An immunohistochemical study of the expression of bcl-2 and p53 oncoproteins in pancreatic intraepithelial neoplasia and pancreatic cancer.

BACKGROUND: The bcl-2 and p53 gene deregulation is frequently involved in several types of malignancies. The purpose of this study was to evaluate the expression of bcl-2 and p53 genes in various types of pancreatic intraepithelial proliferation and in pancreatic cancer and to answer the question of whether they interact in the process of intraductal epithelial proliferation. METHODS: Immunohistochemical staining for p53 and bcl-2 was performed on paraffin embedded sections from 56 patients operated on for pancreatic carcinoma, chronic pancreatitis, and other conditions. RESULTS: Pancreatic cancer in 100% of cases showed p53 expression and in 27.7% bcl-2 expression. The p53 gene was expressed already in pancreatic intraductal neoplasia and its frequency was significantly rising with an increasing degree of hyperplasia. Normal epithelium of pancreatic ducts and ductules showed a high expression of bcl-2, which was decreasing in the process of intraductal proliferation. CONCLUSIONS: Pancreatic cancer is characterized by a high expression of p53 and a low expression of bcl-2. In pancreatic cancers and pancreatic intraepithelial neoplasia, there is an inverse relationship between the expression of bcl-2 and p53. Malignant behavior of pancreatic cancer may be associated with the phenotype bcl-2-/p53+.     

Mutations in the p16 gene in DMBA-induced pancreatic intraepithelial neoplasia and pancreatic cancer in rats

<正>BACKGROUND:7,12-dimethylbenzanthracene(DMBA)-induced pancreatic intraepithelial neoplasia(PanIN)and pancreatic cancer in rats provide a classic model for uncovering the molecular mechanisms underlying pancreatic cancer.However,this model has not been characterized genetically,and in particular,the major genetic alterations in the p16 gene are unknown.     

胰腺腺管内上皮瘤的研究进展

胰腺癌的早期诊断与综合治疗目前缺乏有效的措施，80％的胰腺癌在诊断时已丧失手术机会，5年生存率仅为0．4％～4％。胰腺癌生存时间的延长取决于早发现、早治疗。故充分认识胰腺癌的癌前病变一胰晾腺管内上皮瘤（PanlN），了解其病理分级及与之相关的各级分子生物学水平的改变，讨论PanlN红胰腺癌形成中的作用，对胰腺癌的早期诊断及综合治疗有重要意义。     

p53 and bcl-2 protein expression in rectosigmoid adenomas

Objective: The aim of this study was to evaluate whether p53 or bcl-2 protein expression in rectosigmoid adenomas is associated with histological characteristics of the adenomas and with presence of synchronous advanced proximal neoplasms.
Methods: Seventy-six average-risk patients who underwent total colonoscopy and had rectosigmoid adenoma(s) were studied. An adenoma was considered advanced if villous histology and/or severe dysplasia and/or diameter >1 cm were present. p53 And bcl-2 protein expression was immunohistochemically examined using specific monoclonal antibodies.
Results: p53 Protein was detected in 43% and bcl-2 in 93% of the 76 rectosigmoid adenomas. Advanced compared with nonadvanced adenomas were significantly more frequently p53-positive (28 of 44 or 63.6% vs five of 32 or 15.6%,   p < 10⁻⁴  ) or had a bcl-2 score of 12 (20 of 44 or 45.5% vs five of 32 or 15.6%,   p = 0.007  ). Proximal advanced neoplasms were mainly found in patients with rectosigmoid adenomas positive for p53 and with a bcl-2 score of 12 (six of 17 or 35.3% vs 2/59 or 3.4%, OR: 15.6,   p = 0.001  ) and in particular in those with advanced rectosigmoid adenomas positive for p53 and with a bcl-2 score of 12 (six of 13 or 46.2% vs two of 31 or 6.5%, OR: 12.4,   p = 0.007  ).
Conclusion: p53 Expression and bcl-2 protein overexpression in rectosigmoid adenomas are associated with advanced histology and a high risk of synchronous advanced proximal colon neoplasm.     

