食管鳞癌COX-2蛋白表达意义研究进展

与对食管腺癌的作用相似,环氧合酶-2(COX-2)的表达也可能影响食管鳞癌的发生、发展及预后.多数食管鳞癌有COX-2蛋白不同程度的表达,但其真正临床意义尚未明了.COX-2选择性抑制剂可抑制食管鳞癌细胞生长,诱导细胞凋亡,可能对化疗和放疗起增敏作用.     

HLA-DR antigen expression in squamous epithelial dysplasia and squamous cell carcinoma of the esophagus: an immunohistochemical study

To clarify the biologic significance of esophageal squamous epithelial dysplasia, especially the similarity to carcinoma in situ, immunohistochemical investigation of HLA-DR antigen expression and lymphocyte infiltration was performed. HLA-DR antigen was expressed in 12 of the 35 invasive carcinomas (34.4%), 23 of the 38 intraepithelial carcinomas (60.5%), 21 of the 50 areas of dysplasia (42.0%) and only 2 of the 625 specimens of non-cancerous squamous epithelium (0.3%). The HLA-DR-positive rate of dysplasia localized continuous to HLA-DR-positive carcinoma was 68.4%, which was significantly higher than that for HLA-DR positive dysplasia localized continuous to HLA-DR negative cancer (11.1%) (p<0.05). In areas of dysplasia and intraepithelial carcinoma, T cell infiltration was significantly increased at the sites of HLA-DR antigen expression (P<0.01). B cell infiltration was also more common in areas of positive expression. These results suggest that HLA-DR antigen is associated with the local immune response to squamous epithelial dysplasia, and that HLA-DR antigen expression may prevent tumor invasion similarly to its role in intraepithelial carcinoma.     

Cyclooxygenase-2 expression is related to prognosis in patients with esophageal squamous cell carcinoma

Aim

Esophageal carcinoma is one of the most aggressive malignancies. Many studies have examined various biological factors associated with the malignant potential of esophageal carcinoma. Cyclooxygenase (COX)-2 is overexpressed in various types of human malignancies, including esophageal carcinomas. Although some groups have described COX-2 expression in esophageal adenocarcinoma, few studies have reported COX-2 expression in esophageal squamous cell carcinoma (ESCC).

Methods

We immunohistochemically investigated relationships between COX-2 overexpression in surgical specimens of primary tumors in 228 patients with ESCC. Relationships between COX-2 expression and clinicopathological factors, including prognosis, were analyzed. COX-2 expressions were classified into 4 criteria: Score 0, no staining; Score 1, <10% staining; Score 2, 10–90% staining; and Score 3, >90% staining.

Results

Scores of COX-2 immunoreactivity in 228 patients were as follows: Score 0, 21 of 228; Score 1, 71of 228; Score 2, 117 of 228; and Score 3, 19 of 228, respectively. COX-2 expression was significantly correlated with depth of invasion and tumor stage (p = 0.03 and p = 0.04, respectively). The 5-year survival rate of patients decreased significantly with increased expression of COX-2 (p = 0.005). Multivariate regression analysis indicated COX-2 expression as an independent prognostic factor for ESCC.

Conclusions

COX-2 overexpression was significantly correlated with depth of invasion, tumor stage and survival in ESCC. Evaluation of COX-2 expression should be useful for determining tumor properties, including prognosis, in patients with ESCC.     

口腔鳞癌组织中环氧化酶-2和血管内皮生长因子的表达及其相关性研究

目的:探讨环氧化酶-2(cyclooxyge-nase-2,COX-2)和血管内皮生长因子(vascularen-dothelialgrowthfactor,VEGF)在口腔鳞癌(oralsquamouscellcarcinoma,OSCC)组织中的表达及其相关性。方法:采用免疫组织化学SP法检测COX-2、VEGF在62例OSCC和10例口腔正常黏膜组织中的表达。结果:COX-2和VEGF在OSCC组织中的阳性表达率分别为100%(62/62)和61·3%(38/62),在正常黏膜组织中的阳性表达率均为0,两者差异有统计学意义,P<0·01。COX-2表达与OSCC的分化程度显著相关,P<0·01,但与肿瘤的大小、临床分期及淋巴结转移无相关性。VEGF表达与OSCC的临床分期及淋巴结转移显著相关,P<0·01,与肿瘤的大小、分化程度无相关性。OSCC中COX-2与VEGF的表达呈正相关,rs=0·353,P=0·005。结论:COX-2和VEGF在OSCC组织中呈高表达,并分别与鳞癌分化程度及临床分期相关,两者可作为防治OSCC的潜在靶点。     

