Neural cell adhesion molecule and perineural invasion in gallbladder cancer

To clarify the role of neural cell adhesion molecule (NCAM) in perineural invasion, NCAM expression was studied by immunohistochemical staining in 26 cases with gallbladder cancer. In gallbladder cancer, the incidence of perineural invasion and that of positive NCAM expression was 42% and 31%, respectively, which are less frequent than those of bile duct cancer in our previous report. Perineural invasion was observed in 88% of the patients with positive expression of NCAM and in 22% of those with negative expression. The former is similar to that of bile duct cancer but the latter is significantly lower. Eighty percent of the cancer cells that invaded the perineural space were positive for NCAM, when the primary tumor was positive for NCAM expression. Therefore, in gallbladder cancer, positive cells in NCAM expression likely invade the perineural spaces. However, the perineural invasion of negative cells in NCAM expression is not likely to occur as compared to bile duct cancer. In conclusion, perineural invasion in gallbladder cancer is not as common as in bile duct cancer, but the role of NCAM in perineural invasion is more important in gallbladder cancer than in bile duct cancer. © 1995 Wiley-Liss, Inc.     

Expression of neural cell adhesion molecule in salivary adenoid cystic carcinoma and its correlation with perineural invasion

The expression of neural cell adhesion molecule (NCAM) was analyzed in immunohistochemical preparations from adenoid cystic carcinoma. The goal was to evaluate whether NCAM expression could be used as a biological marker for the perineural invasion of adenoid cystic carcinoma in the head and neck. The presence of perineural invasion and NCAM expression was evaluated in samples from 49 patients. Perineural invasion was identified in 33 of them (67%). A high incidence of perineural invasion was found in adenoid cystic carcinoma in the parotid, hard palate, maxillary sinus and oral cavity. Positive NCAM staining was observed in 28 of 49 patients (57%). Of the 28 patients with NCAM staining, perineural invasion was identified in 24 (86%). In contrast, only 9 (43%) of the 21 tumors without NCAM staining had perineural invasion. The difference in NCAM expression between cases with and without perineural invasion was statistically significant (p<0.01). When positive NCAM staining was used to estimate the presence of perineural invasion, the sensitivity was 73 and the specificity 75%. Histopathologic nodal involvement was found in 6 of 18 cases in which neck dissection had been performed. All 6 cases displayed positive NCAM staining, and 5 displayed perineural invasion in the primary adenoid cystic carcinoma. In conclusion, NCAM expression can, to a certain extent, be used as a predictor of perineural invasion in adenoid cystic carcinoma. Moreover, lymph node metastases could serve as a clinical indicator for perineural invasion and for NCAM expression.     

Expression of highly polysialylated neural cell adhesion molecule in pancreatic cancer neural invasive lesion.

Neurotropism of pancreatic cancer is one of the hypotheses explaining neural invasion, which is one of the characteristics of pancreatic cancer. In these studies, we immunohistochemically examined neural cell adhesion molecules (NCAM), homophilic adhesion molecules expressed on the nerve cells, as a factor of neurotropism, in 15 pancreatic cancer operatively obtained, especially in neural invasive lesions. We also investigated the role of polysialic acid (PSA), which is attached to NCAM and related to the malignant potential of cancers. NCAM was detected in 66.7% of pancreatic cancers, and in all 9 cases with massive perineural invasion. In neural invasive lesions, however, there were perineurium and endoneurium, which do not express NCAM, between the cancer and nerve cells. PSA was also detected in the pancreatic cancers expressing NCAM. Moreover, PSA expression was stronger in the perineural invasive lesions than in the main tumor and was related to the cancer cell proliferation investigated by Ki-67 staining. It is unlikely therefore, that NCAM plays an important role in neurotropism. However, the NCAM expressed on the pancreatic cancer was attached to PSA, which itself plays an important role in the malignant potential of this disease.     

S-100和NCAM在腺样囊性癌组织中的表达及意义

  目的  分析腺样囊性癌(adenoid cystic carcinoma, ACC)的临床病理特点, 观察雪旺细胞标记物S-100和神经细胞粘附分子(neural cell adhesion molecule, NCAM)在ACC中的表达, 探讨S-100和NCAM与ACC嗜神经侵袭性的关系。  方法  对天津医科大学口腔医院42例ACC病例应用免疫组织化学方法检测S-100和NCAM在ACC中的表达, 并探讨其相关性。  结果  S-100在ACC嗜神经组阳性表达率80.0%明显高于非嗜神经组33.3%(P=0.011)。NCAM在嗜神经和非嗜神经侵袭组ACC中的阳性表达差异无统计学意义。S-100与NCAM在ACC中的阳性表达无明显相关性(P > 0.05)。  结论  S-100蛋白的表达与ACC的嗜神经现象密切相关, 在管状型中的表达明显高于充实型, 与肿瘤细胞分化具有一定相关性。NCAM蛋白的表达与ACC的嗜神经现象无统计学相关性, 与S-100蛋白的表达亦无明显相关。      

Expression of glial cell line-derived neurotrophic factor correlates with perineural invasion of bile duct carcinoma