E-钙黏附素和β-连环素在胰腺上皮内瘤变和胰腺癌组织中的表达

目的:探讨胰腺上皮内瘤变PanIN和胰腺癌组织中E-钙黏附素(E-Cad)和β-连环素(β-Cat)异常表达的意义.方法:回顾性研究长海医院2001-01/2003-12间外科切除和同期尸检的156例胰腺标本,并构建了组织芯片,其中含有129灶PanIN-1A,104灶PanIN-1B,22灶PanIN-2,11灶PanIN-3和121例导管腺癌和相应癌旁组织.用EnVision免疫组化技术检测上述病变组织中E-Cad和β-Cat的表达变化,并结合临床病理资料进行相关分析.结果:导管腺癌中E-Cad异常表达率明显高于PanINs和正常导管(64.5%,32.3%,0%),且与胰腺癌的分化程度、淋巴结转移和神经浸润密切相关(P＜0.05).PanINs和导管腺癌中E-Cad胞质表达较正常导管明显增加.β-Cat的异常表达与胰腺癌淋巴结转移和神经浸润有明显相关性(P＜0.05).高级别PanINs和导管腺癌中β-Cat胞质和胞核的表达率明显高于低级别PanINs和正常导管(P＜0.05).PanINs和导管腺癌中E-Cad和β-Cat表达间呈正相关性(P＜0.01,P＜0.05).结论:胰腺癌和PanINs中E-Cad和β-Cat的异常改变提示他们不仅与胰腺癌的生物学行为和预后有关,而且也参与了胰腺癌的发生.     

Clinicopathological significance of p53 and mdm2 protein expression in human pancreatic cancer

AIM: To study the clinicopathological significance of p53 and mdm2 protein expression in human pancreatic cancer. METHODS: To investigate the expression of p53 and mdm2 in pancreatic cancer by immunohistochemistry, and the relationships between the p53 and mdm2 protein expression and clinicopathological parameters in pancreatic cancer. RESULTS: The positive expression of p53 protein was found in 40 of 59 patients (67.8%) and that of mdm2 protein in 17 of 59 patients (28.8%). No obvious relationships were found between p53 as well as mdm2 expression and sex, tumor site,TNM staging and histological differentiation. p53 expression was increased in patients younger than 65 years old, while mdm2 had no relationship with age. The survival time of the patients with the positive expression of p53 and mdm2 proteins was obviously shorter than the other groups. CONCLUSION: Both p53 and mdm2 presented relatively high expression in human pancreatic cancer.The overexpression of p53 and mdm2 might reflect the malignant proliferation of pancreatic cancer and their co-expression might be helpful to evaluate the prognosis of the patients with pancreatic cancer.     

Evaluation of pancreatic intraepithelial neoplasia and mucin expression in normal pancreata

Background/purpose

It has been suggested that pancreatic ductal adenocarcinoma (PDAC) and pancreatic intraepithelial neoplasia (PanIN) are closely related, but several reports indicate PanIN lesions can also be found in normal pancreata (normal PanINs). We examined differences in mucin expression between normal PanIN lesions and PanINs in PDACs (PDAC PanINs).

Methods

We examined 54 autopsied normal pancreata and eight autopsied PDACs for PanIN lesions; graded the pancreata specimens as PanIN-1A (non-papillary hyperplasia), PanIN-1B (papillary hyperplasia), PanIN-2 (atypical hyperplasia) or PanIN-3 (carcinoma in situ); and tested the PanIN lesions for expression of MUC1 (pan-epithelial membrane-associated mucin) and MUC5AC (gastric secretory mucin) which were both previously detected in PDACs.

Results

In normal PanIN-1A, PanIN-1B and PanIN-2 specimens, MUC1 was expressed in 2.8, 10.5 and 9.1%, respectively, compared to 19.1, 27.6 and 13.0% in PDAC PanIN-1A, PanIN-1B and PanIN-2 specimens, respectively. MUC5AC was expressed in 41.0, 65.7 and 36.4% of normal PanIN-1A, PanIN-1B and PanIN-2 specimens, respectively, and in 80.9, 75.8 and 78.3% of PDAC PanIN-1A, PanIN-1B and PanIN-2 specimens, respectively. Differences in the frequency of MUC1 expression were significant between normal and PDAC PanIN-1A (p?<?0.0001) and PanIN-1B (p?<?0.05); and differences in the frequency of MUC5AC expression were significant between normal and PDAC PanIN-1A (p?<?0.0001) and PanIN-2 (p?<?0.05).

Conclusions

Normal PanIN and PDAC PanIN lesions differed in the rates of MUC1 and MUC5AC expression.     

