and is defined as a common mediator Smads (co-Smad) because it forms hetero-oligomeric complexes with activated R-Smads and appears essential for R-Smad function. These then translocate to the nucleus to regulate gene expression; and the third class of Smad is the inhibitory Smads (anti-Smads), which includes Smad6 and 7. These Smads antagonize the activity of the co-Smad/R-Smad complex (2) .

The cell cycle progression of normal epithelial cells is inhibited by exogenous TGF-ß, whereas malignant epithelial cells are often resistant to the growth-inhibitory effects of TGF-ß (7) . The mechanism by which malignant tumor cells subvert normal growth controls is believed to be attributable to acquired resistance to the growth-inhibitory effects of TGF-ß. In some epithelial malignancies, TGF-ß resistance is associated with functional inactivation of either the TGF-ß receptors (8) or of signal transducers of the Smad family (9) , suggesting that resistance to TGF-ß-induced growth inhibition is attributable to disrupted TGF-ß/Smad-dependent transcriptional regulation. On the basis of its role in mediating the growth-inhibitory effects of TGF-ß in normal cells and its loss of function in some tumor types, Smad4 is considered to represent a tumor suppressor protein (10) .

Smad4 is apparently common to all of the ligand-specific Smad pathways and appears to act as a central mediator in TGF-ß superfamily signaling (5 , 11) . Smad4 appears to mediate the actions of the other Smads. In vitro and in vivo studies have shown that the mutation in the smad4 gene, which exists on chromosome 18q21, plays a significant role in tumorigenesis and progression of pancreatic, colorectal, gastric, and other solid tumors (12, 13, 14, 15, 16, 17, 18, 19) .

TGF-ß has a dimeric structure with a molecular weight of Mr 25,000, and there are three forms in humans: TGF-ß1, TGF-ß2, and TGF-ß3. TGF-ß1 is the most prevalent of them (20) and regulates cell growth and differentiation in both normal and tumor cells, as well as being a potent inhibitor of epithelial cell growth. However, TGF-ß1 expression may confer a selective advantage to the tumor by enhancing angiogenesis or modulating stromal characteristics or the immune response to tumor growth, thus leading to increased invasion and metastasis (21, 22, 23) .

The overexpression of TGF-ß1 has been reported in the tissue of various types of carcinomas (24, 25, 26) , and it appears to correlate with the clinicopathological findings, particularly with the prognosis of cancer patients (27, 28, 29, 30) . However, the role of Smad4 remains unclear in human gastric cancer. The purpose of this study was to elucidate the clinical significance of Smad4 and its correlation with TGF-ß expression in cases of advanced gastric cancer.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Specimens.
Formalin-fixed and paraffin-embedded specimens were obtained from 249 consecutive patients with advanced gastric cancer who underwent gastrectomy with lymph node dissection at Kagoshima University Hospital between 1982 and 1992. The patients, 173 males and 76 females, ranged in age from 32 to 88 years, with an average age of 64.3 years. None of the patients had undergone preoperative radiotherapy or chemotherapy. Specimens were cut into 3-µm thick sections and mounted on glass slides. A serial section from each specimen was stained with H&E for histological evaluation. The clinicopathological features were assessed in accordance with the General Rules for the Gastric Cancer Study in Japan (31) . Tumors were divided into two histological subgroups: the differentiated type and the undifferentiated type. Curative surgery was performed on 75.9% (189 of 249) of the patients. The average follow-up period was 73.5 months (54–76 months).

Immunohistochemical Staining and Evaluation.
Immunohistochemical staining was performed using avidin-biotin-peroxidase as described previously (29 , 30 , 32) . Briefly, after deparaffinizing in xylene and rehydrating in ethanol, the sections were heated in citrate buffer (0.01 M, pH 6.5) at 120°C for 10 min to retrieve antigen. Next, sections were incubated with either the primary monoclonal antibody anti-Smad4 (1:300; Smad4: B-8, sc-7966; Santa Cruz Biotechnology, Inc., Santa Cruz, CA) or anti-TGF-ß1 (1:100; TGF-ß1: V, sc-146; Santa Cruz Biotechnology) overnight at 4°C. The sections were incubated with biotinylated antimouse IgG and avidin-biotin-peroxidase (Vector Laboratories, Burlingame, CA) and visualized using diaminobenzidine tetrahydrochloride.

