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Clinical Cancer Research Vol. 8, 817-822, March 2002
© 2002 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Significance of Cyclin B1 Expression as an Independent Prognostic Indicator of Patients with Squamous Cell Carcinoma of the Esophagus1

Tadahiro Nozoe2, Daisuke Korenaga, Akira Kabashima, Takefumi Ohga, Hiroshi Saeki and Keizo Sugimachi

Department of General Surgery, Fukuoka Dental College Hospital, Fukuoka, 814-0193 [T. N., D. K.], and Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582 [A. K., T. O., H. S., K. S.], Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Cyclin B1 plays an important role as a mitotic cyclin in the G2-M phase transition during the cell cycle. The aim of the present study was to elucidate the biological significance of cyclin B1 expression in squamous cell carcinoma (SCC) of the esophagus.

Experimental design: We analyzed immunohistochemically the expression of cyclin B1 in the tumor specimens from 120 patients with SCC of the esophagus that had been treated with surgical treatment without any preoperative therapies.

Results: The positivity rate of cyclin B1 expression was 56.7% (68 of 120). One-, 3-, and 5-year survival rates in esophageal SCCs with cyclin B1 expression were 82.8, 61.6, and 50.7%, respectively, and they were significantly lower than those in esophageal SCCs without cyclin B1 expression (97.8, 85.5, and 78.6%, respectively; P = 0.005). Cyclin B1 expression was found to be an independent prognostic indicator in esophageal SCCs in a multivariate analysis. When immunostaining for cyclin B1 was classified as a nuclear dominant pattern and cytoplasmic dominant pattern, 1-, 3-, and 5-year survival rates in esophageal SCCs with nuclear dominant expression of cyclin B1 were 66.7, 47.9, and 28.7%, respectively, and they were significantly lower than those in esophageal SCCs with cytoplasmic dominant expression (92.5, 70.0, and 66.3%, respectively; P = 0.005). A multivariate analysis demonstrated that the nuclear dominant cyclin B1 expression was an independent prognosticator in patients with esophageal SCCs expressing cyclin B1.

Conclusions: Our results demonstrate that cyclin B1 expression, especially nuclear dominant expression, can be significant as a prognostic indicator in esophageal SCCs.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The proliferation of cancer and carcinogenesis could never be documented without referring to altered regulation of the cell cycle (1) . Cyclin B1 plays an important role as a mitotic cyclin in the G2-M phase transition during the cell cycle (2 , 3) , and it has been found that G2-M arrest was associated with an increase in cyclin B level (4) . Innocente et al. (5) suggest that the cyclin B-dependent G2 checkpoint of the cell cycle has a role in preventing transformation of malignant tumors.

Overexpression of cyclin B1 has been studied in various tumors (6, 7, 8, 9, 10, 11, 12, 13, 14) , and some of the reports emphasized the significance of cyclin B1 expression as an indicator of the malignant potential of the tumors (8, 9, 10 , 13 , 14) . Because the localization and transition of the cyclin B1 expression in cancer cell cycles have been a focus of interest by some investigators (15, 16, 17) , the relationship between the localization of cyclin B1 protein expression either in the nuclei or in the cytoplasm and the biological behavior of the carcinoma cells should be elucidated.

The aim of the present study was to examine the expression of cyclin B1 and to elucidate its clinicopathological significance in a larger series of esophageal SCC.3 Furthermore, we referred to the biological behavior of tumor from the standpoint of the difference in staining pattern of cyclin B1, including nuclear dominant and cytoplasm dominant expressions.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients.
Specimens were collected from tissue samples from the 120 patients with SCC of the esophagus, that had been treated with esophageal resection and reconstruction from January 1990 to December 1999 in the Department of Surgery and Science, Kyushu University. None of the patients was treated with such preoperative therapies as radiation, chemotherapy, or immunotherapy. The study population consisted of 101 males and 19 females, and the age ranged from 36 to 89 years (mean, 65 years).

The clinicopathological investigation was made on the basis of guidelines for clinical and pathological studies on carcinoma of the esophagus established by the Japanese Society for Esophageal Diseases (18) , and the clinical stages were determined according to TNM classification of malignant tumors decided by the International Union Against Cancer (19) .

Immunohistochemistry.
Four-µm-thick sections sliced from paraffin-embedded specimen were prepared on the glass slides precoated with silane. After deparaffinizing in xylene and washing in a graded series of ethanol, the sections were placed in TBS for 10 min. The sections were incubated with a blocking solution for 5 min to block any endogenous peroxidase activity and were placed in TBS. Then the sections were placed in the 0.01 mM Tris buffer (pH 6.0) and heated at 121°C for 10 min in an autoclave oven. Next, the sections were incubated with TBS including 1% concentration of BSA for 20 min to block nonspecific binding of the immunoreagents. After washing in TBS, the sections were incubated with 1:500 diluted mouse antihuman monoclonal cyclin B1 antibody (NCL-Cyclin B1; Novocastra, Newcastle, United Kingdom), which has been commonly used to determine cyclin B1 expression in the investigations by Soria et al. (6) , Allan et al. (8) and Kushner et al. (11) . All of the incubations were carried out overnight at 4°C. After washing in TBS, an immunoperoxidase staining was performed by an EnVision antibody complex method (20 , 21) using ENVISION kit (DAKO. Ltd., Tokyo, Japan). Finally, the localization of cyclin B1 was visualized with diaminobenzidine tetrahydrochloride.