An immunohistochemical analysis of p27 expression in human pancreatic carcinomas

p27 is known as one of the candidate tumor suppressor genes. Although abnormalities including deletion and mutation in this gene are rarely detected, loss of p27 expression has been reported to be correlated with the high degree of malignancy in many human cancers. In the present study, we investigated the status of p27 expression in human pancreatic carcinoma (PC) and assessed the clinicopathologic significance of loss of p27 expression in the development and progression of this malignancy using immunohistochemistry. No nuclear staining for p27 protein existed in 65 (65.7%) of the 99 PC tumors examined. Furthermore, loss of p27 expression was correlated with tumor grade (G1 versus G2 or G3, p < 0.05) or clinical stage (I and II versus III and IV, p < 0.01). The above data suggest that loss of p27 expression is a very common event in PC, and moreover, this alteration might contribute to the progression of this malignant disease. Key Words: Pancreatic carcinoma-p27 protein expression-Immunohistochemistry.     

Quantitative analysis of p53 expression and cell proliferation in gastric carcinomas. An immunohistochemical study

BACKGROUND/AIMS: Adenocarcinoma of the stomach is still among the leading malignancies in human morbidity and mortality statistics in spite of endoscopic screening of the high-risk patients. Investigation of prognostic factors of gastric cancer disease seems to be still very important. The authors present a clinicopathological study based on the analysis of 49 gastric carcinomas. METHODOLOGY: P53 overexpression and proliferation activity of the cells were examined by immunohistological method with peroxidase-antiperoxidase technique. The percentage of the positive cells was calculated after counting of 300 tumor cells in each case. The rate of the labeled cells was related to different pathological characteristics of the carcinomas i.e., TNM stage of the tumor, histological subtypes of Ming's as well as Laurén's and Goseki's classification respectively, grade of differentiation and lymph node status. RESULTS: According to the above-mentioned parameters, p53 overexpression was significantly higher in carcinomas of the cardiac region than in those of the distal parts of the stomach. These findings are consistent with results published in the literature: cell proliferation rate alone is not an independent prognostic factor, but the degree of cell proliferation activity and p53 expression are changing usually parallel with each other and with other prognostic markers as well. CONCLUSIONS: The assessment of p53 activity and cell proliferation rate in gastric carcinoma is of prognostic value especially if evaluated together with other clinical and histopathological characteristics. The examination of these markers is useful in detecting early gastric cancer, in selecting high-risk patients and in planning proper individual treatment.     

Gambogic acid reduced bcl-2 expression via p53 in human breast MCF-7 cancer cells

Purpose  

In this study, we investigated the correlation between p53 and bcl-2 in gambogic acid (GA)-induced apoptosis.     

Expression of COX-2 is associated with accumulation of p53 in pancreatic cancer: analysis of COX-2 and p53 expression in premalignant and malignant ductal pancreatic lesions

OBJECTIVES: Cyclooxygenase-2 (COX-2) and tumor suppressor p53 are molecules that are linked to the oncogenesis of pancreatic cancer. COX-2 represents a key modulatory molecule in inflammation and carcinogenesis, and is known to be implicated in the positive regulation of growth and tumorigenesis. Abnormal expression of p53 is common in many human neoplasms including pancreatic cancer. Recent studies demonstrated functional interactions between p53 and COX-2. The p53-dependent upregulation of COX-2 was proposed to be another mechanism by which p53 could abate its own growth-inhibitory and apoptotic effects. METHODS: In this study, we immunohistochemically analyzed the expression of COX-2 and p53 in 95 pancreatic resection specimens [adenocarcinomas, 95 lesions; pancreatic intraepithelial neoplasias (PanINs), 155; normal ducts, 70]. RESULTS: The expression of COX-2 increased progressively with the grade of ductal lesions (P<0.00001). A statistically significant difference of COX-2 expression between normal ducts and low-grade PanINs was revealed (P=0.0042). COX-2 overexpression was demonstrated in 82 PanINs (52.9%), and in 76 adenocarcinomas (80%). No significant correlation between the grade of adenocarcinoma and COX-2 expression was revealed (P=0.2). The expression of p53 again increased progressively with the grade of lesions (P<0.00001) with a significant increase in high-grade PanINs. A correlation between COX-2 and p53 expression levels in carcinomas was revealed (P=0.0002), and an accumulation of p53 was associated with COX-2 overexpression in premalignant and malignant ductal lesions. CONCLUSION: These findings confirmed the generally accepted pancreatic cancer progression model, and supported the concept of the interactive role of COX-2 and p53 in pancreatic cancer carcinogenesis, which offers opportunities for targeted therapy and chemoprevention of pancreatic cancer using COX-2 inhibitors.     