The expression of Smad4 by malignant cells was compared with that of normal epithelial cells located away from the tumor. Tumor cells that stained as strongly as normal epithelial cells were considered positive (+), whereas those that stained weaker than normal epithelial cells or did not stain at all were considered weak (±) or negative (-), respectively. Tumors were then classified according to their expression of Smad4 upon overview of the section, being considered to have "Smad4 preserved expression" if >50% of the tumor cells were positive. Tumors classified as having "reduced expression" were those that did not fit into the above categories.

The positive expression of TGF-ß1 was determined by counting the number of tumor cells in which the cytoplasm stained with antibody. For evaluation, 10 fields were selected, and a total of 1000 tumor cells (100/field) were counted under high power (x200) microscopy. The average labeling index of TGF-ß1 was assessed according to the proportion of positive cells in each field. The results of TGF-ß1 expression were graded as negative (-) for <=10% stained or positive (+) for >10% of cancer cells stained (28 , 29) .

Statistical Analysis.
Statistical analysis of group differences was performed by the {chi}2 test and t test. The Kaplan-Meier method was used for survival analysis and evaluated by the Wilcoxon test. The prognostic factors were examined by univariate and multivariate analyses (proportional hazard regression model). P < 0.05 was considered as statistically significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Expression of Smad4 and TGF-ß1.
In the majority of cancer cells, Smad4-positive staining was observed in the cytoplasm and simultaneously in the nuclei of some cancer cells. Normal epithelial cells were homogeneously stained by Smad4, whereas in gastric cancerous tissue, the rates of preserved (Fig. 1Citation A) and reduced (Fig. 1Citation B) Smad4 expression were 24.9 and 75.1%, respectively.



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  		Fig. 1. Expression of Smad4 and TGF-ß in gastric cancer. A, preserved expression: both the cytoplasm and nucleus were stained. B, reduced expression: no tumor cells stained. C, positive expression of TGF-ß1 in the cytoplasm of tumor cells.

 
The anti-TGF-ß1 antibody used in this study has no cross-reactivity with other isoforms of TGF-ß. The TGF-ß1 protein was stained mainly in the cytoplasm of cancer cells (Fig. 1Citation C) and was occasionally evident in fibroblasts and smooth muscle cells. The positive tumor cells were heterogeneously distributed within the tumor. TGF-ß1-positive expression was identified in 39.6% (99 of 249) of the tumors.

Smad4 or TGF-ß1 Expression and Clinicopathological Features.
Of the total 249 cases, expression of Smad4 or TGF-ß1 was not associated with most of the clinicopathological factors, including stage grouping or lymph node metastasis (P > 0.05). However, the rate of Smad4 reduced expression increased as tumors invaded deeper layers (P < 0.05). The rate of positive TGF-ß1 expression was higher in polyploid tumors (type 1) than in other types of tumors (P < 0.05; Table 1Citation ).


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  		Table 1 Smad and TGF-ß1 expression in relation to clinicopathology

 
Postoperative Survival and the Expression of Smad4 or TGF-ß1.
The postoperative survival of 189 patients who underwent curative resection was analyzed according to the expression of Smad4 or TGF-ß1. As shown in Fig. 2Citation ), the 5-year survival rates of patients with tumors that preserved and reduced expression of Smad4 were 50.4 and 39.2%, respectively. A significant difference was found between groups of tumors with preserved and reduced expression of Smad4 (P = 0.03). However, the 5-year survival rates did not differ significantly according to TGF-ß1 expression. When survival rates of patients with preserved and reduced expression of Smad4 were analyzed according to TGF-ß1 expression, in patients with TGF-ß1-positive tumors, the 5-year survival rate was significantly higher in the patients with preserved Smad4 expression than in those with reduced Smad4 expression (P < 0.05; Fig. 3Citation A). However, in patients with TGF-ß1-negative tumors, the survival rates did not differ, irrespective of Smad4 expression (Fig. 3Citation B).



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  		Fig. 2. Postoperative survival curve of patients according to the expression of Smad4 (A) or TGF-ß1 (B).

 


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  		Fig. 3. Postoperative survival of patients with TGF-ß1-positive tumors was significantly different according to the expression of Smad4. Patients with preserved expression of Smad4 had a better outcome than those with reduced Smad4 expression (P < 0.05; A). The survival rate did not differ in TGF-ß1-negative tumors (B).