Evaluation for the Cyclin B1 Expression.
All of the samples were analyzed by two observers (T. N., A. K.) who were unaware of the clinical information. The degree of cyclin B1 expression was appreciated as the percentage of cancer cells showing nuclear and/or cytoplasmic staining. The specimens of examined cancer cells with more than 10% cyclin B1-positive cells were considered to have a positive response to cyclin B1. Furthermore, immunostaining for cyclin B1 was classified into two different types, nuclear dominant pattern and cytoplasmic dominant pattern.

Statistical Analysis.
The {chi}2 test and Student’s t test were used to compare the clinicopathological data. The cumulative survival rates were calculated by the Kaplan-Meier method, and the survival curves were tested by the Mantel-Cox method. Multivariate survival analysis was calculated according to Cox’s proportional hazards model with the forward stepwise manner. A P of less than 0.05 was regarded as significant.


   RESULTS
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Of the 120 esophageal SCCs, 68 (56.7%, Group P) responded positively to immunohistochemical staining of cyclin B1, and 52 (43.3%, Group N) did not. The representative pattern of cyclin B1 expression was demonstrated in Fig. 1aCitation , with a homogeneous expression in the cytoplasm and nuclei of carcinoma cells. In normal mucosa concomitant with carcinoma tissue, the nuclei of the basal cells had positive response to cyclin B1 (Fig. 1b)Citation .



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  		Fig. 1. In a, cyclin B1 expression was demonstrated by a homogeneous expression in the cytoplasm and nuclei of carcinoma cells; x100. In b, in normal mucosa concomitant with carcinoma tissue, the nuclei of only the basal cells had positive response to cyclin B1; x100. c, nuclear dominant expression of cyclin B1; x200. d, cytoplasmic dominant expression of cyclin B1; x200.

 
The relationships between clinicopathological background and cyclin B1 expression is shown in Table 1Citation . No significant difference was observed with regard to clinicopathological features, stage of the disease, and the curability.


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  		Table 1 Clinicopathological comparison between patients with carcinomas with and without cyclin B1 expressiona

 
One-, 3-, and 5-year survival rates of patients with esophageal SCCs with cyclin B1 expression were 82.8, 61.6, and 50.7%, respectively, and they were significantly lower than those of patients with esophageal SCCs without cyclin B1 expression (97.8, 85.5, and 78.6%, respectively; P = 0.005; Fig. 2Citation ).



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  		Fig. 2. Survival curves. The survival in esophageal SCCs with cyclin B1 expression (n = 68, thick line) was significantly lower than that in esophageal SCCs without cyclin B1 expression (n = 52, thin line; P = 0.005).

 
A multivariate analysis revealed that the cyclin B1 expression as well as length of tumors, depth of tumors, lymph node metastasis, and TNM stage of tumors were the independent prognostic indicators in esophageal SCCs (Table 2)Citation .


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  		Table 2 Multivariate analysis on prognosis of the patients

 
We noted that there were two different types in the immunostaining for cyclin B1, i.e., nuclear dominant expression and cytoplasmic dominant expression. Among the specimens with cyclin B1 expression, the section was regarded to have nuclear dominant expression when the percentage of carcinoma cells with nuclear staining was more than 20%, and the section was regarded to have cytoplasmic dominant expression when the percentage of carcinoma cells with nuclear staining was less than 20%. Then we made a comparison with regard to clinicopathological features and prognosis between patients with carcinomas with nuclear dominant expression and patients with carcinomas with cytoplasmic dominant expression (Table 3)Citation . The proportion of patients who had been treated with curative resection was significantly lower in patients with carcinomas with nuclear dominant expression of cyclin B1 than that in patients with carcinomas with cytoplasmic dominant expression (P = 0.044). One-, 3-, and 5-year survival rates in esophageal SCCs with nuclear dominant expression were 66.7, 47.9, and 28.7%, respectively, and they were significantly lower than those in esophageal SCCs with cytoplasmic dominant expression (92.5, 70.0, and 66.3%, respectively; P = 0.005; Fig. 3Citation ). Likewise, a multivariate analysis demonstrated that the nuclear dominant cyclin B1 expression as well as length of tumors, depth of tumors, lymph node metastasis, and TNM stage of tumors were the independent prognosticators in patients with esophageal SCCs expressing cyclin B1 (Table 4)Citation .