乳腺癌患者bcl-2、p53、组织蛋白酶D因子表达的临床意义

目的 观察bcl-2、p53和组织蛋白酶D（CD）在乳腺癌组织中的表达,探讨其与乳腺癌组织学分级、腋淋巴结转移及预后的关系。方法 应用免疫组化方法（SP方法）检测bcl-2、p53、CD在86例乳腺癌及33例乳腺良性病变的表达。结果 bcl-2表达与组织学分级呈负相关,其阳性表达水平可反映肿瘤属分化程度,但其与腋淋巴结转移和预后无关。p53与组织学分级呈正相关、CD与组织学分级无关;p53和CD表达与腋淋巴结转移呈正相关,与预后呈负相关。结论 bcl-2、p53和CD可作为乳腺癌组织学分级、腋淋巴结转移和预后的判断指标。     

Evaluation of p53 and bcl-2 oncoprotein expression in precancerous lesions of the oral cavity

The oral cavity is continually exposed to various traumas due to the effect of thermal, mechanical and chemical stimuli, which when accompanied by inflammatory states may promote the growth of neoplastic changes. Numerous studies have revealed a correlation between the expression of p53 and Bcl-2 proteins and the progression of neoplastic disease. It cannot be excluded that these proteins act as biomarkers of a neoplastic transformation threatening in precancerous states (including leukoplakia) or the already existing neoplastic transformation (e.g. in oral squamous cell carcinoma). The aim of the study was to evaluate the expression of p53 and Bcl-2 proteins in the proliferating epithelium in relation to leukoplakia degree and with regard to the lesions accompanied and not accompanied by squamous cell carcinomas. Fifty-five cases of proliferating changes in the oral epithelium (leukoplakia) were investigated. Group I contained 20 leukoplakias not accompanied by oral squamous cell carcinomas. Groups II, III and IV included 35 cases of changes in the vicinity of carcinomas on the lower lip (group II), in the front 2/3 of the tongue (group III) and in the oral floor (group IV). Staining was performed according to the immunohistochemical method with the use of monoclonal antibodies against human p53 protein (DAKO No M7001) and Bcl-2 (DAKO No M0887). A higher expression of p53 protein (54%) was found in leukoplakia changes coexisting with squamous cell carcinomas, compared with the non-accompanied ones (p53--45%). The results indicate a correlation between epithelial dysplasia degree and p53 and Bcl-2 protein expression--severe dysplasia occurred with an increase in the expression of both proteins. Leukoplakias situated in the vicinity of squamous cell carcinomas showed higher expression of p53 and Bcl-2 compared with the non-accompanied alterations. A correlation was also revealed between the location and p53 and Bcl-2 protein expression degree in the non-accompanied changes; no such correlations were found in proliferating epithelial changes adjacent to neoplastic tumors.     

Correlations in survivin expression with the expression of p53 and bcl-2 in invasive ductal carcinoma of the breast

This work studied the correlations between survivin, bcl-2 and p53 in infiltrating ductal carcinoma of the breast. A total number of 382 cases were collected from 3 hospitals in northeastern Malaysia. Survivin, bcl-2 and p53 were detected by immunohistochemistry on samples prepared from tissue blocks. Significant correlations were found between tumor histological grades and tumor size and lymph node involvement. Highly significant statistical correlations (p<0.001) were found in expression of the markers under study. It is concluded that such significant correlations may imply that the alterations in the expression take place in a concerted fashion, implying that many of these cases may share common abnormalities.     

三氧化二砷诱导小细胞肺癌细胞凋亡及p53、bcl-2基因表达的研究

目的：研究三氧化二砷（As2O3）诱导小细胞肺癌细胞凋亡及其机制。方法：采用末端脱氧核苷酰转移（TUNEL）法检测细胞凋亡，免疫组织化学（SABC）法分析As2O3对小细胞肺癌细胞（NeI-H细胞）p53、bcl-2基因蛋白表达的影响。结果：As2O30.5μmol/L、1.0μmol/L、2.0μmol/L作用72h，NeI-H细胞均可呈现凋亡所特有的亚G1峰，凋亡比率随药物作用浓度增加和作用时间延长而增高。实验组p53基因蛋白表达较对照组明显增多，药物浓度越高表达越多（P=0.001）；bcl-2基因蛋白表达较对照组明显减少，药物作用浓度越高表达越少（P=0.001）。结论：As2O3抗肿瘤作用主要是通过诱导细胞凋亡实现的，其机制与上调p53基因表达及下调bcl-2基因表达有密切关系。     