Keratin expression in normal esophageal epithelium and squamous cell carcinoma of the esophagus

The 8-nm keratin filament is a major component of the cytoskeleton of epithelial cells and epithelial-derived cancers (carcinomas). Recently, it has been shown that the pattern of keratins produced by an esophageal epithelial cell undergoes change upon malignant transformation. In order to evaluate the potential importance of these differences in providing improved diagnostic techniques for pathology, we have investigated the consistency of the patterns of keratins expressed in normal esophageal epithelium, squamous cell carcinoma (SQCC) of the esophagus, and cultured esophageal epithelial cells. In six patients, the keratin pattern expressed by SQCC of the esophagus and corresponding normal esophageal epithelium was consistently different as judged by immunoblot analysis of electrophoretically separated protein extracts. Whereas the SQCCs typically expressed major keratins with molecular weights of 58,000, 56,000, 50,000, and 46,000, the normal esophageal epithelium produced two major keratins with molecular weights of 58,000 and 52,000 and a minor keratin with a molecular weight of 56,000. When normal esophageal epithelial cells were grown in tissue culture, their keratin pattern changed, and keratins with molecular weights of 58,000, 56,000, 52,000, 50,000, 46,000, and 40,000 were expressed. Although some minor variations in keratin patterns were seen, the major differences in keratin pattern expressed by normal esophageal epithelial tissue, SQCC of the esophagus, and cultured esophageal cells were consistent and reproducible.     

食管鳞状细胞癌p16基因突变及表达分析

目的探讨食管鳞状细胞癌p16基因突变及mRNA表达情况与临床病理的关系。方法采用PCR-SSCP、DNA测序技术及RT-PCR技术检测31例ESCCp16基因突变及mRNA表达情况。结果31例ESCC有6例发生基因突变,3例发生基因纯合性缺失,p16基因mRNA表达癌组织显著低于癌旁正常组织(P<0.05)。在癌组织中p16基因变异组mRNA表达显著低于p16基因正常组(P<0.05),mRNA表达与性别、年龄、浸润深度、淋巴结转移、远处转移等无显著性相关。结论p16基因mRNA的异常表达可能与ESCC发生有关,但单纯检测p16基因mRNA表达水平与预测ES-CC患者预后的意义不大。     

Polypoid squamous cell carcinoma of the esophagus

Since 1971, 111 patients with esophageal carcinoma have undergone esophagectomy at the affiliated hospitals of Nippon Medical School. Of the 101 patients with ordinary squamous cell carcinoma, seven (7%) had intraluminal polypoid masses, endoscopically, and radiologically. The criteria used to select cases were as follows: (1) a size greater than 3 cm, (2) an intraluminal polypoid or pedunclated tumor, and (3) absence of wall construction and ulceration. Four of the seven polypoid cases have survived more than 5 years. One has lived more than 3 years. The 5-year survival rate of those patients with the polypoid type was 71%, but it was only 11% for the other types (P less than 0.05). Age, sex, size or location of the tumor, histologic grade, or lymph node metastasis did not affect survival. Only the incidence of adventitial involvement was significantly lower for the polypoid type. These results indicate that polypoid-type squamous cell carcinoma of the esophagus has a fairly good prognosis after surgery.     

尼美舒利对不同COX-2表达水平的食管鳞癌细胞的抑制作用

目的：比较选择性环氧合酶-2（COX-2）抑制剂尼美舒利对不同COX-2表达水平的食管鳞癌细胞的抑制作用。方法：选取食管鳞癌细胞株EC 109、KYSE 150和TE-1,采用Western blot方法测定COX-2蛋白表达、MTT法检测细胞增殖抑制,流式细胞术检测细胞周期和细胞凋亡,观察尼美舒利对各组细胞的增殖抑制和促凋亡作用。结果：COX-2蛋白在EC 109细胞中呈高表达,KYSE 150细胞中呈中等度表达,TE-1细胞不表达COX-2蛋白。尼美舒利在50μmol/L-400μmol/L浓度区间可抑制EC 109、KYSE 150细胞的增殖（P〈0.05）,并呈剂量依赖性,在400μmol/L时对TE-1细胞有抑制作用。EC 109细胞尼美舒利的IC50值最低,KYSE150次之,TE-1最高。尼美舒利可使EC 109和KYSE 150的细胞周期阻滞于G0/G1期,并诱导细胞凋亡,但对TE-1细胞无上述作用。结论：尼美舒利对表达COX-2的食管鳞癌细胞有较好的增殖抑制和促凋亡作用。     