 
Prognostic Significance of Smad4 Expression in Advanced Gastric Cancer.
Factors related to patient prognosis were evaluated by univariate and multivariate analyses for the 189 patients who underwent curative operation (Table 2)Citation . The univariate analysis showed that age, tumor size, gross type, depth of invasion, lymph node metastasis, stage, and Smad4 expression were related to postoperative survival rate (P < 0.05). However, according to multivariate regression analysis, patient age, lymph node metastasis, stage, and Smad4 expression were independent prognostic factors.


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  		Table 2 Univariate and multivariate analyses of prognostic factors in advanced gastric cancer

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Smad4 combines with phosphorylated R-Smad to form R-Smad/co-Smad complex and then translocates into the nucleus (2) . In the present study, Smad4 staining was observed both in the cytoplasm and nuclei, as is reported in cases of colorectal cancer (32) . In the present study, Smad4 expression related to the depth of tumor invasion; furthermore, we found that numerous cases showed that Smad4 expression decreased from the superficial to deep layer in the same tumor. These results suggest that Smad4 expression correlates with the progression of gastric cancer. Takaku et al. (33) reported that inflammatory polyps developed into the glandular components in the stomach and duodenum in Smad4 knockout mice, which is similar to those in human juvenile polyposis. In addition, foci of adenocarcinoma with signet ring cells were also found in these inflammatory polyps. These findings confirmed that Smad4 mutation was closely related to carcinogenesis of the stomach.

In the present study, prognosis was better in patients with tumors that preserved expression of Smad4 than in those with reduced expression of Smad4. Furthermore, multivariate analysis revealed that Smad4, together with stage, lymph node metastasis, and age, were independent prognostic factors. These results confirmed that Smad4 acts as a tumor suppressor gene, as reported by Duff and Clarke (12) and as a central mediator in TGF-ß superfamily signaling (5 , 11) . Mutation in the Smad4 gene and loss of smad4 protein either resulted in tumorigenesis or was associated with malignancy and progression of tumors. Therefore, patients may have a poor prognosis if their tumors show reduced expression of Smad4.

For the role and relationship of Smad4 to the TGF-ß superfamily, we simultaneously studied TGF-ß1 expression. In several studies, TGF-ß1 expression reportedly related to the prognosis of patients with various types of carcinomas (27, 28, 29, 30 , 34) . Ebert et al. (35) also reported that among gastric cancer patients, the majority of the patients’ first-degree relatives also expressed TGF-ß1 in their gastric mucosa. The induction of TGF-ß1 expression in first-degree relatives of patients with gastric cancer points to the presence of specific molecular alterations in a subgroup of individuals with an increase risk of developing gastric cancer. In the present study, we did not find a correlation between TGF-ß1 expression and the prognosis of patients with advanced gastric cancer. These conflicting results may be attributable to the selection of patients and antibodies used in studies or evaluation of the results. Further studies are required to confirm its role in the prognosis of cancers.

Because TGF-ß1 acts as an inhibitor of the cell cycle, which has been described to have a biphasic effect on tumor growth, some factors influence TGF-ß1 activity. Therefore, in the present study, we analyzed survival rates by both TGF-ß1 and Smad4 expression and found that in the group of patients with TGF-ß1-positive tumors, the postoperative survival was significantly worse for patients who had reduced Smad4 expression. This in one way reflects the promoted effects of TGF-ß1 on the progression of advanced tumors, and on the other hand, reflects the relationship between TGF-ß1 and its signaling transducer Smad4. The correlation of TGF-ß1 and Smad4 thus influences the prognosis of gastric cancer patients.

Smad4 appears to be the key regulatory protein of the TGF-ß superfamily signaling pathway and of control transcription driven by this superfamily. Furthermore, loss of Smad4 is associated primarily with the development of several tumors, which may implicate it as a tumor suppressor gene (10 , 12) . In conclusion, reduced Smad4 expression is an unfavorable prognostic factor for advanced gastric cancer. The relationship between Smad4 and TGF-ß1 has also been observed. An examination of Smad4 and TGF-ß1 is useful for predicating the outcome of patients with advanced gastric cancer.


   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.

1 Supported in part by Grant-in-Aid 08407032 for scientific and cancer research from the Ministry of Education, Science, Sports and Culture of Japan. Back

2 To whom requests for reprints should be addressed, at First Department of Surgery, School of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. Phone: 81-99-275-5358; Fax: 81-99-265-7426. Back

3 The abbreviation used is: TGF, transforming growth factor. Back

Received 8/15/00; revised 11/28/00; accepted 12/ 4/00.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Cancer Research Clinical Cancer Research
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