Expression of cyclin E in dysplasia, carcinoma, and nonmalignant lesions of Barrett esophagus

BACKGROUND: Barrett esophagus (BE) is a condition in which the normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. BE is a premalignant lesion because it is the initiating factor in a metaplasia-dysplasia-carcinoma sequence. METHODS: Expression of the proliferation-associated molecule cyclin E was immunohistochemically determined in metaplastic specialized epithelium (SE; n = 24), low grade dysplasia (LGD; n = 21), high grade dysplasia (HGD; n = 17), and invasive adenocarcinoma (CA; n = 35) from 36 esophagectomy specimens. In addition, endoscopically obtained samples of SE with minimal inflammatory changes (n = 11) and SE adjacent to erosions or ulcerations were tested for cyclin E expression. RESULTS: In the surgical specimens, expression of cyclin E was found in 0 of 24 SE (0%), 2 of 21 LGD (9.5%), 3 of 17 HGD (17.6%), and 5 of 35 CA (14. 3%). In the biopsy specimens, expression of cyclin E was found in all samples adjacent to erosions or ulcerations, whereas SE with minimal inflammatory changes was invariably negative for cyclin E. CONCLUSIONS: Accumulation of cyclin E can be found by means of immunohistochemistry in premalignant and malignant lesions in BE as well as in regenerative metaplastic epithelium. The determination of cyclin E expression is therefore not useful in the identification of BE patients with an increased risk for the development of carcinoma.     

Dysplasia in Barrett esophagus

BACKGROUND: Dysplasia in Barrett esophagus is a premalignant condition that is associated with an increased risk of developing esophageal adenocarcinoma. Unfortunately, clinical investigation aimed at prevention of progression to malignant disease has been hampered by the variable prevalence of dysplasia reported in the literature. The objective of the current study was to more accurately determine the prevalence of dysplasia among individuals with Barrett esophagus who would be available for enrollment in a chemoprevention trial. METHODS: The pathology archives of 3 institutions were reviewed over a 5-year period for all reports of diagnoses of Barrett esophagus. Surgical cases, malignancies, and duplicate or referral cases were excluded from the analysis. RESULTS: A total of 790 cases of Barrett esophagus were identified. Of these, 37 (4.7%) were cases of low-grade dysplasia (LGD), and 20 (2.5%) were cases of high-grade dysplasia. The University of Michigan Medical Center (Ann Arbor, MI) diagnosed 18 cases of LGD, Henry Ford Hospital (Detroit, MI) diagnosed 15 cases of LGD, and Brigham and Women's Hospital (Boston, MA) diagnosed 4 cases of LGD in patients with Barrett esophagus over the 5-year study period. CONCLUSIONS: The confirmed low prevalence of cases of LGD will affect the design of future clinical trials of chemopreventive interventions for Barrett esophagus.     

Esophageal adenocarcinoma arising in Barrett esophagus

The major risk factors for esophageal adenocarcinoma are gastroesophageal reflux disease (GERD) and Barrett esophagus, a squamous-to-columnar cell metaplasia that predisposes to malignancy. Adenocarcinomas in Barrett esophagus are thought to arise through a sequence of growth-promoting, genetic alterations that accumulate until the cells have acquired the physiologic hallmarks of cancer proposed by Hanahan and Weinberg. Moreover, GERD and Barrett esophagus are associated with chronic esophagitis, and inflammation is a well known risk factor for cancer formation. The cell that gives rise to Barrett metaplasia is not known. It has been proposed that the metaplasia may arise from a change in the differentiation pattern of stem cells that either reside in the esophagus or are recruited to the esophagus from the bone marrow. Alternatively, it is possible that Barrett metaplasia develops through the conversion of one differentiated cell type into another. Regardless of the cell of origin, Barrett metaplasia ultimately must be sustained by stem cells, which might be identified by intestinal stem cell markers. An emerging concept in tumor biology is that cancer stem cells are responsible for sustaining tumor growth. If Barrett cancers develop from Barrett stem cells, then a therapy targeted at those stem cells might prevent esophageal adenocarcinoma. This report reviews the risk factors for Barrett esophagus and esophageal adenocarcinoma, the mechanisms by which genetic alterations might contribute to carcinogenesis in Barrett esophagus, and the role of stem cells in the development of Barrett metaplasia and adenocarcinoma.     