尼美舒利对不同COX-2表达水平的食管鳞癌细胞的抑制作用

目的:比较选择性环氧合酶-2(COX-2)抑制剂尼美舒利对不同COX-2表达水平的食管鳞癌细胞的抑制作用。方法:选取食管鳞癌细胞株EC 109、KYSE 150和TE-1,采用Western blot方法测定COX-2蛋白表达、MTT法检测细胞增殖抑制,流式细胞术检测细胞周期和细胞凋亡,观察尼美舒利对各组细胞的增殖抑制和促凋亡作用。结果:COX-2蛋白在EC 109细胞中呈高表达,KYSE 150细胞中呈中等度表达,TE-1细胞不表达COX-2蛋白。尼美舒利在50μmol/L-400μmol/L浓度区间可抑制EC 109、KYSE 150细胞的增殖(P<0.05),并呈剂量依赖性,在400μmol/L时对TE-1细胞有抑制作用。EC 109细胞尼美舒利的IC50值最低,KYSE150次之,TE-1最高。尼美舒利可使EC 109和KYSE 150的细胞周期阻滞于G0/G1期,并诱导细胞凋亡,但对TE-1细胞无上述作用。结论:尼美舒利对表达COX-2的食管鳞癌细胞有较好的增殖抑制和促凋亡作用。     

hMLH1蛋白在食管鳞状细胞癌和不典型增生组织中的表达

目的：探讨同一食管癌患者食管的鳞状细胞癌组织、不典型增生组织、正常鳞状上皮组织中错配修复基因1（human mutl homolog 1，hMLH1）的蛋白表达情况，深入研究它与食管鳞状细胞癌发生发展的关系。方法：取92例食管鳞状细胞癌患者的病变组织，其病理切片中鳞状细胞癌组织、不典型增生组织和正常鳞状上皮组织均存在，采用免疫组织化学的方法，检测hMLH1蛋白在3种不同组织中的表达，并分析其与性别、年龄、分化程度、浸润深度、肿瘤分期、淋巴结转移等临床病理参数之间的关系。结果：hMLH1蛋白在食管鳞状细胞癌组织、不典型增生组织、正常鳞状上皮组织细胞核中的阳性表达率分别为36．96％、56．52％、84．78％，鳞状细胞癌组织和不典型增生组织均显著低于正常食管鳞状上皮组织（P〈0．01）。鳞状细胞癌组织中hMLH1蛋白表达阴性者，年龄较阳性者大（P〈0．05）；hMLH1蛋白表达与肿瘤分期、淋巴结转移等有明显相关性（P〈0．05）。结论：hMLH1基因缺失可能在早期就参与了食管鳞状细胞癌的发生过程，hMLH1蛋白可能抑制或延缓食管鳞状细胞癌的发生和发展。     

The relationship between dysplasia and squamous cell carcinoma of the esophagus and the consumption of alcohol and tobacco

Forty-nine cases of esophagectomy and 242 autopsied cases were studied to delineate the pattern of the genesis of esophageal carcinoma. Severe dysplastic lesions found to be commonly associated with carcinoma of the esophagus, but with the exception of one case, these lesions were not associated with other carcinomas. They were more frequent in the cases of multiple primary cancer. This suggests that squamous carcinoma of the esophagus develops from severe dysplasia in a very similar manner to a carcinoma of the cervix uteri. Almost all cases of multiple primary cancers of the oropharynx and the esophagus had a history of heavy smoking and alcoholic drinking habits; so, in some manner, alcohol and tobacco consumption appear to increase the susceptibility of the squamous mucosa to a malignant transformation.     

