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Annals of Surgical Oncology 8:598-604 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Clinical Significance and Prognostic Value of Apoptosis Related Proteins in Superficial Esophageal Squamous Cell Carcinoma

Masataka Matsumoto, MD, Shoji Natsugoe, MD, PhD, Saburo Nakashima, MD, Hiroshi Okumura, MD, Hironori Sakita, MD, Masamichi Baba, MD, PhD, Sonshin Takao, MD, PhD and Takashi Aikou, MD, PhD

From The First Department of Surgery, Kagoshima University School of Medicine, Kagoshima, Japan.

Correspondence: Address correspondence and reprint requests to: Masataka Matsumoto, MD, The First Department of Surgery, Kagoshima University School of Medicine, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan; Fax: 81-99-265-7426.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The purpose of the present study was to examine the expression of cell cycle regulators [p53, p21WAF1/CIP1 (p21), and Rb] and apoptosis related proteins Bax and Bcl-XL and to evaluate the relationship between their expressions and clinicopathological findings in patients with superficial squamous cell carcinomas of the esophagus.

Methods: We immunohistochemically investigated the expression of p53, p21, Rb, Bax, and Bcl-XL in 79 patients with superficial esophageal carcinoma.

Results: p21 overexpression was found in mucosal carcinoma (P = 0.05) and a high Bcl-XL score was observed for submucosal carcinoma (P = 0.03). The patients with high Bcl-XL score had more frequent lymphatic invasion and lymph node metastasis than did those with low Bcl-XL score (P < 0.05). Univariate analysis revealed significantly shorter survival in patients with high Bcl-XL expression than in those with low Bcl-XL expression, but Bcl-XL expression was not identified as an independent prognostic factor by multivariate analysis.

Conclusions: Because Bcl-Xl expression correlated well with depth of tumor invasion, lymphatic invasion, and lymph node metastasis, examination of Bcl-XL expression will help to estimate the properties in superficial squamous cell carcinoma of the esophagus.

Key Words: Superficial esophageal squamous cell carcinoma • p53 - p21WAF1/CIP1 • Rb • Bax • Bcl-XL • Apoptosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The remarkable proliferative ability of carcinoma cells is due to an aberration in the regulation of proliferation and differentiation. In fact, oncogenes and tumor suppressor genes play several important roles in these systems. Recent studies have indicated that apoptosis is related to cell transformation into cancer. Because bcl-2 gene was found to be an apoptosis suppressor gene, many oncogenes and tumor suppressor genes related to apoptotic pathway have been identified. Bcl-2 family proteins regulate one of the steps in a pathway for programmed cell death,1–4 which has been conserved by evolution. Some of the members of this gene family, including Bcl-2 and Bcl-XL, are inhibitors of cell death, whereas others such as Bax, Bak, and Bcl-XS are promoters of apoptosis. Furthermore, in many tumors, these proteins can physically interact with each other in a network of homo- and heterodimers in which the relative proportions of the anti-apoptotic and pro-apoptotic members of this family determine the ultimate sensitivity of cells to cell death stimuli.4– 12

Cell cycle regulators also play an important role in tumor proliferation. p53 responds to different forms of cellular stress by targeting and activating genes involved in growth arrest and cell death. One of the major targets of p53-induced transcription is the p21WAF1/CIP1 (p21) gene. The p21 gene encodes a nuclear protein member of the cyclin-dependent kinase inhibitory KIP family, which is related to senescence and cell quiescence.13 p21 is also transcriptionally regulated by p53. After wild-type p53 is activated by DNA damage, p21 induces G1 arreSt. The apoptotic gene Bax and the antiapoptotic gene Bcl-XL of p53 dependent pathway, are involved in an apoptotic pathway. Retinoblastoma gene (Rb) is a suppressor gene whose inactivation has been shown in various types of carcinoma, including esophageal squamous cell carcinoma (SCC). The primary mechanisms in esophageal carcinogenesis include defects in the Rb and p53 pathways, and their potential synergistic effect in deregulating the cell cycle and apoptosis.