Apoptotic activity is increased in parallel with the metaplasia-dysplasia-carcinoma sequence of the bronchial epithelium

A high level of apoptotic activity and an independence of apoptosis from the expression of p53 and bcl-2 have been observed in non-small-cell lung carcinoma. We examined 44 samples of normal, metaplastic and premalignant (i.e. mild, moderate and severe dysplasias and carcinoma in situ) bronchial epithelia to evaluate whether differences in the apoptotic activity could already be seen in the stages preceding squamous cell carcinoma of the lung (SQCLC). Apoptotic cells and bodies were visualized by 3' end labelling. The expression of p53 and members of the bcl-2 gene family, such as bcl-2, bax and mcl-1, were determined immunohistochemically with specific antibodies. The relative number of apoptotic cells and bodies [apoptotic index (AI%)] was already increased threefold as the normal bronchial epithelium changed to squamous metaplasia, and the AIs of the dysplastic lesions were about four times higher than those of the normal epithelium. Apoptosis was significantly associated with cell proliferation, as determined by proliferating cell nuclear antigen (PCNA) immunohistochemistry. However, the extent of apoptosis did not correlate with the expression of p53, bcl-2, bax and mcl-1. We conclude that, in the metaplasia-dysplasia-carcinoma sequence in the lung, the elevation of the AI% is an early event associated with cell proliferation activity, but is independent of the expression of p53, bcl-2, mcl-1 and bax.     

DNA甲基化在Barrett食管和食管腺癌的研究

 近年来大量研究表明,肿瘤相关基因启动子区的高甲基化是引发食管腺癌的重要原因之一,并与肿瘤的分化、侵袭、转移、分期和预后等密切相关,可作为食管腺癌临床检测和治疗的新靶点。     

cyclin D1在喉癌组织中的表达研究

目的　探讨cyclinD 1在喉癌组织中的表达及其临床意义。方法　采用免疫组织化学S P法检测 41例喉癌组织中cyclinD 1的表达 ,并以 12例癌旁正常组织作对照 ,进行比较分析。 结果　 41例喉癌组织中cyclinD 1阳性表达率为 5 1.2 % ,12例癌旁正常组织阳性表达率为 16.7% ,两者有显著性差异 (P <0 .0 5 )。cyclinD1的阳性表达率与喉癌患者的性别、年龄、病程、吸烟、饮酒、肿瘤部位和TNM分期无关 (P >0 .0 5 ) ,但与淋巴结有无转移以及喉癌组织的病理分级有显著相关性 (P <0 .0 1)。结论　cy clinD1在喉癌的发生发展过程中起着一定的作用 ,可作为判断喉癌恶性程度和预后的 1个重要参考指标。     

Expression of cyclin E and cyclin D1 in non-small cell lung cancers

The relationships between overexpression of cyclin D1 or cyclin E and clinicopathological factors were investigated in 157 patients with non-small cell lung cancers (NSCLCs) using immunohistochemical analysis. Fifty-eight cases of NSCLCs (58/157, 37%) showed the overexpression of cyclin D1, and 64 cases (64/157, 41%) were positive for cyclin E. Cyclin E and cyclin D1 were infrequently concurrently overexpressed (17/157, 10.8%). Overexpression of cyclin E was more frequently observed in squamous cell carcinoma (29/57, 51%) compared with that in adenocarcinoma (28/86, 33%) (P<0.05). In addition, overexpression of cyclin E was more frequently observed in poorly or moderately differentiated NSCLCs (52/103, 50%) than in well-differentiated ones (12/54, 22%) regardless of their histological types (P<0.01). On the contrary, there was no statistically significant relationship between cyclin D1 overexpression and histological types or grade of tumor differentiation. These findings suggest that expression of cyclin E was frequently independent of that of cyclin D1 and played some roles in the grade of tumor differentiation in NSCLCs.     

亚甲蓝染色内镜诊断Barrett食管的研究进展

近年来西方国家食管贲门交界部腺癌的发病率显著升高。研究认为,Barrett食管是食管腺癌最重要的癌前病变。准确的早期诊断和有效随访是提高Barrett食管患者生存率的重要环节。目前对Barrett食管的诊断主要依靠内镜和病理,即内镜下任何长度的食管黏膜出现柱状上皮样改变并经病理确诊为特异性肠化上皮。但由于早期病灶的微小性和局灶性,内镜下准确的识别特异性肠化上皮及不典型增生在临床上仍比较困难。亚甲蓝染色内镜利用亚甲蓝可以被吸收活跃的细胞吸收着色的原理,通过内镜下喷洒对胃肠道黏膜进行染色,提高内镜对胃肠道黏膜结构的观察能力,有助于内镜医师对肠化上皮的鉴别,但是否可以提高Barrett食管的检出率还存在争议。     

Expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and p53 tumor suppressor in dysplastic progression and adenocarcinoma in Barrett esophagus