Gene expression of differentiation-specific keratins in oral epithelial dysplasia and squamous cell carcinoma

The aim of the study was to investigate the differentiation-specific keratins (K4, K13, K1 and K10) in oral epithelial dysplasia and squamous cell carcinoma (SCC). Alterations in keratin gene expression were determined by in situ hybridization using 35S-labeled riboprobes and immunohistochemistry with monoclonal antibodies. In mild dysplasia, both sets of differentiation keratins were expressed in the same group of cells but in moderate lesions, expression of K4 and K13 was reduced in the presence of enhanced K1 and K10 synthesis. In severe dysplasia, neither mRNAs nor proteins were detected. In tumor islands of well and moderately differentiated SCCs, the K4/K13 complex was co-expressed with K1/K10, but in poorly differentiated carcinomas, differentiation keratins were absent. Consequently, mild oral epithelial dysplasia and well differentiated SCC retain an essentially normal pattern of keratin gene expression and hence epithelial differentiation while in severe dysplasia and poorly differentiated SCC keratin gene expression reflects the gross changes in epithelial differentiation and maturation.     

Intramural squamous cell carcinoma of the esophagus.

A case of squamous cell carcinoma arising from an esophageal intramural squamous epithelial cyst is reported. Review of the literature reveals no previous reports of malignant transformation of esophageal cysts, although there have been reports of approximately 64 cases of benign esophageal cysts, and 35 cases of carcinoma arising in esophageal diverticula. In the present case, there was a history of increasing dysphagia for 2 months. Esophagram demonstrated a 4.5-cm concentric narrowing of the proximal esophagus just below the superior esophageal ring. Esophagoscopies revealed an esophageal stricture with intact mucosa, and bronchoscopy showed the lesion to be producing tracheal deviation. Multiple esophageal biopsies revealed mild mucosal hyperplasia with deep submucosal inflammatory changes suggesting an underlying lesion. Despite lack of histologic proof of malignancy, the patient underwent radiation therapy and bleomycin chemotherapy on the basis of the highly suggestive radiographic findings, but died with bilateral bronchopneumonia 6 months after admission. Autopsy demonstrated a 1.5-cm long intramural esophageal squamous epithelial cyst, from which arose a locally invasive squamous cell carcinoma, without mucosal involvement or metastases. There was no demonstrable evidence of any associated esophageal diverticulum.     

The vulnerable esophagus: riboflavin deficiency and squamous cell dysplasia of the skin and the esophagus

Eleven male baboons fed a synthetic diet completely lacking in riboflavin developed, after 15-36 weeks, profound macroscopic and microscopic architectural disorganization of the skin, mouth, and esophagus. The cutaneous lesions showed hyperkeratosis, gross derangement of keratinization with acanthosis, and impressive pseudocarcinomatous hyperplasia. In 5 baboons that died or were killed, there were large penetrating lesions having raised epithelial edges at the lower third of the esophagus or at the cardioesophageal junction, with gross epithelial hyperplasia and grossly deranged and thickened keratinization and numerous mitotic figures. None of the 8 control animals given riboflavin showed these abnormalities.     

VEGF-C expression correlates with histological differentiation and metastasis in squamous cell carcinoma of the esophagus

Vascular endothelial growth factor C (VEGF-C) is known to act in lymphangiogenesis. Recent reports suggest VEGF-C plays a role in the spread of several cancers to the lymph system. Lymphatic spread is a critical prognostic factor in esophageal cancer, however, the molecular mechanism involved in the spread of cancerous cells remains unclear. In the present study the clinicopathological implication of VEGF-C was analyzed using immunohistochemistry. Seventy-one patients with esophageal squamous cell carcinoma (ESCC) resected in our institute were included in this study. Formalin-fixed paraffin-embedded specimens were stained for VEGF-C and the correlation between the staining, its clinicopathological parameters and its prognostic power were analyzed statistically. Only histological grade (differentiation) was shown to have a statistically significant correlation with VEGF-C expression (p=0.028). Age (p=0.064), lymph node metastasis (pN) (p=0.085) and vascular invasion (p=0.092) tended to correlate with VEGF-C expression although on analysis this correlation was not statistically significant. The results suggested there is no prognostic implication for VEGF-C in ESCC (p=0.80). There is no significant correlation between VEGF-C expression and clinicopathological parameters involved in lymphatic spread. However, VEGF-C expression might play an important role in metastasis of ESCC since histological grade was closely related to lymph node metastasis and distant metastasis.