The prognosis of patients with esophageal carcinoma is still poor. Cell proliferation and apoptosis might be key targets for regulating tumor progression, including esophageal SCC. Some molecular mechanisms that inhibit tumor proliferation may act specifically in the early stage of esophageal SCC.

In the present study, we examined immunohistochemical expression of cell cycle regulators (p53, p21 and Rb) and apoptosis related proteins (Bax and Bcl-XL) in superficial esophageal SCCs, and analyzed their relationship with clinicopathological findings. Furthermore, we evaluated the correlation between p53 expression and expression of the other proteins.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Seventy-nine consecutive patients with superficial esophageal SCC underwent esophagectomy at Kagoshima University Hospital from 1985 to 1996. The ages of the 74 males and 5 females ranged from 36 to 84 years (mean, 63.7 years). None of the patients received radiotherapy or chemotherapy prior to surgery.

Clinicopathological findings were based on the criteria established by the TNM classification for esophageal carcinoma of the International Union Against Cancer.14 The superficial esophageal SCCs consisted of 21 well differentiated, 47 moderately differentiated, and 11 poorly differentiated types. Eight tumors were located in the upper third of the esophagus, 43 in the middle third, and 28 in the lower third. According to the subdivision of tumor depth, 38 patients had lesions localized to mucosal layer and 41 had lesions invading the submucosa. Lymph node metastasis was found in 24 of 79 patients (30.4%). Lymphatic and venous invasion was found in 40.5% (32/79) and 10.1% (8/79) of the patients, respectively (Table 1).


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  		TABLE 1. Clinicopathologic characteristics of 79 patients with superficial esophageal squamous cell carcinoma
 
Immunohistochemistry
After primary lesions were fixed in 10% formaldehyde, and routinely embedded in paraffin, 3-micrometer thick sections were prepared for immunohistochemistry. Sections were deparaffinized in xylene, rehydrated in graded ethanol, and incubated in 0.3% H2O2 solution in methanol for 30 minutes to block the endogeneous peroxidases. All sections were autoclaved in 10 mM sodium citrate (pH 6.0) for 10 minutes and allowed to cool at room temperature. After incubation in 3% skimmed milk for 30 minutes at room temperature, the sections were incubated overnight at 4°C with the following five antibodies: Bax (Rabbit anti-human Bax, rabbit polyclonal antibody, DAKO, 1:50), Bcl-XL (Bcl-xL, goat polyclonal antibody, Santa Cruz Biotechnology, 1:50), p53 (p53, mouse monoclonal antibody, Novo Castra, 1:500), p21 (p21, mouse monoclonal antibody, Santa Cruz Biotechnology, 1:500), and Rb (Rb, mouse monoclonal antibody, Santa Cruz Biotechnology, 1:100). These reactions were developed with an avidin-biotin immunoperoxidase technique (ABC method).15 The reaction was visualized using the Vectastain Elite ABC kit and a 3,3-diaminobenzidine solution (Vector Laboratories, Inc., Burlingame, CA). Sections were then slightly counterstained with hematoxylin.

Expression of p53 and p21 in over 10% of the cells examined was considered positive. Staining results of Rb were assigned to one of the following categories: 0 (0%), 1 (1–25%), 2 (26–50%), 3 (51–75%), or 4 (76–100%). The following parameters were assessed for Bax and Bcl-XL,: (a) the percentage of Bax or Bcl-XL positive tumor cells was determined semiquantitatively by assessing the whole tumor section, and each sample was then assigned to a group (0, 0–5%; 1, 6–25%; 2, 26– 50%; 3, 51–75%; 4, 76–100%); (b) the intensity of Bax or Bcl-XL immunostaining was determined as 0 (negative), 1 (weak), 2 (strong), 3 (very intense). Intensity was judged relative to normal esophageal squamous epithelium within the sample, which was arbitrarily designated as 2; and (c) an immunoreactive score was calculated by multiplication of the percentage of positive cells and the staining intensity, as proposed by Krajewska et al.16 Because heterogeneous staining intensities were observed within each sample, each component intensity was scored independently and the results were summarized. For example, a specimen containing 25% tumor cells with very strong intensity (1 x 3 = 3), 25% tumor cells with strong intensity (1 x 2 = 2), and 50% tumor cells with weak immunoreactivity (2 x 1 = 2) received a score of 3 + 2 + 2 = 7. Sections without primary antibodies as well as those with nonimmunized rabbit serum for Bax, goat serum for Bcl-XL, and mouse serum for p53, p21 and Rb, served as negative controls. All immunostained slides were evaluated by two independent observers (MM and SN). Although the results of immunohistochemical expression were different in five sections between two observers, these were evaluated by third observer (HO).