BACKGROUND: Barrett esophagus predisposes individuals to esophageal carcinoma, which develops from intermediate stages of tissue dysplasia primarily in the vicinity of the gastroesophageal junction. Understanding the cellular and molecular events in the progression of Barrett esophagus to adenocarcinoma may contribute to its early diagnosis and treatment. Mutation and overexpression of the tumor suppressor p53 have previously been observed in Barrett high grade dysplasia and adenocarcinoma. The expression of the cyclin-dependent kinase (CdK) inhibitor p21 can be up-regulated by p53, resulting in the down-regulation of cell division at the G(1)/S-phase transition. The current study examined the correlation between the expression of p21 and p53 by quantifying their levels during the progression of dysplasia and adenocarcinoma in Barrett esophageal tissues. METHODS: Barrett esophageal tissue samples that were negative or indefinite for dysplasia, contained dysplasia, and contained adenocarcinoma were examined by immunohistochemistry. Paraffin embedded sections of lining and glandular epithelia were adsorbed with primary murine antibodies against human p21 or p53 followed by horseradish peroxidase secondary antibody. An immunoreactivity score for each primary antibody and section was obtained by multiplying a staining intensity factor by the percent of positively stained cells. RESULTS: Nuclear p21 expression was detectable immunohistochemically in Barrett esophagus that was negative for dysplasia, but it was significantly elevated (P 相似文献   

Significance of cyclin B1 expression as an independent prognostic indicator of patients with squamous cell carcinoma of the esophagus.

PURPOSE: Cyclin B1 plays an important role as a mitotic cyclin in the G(2)-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.     

细胞周期蛋白D1和E在食管鳞状细胞癌中的表达及意义

目的　探讨细胞周期蛋白 D1 和 E( cyclin D1 and cyclin E)在食管鳞状上皮癌中的表达及意义。方法　采用 S- P免疫组化方法 ,检测了周期蛋白 D1 和 E在正常食管上皮 ( 2 0例 )、增生上皮 ( 2 1例 )和鳞癌 ( 6 2例 )中的阳性率。结果　正常鳞状上皮中 cyclin E无阳性表达 ,在增生上皮中 cyclin E阳性率为 33.3% ,在鳞癌中阳性率为5 3.2 % ;cyclin D1 在正常鳞状上皮阳性率为 5 .0 % ,在增生和鳞癌中阳性率分别为 4 2 .9%和 4 6 .8% ;cyclin E在低分化鳞癌组阳性率 ( 80 .0 % )明显高于高分化组 ( 2 9.0 % ) ( P<0 .0 5 )。 cyclin D1 和 cyclin E在鳞癌中的阳性表达呈正相关 ( r=0 .782 )。结论　 cyclin D1 和 cyclin E过表达与食管鳞状细胞癌的发生和分化程度有关。     

Basaloid squamous cell cancer arising in Barrett’s esophagus

Basaloid squamous cell carcinoma (BSCC) is a rare form of cancer that arises primarily in the upper aerodigestive tract. Esophageal BSCC is extremely rare, accounting for less than 2% of primary esophageal malignancies. It is histopathologically distinct from squamous cell carcinoma and has an aggressive biological behavior with poor survival outcomes. There is no known association of Barrett’s esophagus with esophageal BSCC. Here, we report what we believe is the first such case of esophageal BSCC occurring in the setting of Barrett’s esophagus.     

Iatrogenic esophagobronchial fistula arising in irradiated Barrett’s esophagus

A 47-yr-old male underwent a right upper lobectomy for stage IIB bronchoalveolar carcinoma followed by 4600 Gy of irradiation. One year later a fistula formed from an ulcerated region of Barrett’s esophagus into the left main bronchus. Bronchotomy repair with onlay patch intercostal muscle flap and esophageal repair with serratus anterior muscle flap plus postoperative esophageal stent placement for stricture resulted in good functional results.     

NF-κB、cyclin D1和p27在非小细胞肺癌中的表达及意义

目的:探讨核转录因子-κB(NF-κB)、细胞周期素D1(cyclin D1)和p27在非小细胞肺癌中的表达及临床意义.方法:应用免疫组化S-P法检测58例非小细胞肺癌(NSCLC)和15例正常肺组织中NF-κBp65、cyclin D1、p27的表达.结果:NSCLC组织中NF-κBp65和cyclin D1的表达明显高于正常肺组织中的表达(P＜0.01),p27表达则明显低于正常肺组织(P＜0.01).NF-κBp65表达与NSCLC瘤体大小、淋巴结转移、临床分期密切相关(P＜0.05);cyclin D1表达与瘤体大小、肿瘤分化、淋巴结转移、临床分期密切相关(P＜0.05);p27表达与瘤体大小、肿瘤分化密切相关(P＜0.05).NF-κBp65与cyclin D1在NSCLC组织中的表达呈正相关(P＜0.05),cyclin D1与027的表达呈负相关(P＜0.05),NF-κBp65与p27的表达无相关性(P＞O.05).结论:NF-κB、cyclin D1、p27与非小细胞肺癌的发生、发展有关,检测三种蛋白的表达可以间接判断NSCLC的生物学行为.     