大鼠胰腺上皮内瘤变和胰腺癌模型血清蛋白质谱的差异表达

目的:利用表面增强激光解析离子化飞行时间质谱(SELDI-TOF MS)技术,分析由7,12-二甲基苯并蒽(DMBA)诱导建立的大鼠胰腺上皮内瘤变(PanIN)和胰腺癌(PC)模型血清蛋白质谱的差异表达.方法:40只♂清洁级SD大鼠为模型组,DMBA胰腺局部种植建立PanIN和PC模型,根据PanIN标准进行病理学分级.26只♂清洁级SD大鼠为正常对照组.采用SELDI-TOF MS和铜离子鳌合芯片(IMAC-Cu2 芯片)检测大鼠血清蛋白质谱, Biomarker Wizard 3.0软件分析比较对照组、PanIN组和PC组之间的差异表达蛋白.结果:DMBA胰腺局部种植后共获得PC 11例,PanIN 18例.与对照组比较, PanIN组和PC组表达强度显著上调(P<0.001)的蛋白质峰有19个,显著下调(P<0.001)的蛋白质峰有11个;其中质荷比分别为5835.2、4087.3、4786.5、4800.5、3932.2、5765.9、5924.8、5001.9、3913.7的9个蛋白质峰表达强度在对照组、PanIN组和PC组呈逐级递增趋势, 质荷比分别为1096.9、1478.9、8572.9、1007.1的4个蛋白质峰表达强度呈逐级递减趋势.结论:与正常大鼠比较,PanIN和PC模型大鼠血清蛋白质谱表达发生显著变化,这些差异表达蛋白质在胰腺癌中的作用值得进一步深入研究.     

In vivo diagnosis of murine pancreatic intraepithelial neoplasia and early-stage pancreatic cancer by molecular imaging

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor patient outcome often resulting from late diagnosis in advanced stages. To date methods to diagnose early-stage PDAC are limited and in vivo detection of pancreatic intraepithelial neoplasia (PanIN), a preinvasive precursor of PDAC, is impossible. Using a cathepsin-activatable near-infrared probe in combination with flexible confocal fluorescence lasermicroscopy (CFL) in a genetically defined mouse model of PDAC we were able to detect and grade murine PanIN lesions in real time in vivo. Our diagnostic approach is highly sensitive and specific and proved superior to clinically established fluorescein-enhanced imaging. Translation of this endoscopic technique into the clinic should tremendously improve detection of pancreatic neoplasia, thus reforming management of patients at risk for PDAC.     

High-grade pancreatic intraepithelial lesions: prevalence and implications in pancreatic neoplasia

BACKGROUND: High-grade pancreatic intraepithelial neoplasia(Pan IN-3), a precursor of pancreatic ductal adenocarcinoma(PDAC), is not universally detected in resected pancreatic neoplasms. We sought to determine the prevalence and prognostic relevance of Pan IN-3 lesions in primary surgical resections of PDACs and intraductal papillary mucinous neoplasms(IPMNs).METHODS: A retrospective review of a tertiary care center pathology database(1/2000-6/2014) was performed. Demographics, imaging, pathology, disease-recurrence, and survival data were reviewed.RESULTS: A total of 458 patients who underwent primary pancreatic resection were included. "Pan IN-3" lesions were found in 74(16.2%) patients who either had PDAC(n=67) or main duct(MD)-IPMN(n=7). Among IPMN-MDs, Pan IN-3 lesions were exclusively found in those with pathological evidence of chronic pancreatitis. For PDACs, the median overall survival(OS) for pancreata with Pan IN-3 lesions was significantly better than those without(OS 1.12 years, interquartile range [IQR] 0.72, 2.05 years vs OS 0.86 years, IQR 0.64,1.60 years respectively; P=0.04). Multivariate Cox regression analysis demonstrated that the presence of Pan IN-3 lesions was associated with a reduced risk of death(HR=0.43; 95% CI: 0.23-0.82; P=0.01).CONCLUSIONS: Following primary resection of pancreatic adenocarcinoma, the lower survival observed in patients without Pan IN-3 lesions might suggest a state of complete or accelerated transformation. Further investigations are necessary to validate these findings that might impact disease prognosis and management.     

Stepwise overexpression of p63, p53, and cytokeratin 14 during progression of esophageal squamous intraepithelial neoplasia: useful immunohistochemical markers for differential diagnosis

Background  

Esophageal squamous intraepithelial neoplasia (ESIN) as a precursor for invasive carcinoma is classified into low-grade IN (LIN) and high-grade IN (HIN), the latter including carcinoma in situ (CIS). Increasing grades of ESIN are associated with increasing risk of invasive carcinoma, but differentiation among LIN, HIN, and CIS is subjective and challenging. As p63, a member of the p53 family, is known to regulate differentiation and proliferation in epithelial progenitor cells, its expression, along with that of cytokeratin (CK) 14 (basal squamous marker) and Ki-67 (proliferation marker), might be of diagnostic assistance.