Statistical Analyses
Statistical analysis was performed by the Student’s t-test and {chi} 2 teSt. The Kaplan-Meier method was used, and analysis was also evaluated by the Log-rank teSt. Prognostic factors were tested by univariate and multivariate analyses (proportional hazard model). A P value of < 0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Expression of p53, p21, Rb, Bax, and Bcl-XL
p53, p21, and Rb were expressed in the nuclei (Fig. 1a) and Bax and Bcl-XL were expressed in the cytoplasm (Fig. 1b). The positive rate of p53 and p21 expression was 58.2% and 45.6%, respectively. The mean score of Rb, Bax, and Bcl-XL was 1.7 ± 0.9, 6.1 ± 1.2, and 4.7 ± 1.8, respectively.



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  		FIG. 1. Examples of positive immunostaining in superficial esophageal squamous cell carcinoma. (A) Expression of Rb in the nuclei is shown (original magnification, x400). (B) Expression of Bcl-XL in the cytoplasm is shown (original magnification, x 100).

 
Expression of p53, p21, Rb, Bax, and Bcl-XL versus Pathological Findings
Table 2 shows the relationship between p53, p21, Rb, Bax, Bcl-XL, and pathological findings. p21 expression significantly correlated with histological grading and depth of tumor invasion (P = 0.004 and P = 0.05, respectively). Bcl-XL expression was found to differ significantly based on depth of tumor invasion, lymphatic invasion, and lymph node metastasis (P = 0.03, P = 0.02, and P = 0.04, respectively). No significant differences were found in the expression of p53, Rb, and Bax with regard to histological grading, tumor depth, lymphatic invasion, venous invasion, and lymph node metastasis.


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  		TABLE 2. Correlation between expression of p53, p21, Rb, Bax, and Bcl-XL in superficial esophageal SCCs and pathological findings
 
Rb Expression as a Factor of p53 and p21 Expression
Rb expression was divided into four groups according to p53 and p21 expression. The mean score of Rb expression in each group was as follows: p53-/p21-; 1.6 ± 1.0, p53-/p21+; 2.1 ± 0.7, p53+/p21-; 1.4 ± 1.0, p53+/p21+; 1.9 ± 0.9 (Table 3). A significant difference was found in Rb expression between the p53-/p21+ group and the p53+/p21- group (P = 0.032).


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  		TABLE 3. Correlation between expression pattern of p53/p21 and Rb in superficial esophageal SCCs
 
p53 Expression versus Bax and Bcl-XL Expression
The mean score of Bax expression in p53 positive and p53 negative tumors was 6.1 ± 1.3 and 6.1 ± 1.2, respectively. The mean score for Bcl-XL expression in the p53 positive and negative tumors was 4.7 ± 1.5 and 4.7 ± 1.9, respectively. Neither Bax nor Bcl-XL expression correlated with p53 expression (Table 4).


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  		TABLE 4. Correlation between expression of Bax, Bcl-XL, and p53 in superficial esophageal SCCs
 
Survival Analyses
Five-year survival rate was analyzed according to the expression of each marker. The 5-year survival rate was significantly better in the patients with negative Bcl-XL expression than in those with positive expression (74% vs. 56%, P = 0.048)(Fig. 2). A significant difference was not found in the expression of the remaining markers. Factors related to prognosis were evaluated by univariate and multivariate analyses. According to the univariate analysis, lymph node metastasis and Bcl-XL were related to prognosis. However, only lymph node metastasis was identified as an independent prognostic factor by multivariate regression analysis (Table 5).