Inverse regulation of cyclin B1 by c-Myc and p53 and induction of tetraploidy by cyclin B1 overexpression

We have shown previously that mitotic spindle inhibitors allow the c-Myconcoprotein to uncouple mitosis from DNA synthesis, resulting in the acquisition of tetraploidy. This can also occur in the absence of spindle inhibition if c-Myc deregulation is combined with inactivation of the p53 tumor suppressor. Under these conditions, cyclin B1 protein is induced but retains its normal cell cycle regulation. We now show that the cyclin B1 promoter is directly but oppositely regulated by c-Myc and p53. Enforced expression of cyclin B1 also induces tetraploidy, either after mitotic spindle inhibition or in the absence of such inhibition if cyclin B1 is coexpressed with c-Myc. Cyclin B1 represents a new class of c-Myc target genes that is also regulated by p53. It is also the first identified downstream effector of c-Myc able to produce the chromosomal instability that characterizes virtually all tumor cells.     

Cyclin D1在口腔鳞癌中的表达及临床意义

目的 探讨口腔鳞状细胞组织中Cyclin D1的表达与临床和病理学特征之间的关系。方法 应用免疫组化Envision二步法检测43例口腔鳞癌组织中Cyclin D1的表达情况，并将其阳性表达率与口腔鳞癌的患者性别、临床分期、病理分化程度、淋巴结转移情况以及预后做统计学分析。结果 Cyclin D1在口腔鳞癌中的阳性表达率增加，其阳性表达率与颈淋巴结转移和预后相关，但与患者性别、病理分化程度以及临床分期之间无相关性。结论 Cyclin D1异常表达在口腔鳞癌的发生、发展中发挥了重要作用，可作为判断口腔鳞癌颈淋巴结转移和预后的一个重要指标。     

Cyclin B1在结直肠癌中的表达及意义

Objective： To study the relationship between the expression of human cyclin B1 in colorectal carcinomas and the pathological characters. Methods： The Expression of cyclin B1 in 66 cases of colorectal carcinomas were detected by flow cytometry and immunohistochemistry. Then the relationship between the expression of cyclin B1 in colorectal carcinomas and pathological characters was analyzed with statistics. Results： The expression of cyclin B1 in colorectal carcinomas had associativity with the cancer cell differentiation （P〈0.05）; However, the expression of cyclin B1 in colorectal carcinomas had no obvious associativity with cancer cell infiltrate depth and lymph nodes metastasis （P〉0.05）. Conclusion： In the colorectal cancers with high expression of cyclin B1, the cancer cells would present high differentiation; with low expression of cyclin B1 the cancer cells would present low differentiation. Along with the expression of cyclin B1 from high to low, the cancer cells differentiation has the tendency from high to low too.     

食管癌变过程中cyclin D1和Rb的表达及其意义的前瞻性研究

目的:探讨cyclin D1和Rb基因在食管癌变过程中的表达及其意义.方法:应用免疫组织化学S-P法检测cyclin D1和Rb基因在17例癌变组和40例非癌变组中的表达.结果:Cyclin D1在癌变组中的表达增高(P＜0.05),cyclin D1与Rb在早期癌中的表达存在正相关(P＜0.05).结论:Cyclin D1基因的过表达和食管癌的发生有关,cyclin D1和Rb基因表达的变化可能是食管癌发生中的早期事件.     

Risk factors for the development of an adenocarcinoma in columnar-lined (Barrett) esophagus

Background. To evaluate the importance of the length of columnar-lined esophagus, sex, age, smoking, and drinking habits as risk factors for malignant degeneration, the authors performed a retrospective case-control study comparing patients with and without adenocarcinoma in Barrett esophagus. Methods. The records of 96 patients (53 male and 43 female; mean age, 61 years) with a benign columnar-lined esophagus and 62 patients (47 male and 15 female; mean age, 62 years) with an adenocarcinoma in columnar-lined esophagus referred to the Rotterdam Esophageal Tumor Study Group, diagnosed over the same period (1978–1985), were reviewed. A frequency distribution of the length of columnar-lined esophagus in both groups was made. Statistical analysis was performed with multivariate methods. Results. The length of columnar-lined esophagus was related significantly to carcinoma: a doubling of the length resulted in a 1.7 times increased risk. Smokers had a 2.3-fold increased risk as compared with nonsmokers. Male sex as a risk factor approached statistical significance (P = 0.06). Adjusted for these risk factors, no relation between carcinoma and age or alcohol consumption was found. Conclusions. The risk of development of an adenocarcinoma in Barrett esophagus increased with the length of Barrett epithelium. Smoking and possibly male sex were also risk factors. The identification of these risk factors may help in developing more efficient screening programs for patients with Barrett esophagus.