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  		Table 3 Clinicopathological comparison between patients with carcinomas with nuclear dominant and cytoplasmic dominant expression of cyclin B1a

 


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  		Fig. 3. Survival curves. The survival in esophageal SCCs with nuclear dominant expression of cyclin B1 (n = 28, thick line) was significantly lower than that in esophageal SCCs cytoplasmic dominant expression (n = 40, thin line; P = 0.005).

 

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  		Table 4 Multivariate analysis on prognosis of the patients with carcinoma expressing cyclin B1

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Expressions of cyclins controlling the cell cycle have been variously investigated in SCC of the esophagus. Expression of cyclin D1, G1-phase cyclin, has been the chief focus and many investigations have documented its biological significance as an indicator of invasiveness (22, 23, 24, 25, 26) or a biomarker of the carcinogenesis of esophageal SCC (27 , 28) .

To the best of our knowledge, only one report has been released with regard to the relationship between immunohistochemical expression of cyclin B1, namely G2-M cyclin, and the prognosis of esophageal SCC (9) . Concerning SCC, similar results have also been reported, showing the significance of cyclin B1 overexpression as a prognostic indicator for patients with SCC of the lung (6) , or as a marker of the malignant potential in patients with SCC of the head and neck (11) .

Murakami et al. (9) reported the positivity for expression of cyclin B1 as 72.4% and emphasized that cyclin B1 may play an important role in the proliferation of esophageal SCC. Our positivity rate of cyclin B1 (56.7%) and the immunoresponse of basal cells of the normal mucosa, with nucleolar staining, was consistent with their report.

Soria et al. (6) reported that although no significant difference was observed in prognosis between cancers with and without cyclin B1 expression in non-small lung cancer, the prognosis of SCCs with cyclin B1 expression was significantly worse than that in SCCs without cyclin B1 expression. In addition, Kushner et al. (11) reported that SCCs of the head and neck with cyclin B1 expression have a more advanced stage than those SCCs without cyclin B1 expression. Therefore, there may be some special biological significance of cyclin B1 expression in SCCs.

Our results demonstrated that immunohistochemical expression of cyclin B1 protein as well as length of the tumors, depth of the tumors, lymph node metastasis, and TNM stage could be an independent prognostic indicator in esophageal SCCs.

Furthermore, we noted that the staining pattern of cyclin B1 in esophageal SCC varied and was divided into nuclear dominant expression and cytoplasmic dominant expression. Our most prominent discovery was that the prognosis in esophageal SCCs with nuclear dominant expression of cyclin B1 was significantly more unfavorable than that of tumors with cytoplasmic dominant expression. And a multivariate analysis demonstrated that the nuclear dominant cyclin B1 expression was found to be an independent prognosticator in patients with esophageal SCCs expressing cyclin B1. In the previous study of Kawamoto et al. (12) , it has been also reported that the cytoplasmic expression of cyclin B1 protein was recognized in the nonmitotic phase, and nuclear expression in the mitotic phase in human breast cancer. There have been some investigations regarding the mechanism of transition of the cyclin B protein expression in the cancer cell and the difference of the function. Cyclin B1 appears in the cytoplasm of cancer cells in S-phase, it is transported to the nucleus at the G2-M transition and is broken down in anaphase by a ubiquitin-dependent pathway (17) . Cyclin B1 binds to the protein kinase p34cdc2 in the cytoplasm of dividing cells, and this complex is transported in the nucleus at the G2-M transition (16) . Toyoshima et al. (15) showed that cytoplasmic localization of cyclin B1 during interphase was directed by its nuclear export signal-dependent transport mechanism. Our further study was motivated by the hypothesis that the nuclear predominant expression of cyclin B1 might indicate the repeated rounds of the cell cycle, reflecting the mitotic activity and the malignant potential of the carcinoma cells. Although the functional mechanism of cyclin B1 protein on the proliferation of carcinoma cells still remains under investigation, esophageal SCCs with cyclin B1 expression, especially with nuclear dominant expression of cyclin B1 may have a more malignant potential.

In conclusion, cyclin B1 expression, especially nuclear dominant expression, can be significant as a prognostic indicator in patients with esophageal SCCs. We believe that our findings must make a hint to resolve the relation of the cell cycle to the proliferation and invasiveness of tumor in SCC of the esophagus.


   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 a research grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan. Back

2 To whom requests for reprints should be addressed, at Department of General Surgery, Fukuoka Dental College Hospital, 2-15-1, Tamura, Sawara Ward, Fukuoka, 814-0193, Japan. Phone: 81-92-801-0526; Fax: 81-92-801-0735; E-mail: nozoet{at}surg2.med.kyushu-u.ac.jp Back

3 The abbreviations used are: SCC, squamous cell carcinoma; TBS, Tris-buffered saline. Back

Received 7/27/01; revised 10/23/01; accepted 11/ 6/01.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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