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  		FIG. 2. Survivals according to Bcl-XL expression. Five-year survival rate of patients with high Bcl-XL score was 52.3%, whereas those with low Bcl-XL score was 75.8% (Log-rank test, P = 0.048).

 

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  		TABLE 5. Univariate and multivariate analyses of prognostic factors for survival using Cox’s proportional hazard model
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
p53 plays an important role in cell cycle regulation and induction of apoptosis. Dysfunction of p53 may cause tumor progression and inhibit apoptosis. To date, the relationship between cell regulation and apoptosis has not been elucidated in superficial esophageal carcinoma. p53 overexpression is related to both the vertical and horizontal extent of early stage carcinoma of the esophagus. Wang et al.17 reported that p53 protein accumulation and mutation occurred in the early stage of human esophageal carcinogenesis. In the present study, because a significant difference was found in Rb expression between p53-/p21+ group and the p53+ /p21- group, G1 cell cycle arrest might be easily induced in the former group. In our previous study on advanced esophageal carcinoma, the 5-year survival rate of patients positive for p21 expression was significantly better than that of p21 negative patients in the p53 negative group.18 Hashimoto et al.19 reported that patients with positive p53 expression and low Rb expression had significantly worse survival rates and deeper tumor invasion than other groups. The proliferation of cancer cells, evaluated by MIB-1, was related to the depth of invasion, lymph node metastasis, and lymphatic invasion.20 These results indicated that cell regulation was closely associated with malignancy in esophageal carcinoma.

Bcl-XL overexpression was found in the tumors with deeper invasion or lymph node metastases. Conversely, no significant difference was found between Bax expression and clinicopathological findings. These results suggest that induction of apoptosis might be inhibited even in highly malignant early stage carcinomas such as tumors showing deeper layer invasion and lymph node metastasis. In the present study, the 5-year survival rate was significantly higher in patients with low Bcl-XL scores than in those with high Bcl-XL scores. Torzewski et al.21 reported that no correlation was found in patients with invasive esophageal carcinoma between Bcl-XL expression and pT or pN category. However, patients with low immunoreactive Bcl-XL expression scores had a lower 5-year survival rate than patients with high immunoreactive scores. This result differs from our findings, as a result of different scores of Bcl-XL expression and different study group.

Experimental data indicate that the relative ratio between proapoptotic and antiapoptotic molecules determines the susceptibility of cells to apoptosis.5 In the majority of locally advanced head and neck SCCs, Bcl-XL overexpression was found.22 Bcl-XL immunoreaction is stronger in colorectal carcinomas23 and gastric carcinomas24 than in normal controls, and enhanced expression of Bcl-XL in pancreatic cancer is associated with decreased patient survival.25 In breast cancer, Bcl-X overexpression is correlated with higher tumor grade, increased number of positive nodes, and decreased survival time.26 In the present study, we did not observe a significant relationship between Bax expression and clinicopathological findings. Bax overexpression in patients with breast adenocarcinoma, glottic SCC, and colorectal carcinoma was indicative of favorable outcome,27–29 but in ovarian carcinomas, overexpression indicated poor prognosis.30 No significant relationship between Bax expression and prognosis was found in gastric carcinoma.31 These results suggest that induction of apoptosis differs in various types of tumors. p53 status did not correlate with Bax and Bcl-XL expression in the present study which suggests that a different apoptotic pathway may be related to tumor progression in early stage carcinoma of the esophagus.

In conclusion, G1 cell cycle arrest occurs in p53 negative and p21 positive tumors, due to the high level of Rb protein induction. Bcl-XL expression indicated that apoptosis was inhibited in patients with malignancies such as deep tumor invasion and lymph node metastasis.

Received for publication November 17, 2000. Accepted for publication April 6, 2001.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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