BACKGROUND: Perineural invasion is one of the important prognostic factors for patients with bile duct carcinoma, and extensive surgery has not always improved their prognosis. It is necessary, therefore, to investigate not only clinicopathologic characteristics but also molecular mechanisms in patients with perineural invasion. The authors studied the relation between perineural invasion in patients with bile duct carcinoma and the expression of glial cell line-derived neurotrophic factor (GDNF), GDNF family receptor alpha1 (GFRalpha1), and RET receptor tyrosine kinase, which are expressed in both central and peripheral nerve tissues. METHODS: Immunohistochemical staining of GDNF, GFRalpha1, and RET was performed in 58 paraffin embedded tissue sections, including 38 sections from patients with bile duct carcinoma with perineural invasion and 20 sections from patients with bile duct carcinoma without perineural invasion. The migration of cells that expressed GDNF was analyzed by cocultivation with cells that expressed both RET and GFRalpha1. RESULTS: Moderate to strong staining of GDNF in tumor cells was observed more frequently in the sections with perineural invasion compared with the sections without invasion (P < 0.05), whereas GFRalpha1 expression in the same sections was not correlated with perineural invasion. RET expression was undetectable in specimens of bile duct carcinoma. Conversely, RET and GFRalpha1 expression were detected consistently in peripheral nerve tissues. An in vitro cell migration assay revealed that the migration of cells that expressed GDNF was enhanced by cocultivation with cells that expressed RET and GFRalpha1. The cell migration was also enhanced by the conditioned media from GDNF-treated cells that expressed RET and GFRalpha1. CONCLUSIONS: The results suggest that GDNF expression in tumor cells and GFRalpha1 and RET expression in peripheral nerve tissues may play a role in perineural invasion in patients with bile duct carcinoma through chemoattraction among these molecules.     

Cimetidine induces apoptosis of human salivary gland tumor cells

It has been reported that cimetidine, a histamine type-2 receptor (H2R) antagonist, inhibits the growth of glandular tumors such as colorectal cancer. However, its effects against salivary gland tumors are still unknown. We demonstrated previously that human salivary gland tumor (HSG) cells spontaneously express the neural cell adhesion molecule (NCAM) and also that HSG cell proliferation could be controlled via a homophilic (NCAM-NCAM) binding mechanism and that NCAM may be associated with perineural invasion by malignant salivary gland tumors. In the present study, we investigated the effects of cimetidine via the expression of NCAM on tumor growth and perineural/neural invasion in salivary gland tumor cells. Expression of both NCAM mRNA and protein was found to decrease in a dose-dependent manner upon treatment with cimetidine for 24 h. The MTT assay and confocal laser microscopy clearly showed that HSG cells underwent apoptosis after treatment with cimetidine. Activation of caspases 3, 7, 8 and 9 was observed in HSG cells after cimetidine treatment, thus confirming that the apoptosis was induced by the activated caspases. Apaf-1 activity was also detected in HSG cells in a dose-dependent manner after treatment with cimetidine. We also found that the cimetidine-mediated down-regulation of NCAM expression in HSG cells did not occur via blocking of the histamine receptor, even though H2R expression was observed on HSG cells, as two other H2R antagonists, famotidine and ranitidine, did not show similar effects. We demonstrated for the first time that cimetidine can induce significant apoptosis of salivary gland tumor cells, which express NCAM, at least in part by down-regulation of NCAM expression on the cells. These findings suggest that the growth, development and perineural/neural invasion of salivary gland tumor cells can be blocked by cimetidine administration through down-regulation of NCAM expression, as well as induction of apoptosis.     

神经细胞黏附分子49例涎腺腺样囊性癌表达及临床意义

[目的]探讨神经细胞黏附分子（NCAM）在涎腺腺样囊性癌（SACC）中的表达及临床意义。[方法]应用免疫组织化学方法检测49例涎腺腺样囊性癌中NCAM的表达情况。[结果]NCAM阳性表达率为57.14%（28/49）。NCAM在涎腺腺样囊性癌的表达与患者性别、肿瘤部位、原发灶分期无相关性。NCAM阳性表达率在管状型与实性型有显著性差异（χ^2=4.07,P=0.04）。有无神经侵犯NCAM阳性表达存在显著性差异（χ^2=10.02,P〈0.05）。[结论]神经细胞黏附分子与涎腺腺样囊性癌的神经侵袭性显著相关,NCAM在SACC中起到了重要作用。     

Cimetidine inhibits salivary gland tumor cell adhesion to neural cells and induces apoptosis by blocking NCAM expression

Background  

Cimetidine, a histamine type-2 receptor antagonist, has been reported to inhibit the growth of glandular tumors such as colorectal cancer, however the mechanism of action underlying this effect is unknown. Adenoid cystic carcinoma is well known as a malignant salivary gland tumor which preferentially invades neural tissues. We demonstrated previously that human salivary gland tumor (HSG) cells spontaneously express neural cell adhesion molecule (NCAM), that HSG cell proliferation may be controlled via a homophilic (NCAM-NCAM) binding mechanism and that NCAM may be associated with perineural invasion by malignant salivary gland tumors. We further demonstrated that cimetidine inhibited NCAM expression and induced apoptosis in HSG cells. Here, we investigated the effects of cimetidine on growth and perineural/neural invasion of salivary gland tumor cells.     

Induction of apoptosis in human salivary gland tumor cells by anti-NCAM antibody

Neural cell adhesion molecule (NCAM) is a type of cell surface glycoprotein and a member of the immunoglobulin superfamily. It has been reported that NCAM may be associated with perineural invasion by malignant salivary gland tumors such as adenoid cystic carcinoma. We have previously demonstrated that NCAM is constitutively expressed in the human salivary gland tumor cell line HSG, in vitro. In the present study, we have aimed to clarify the hypothesis that NCAM-mediated inhibition of salivary gland tumor proliferation is caused by homophilic binding and involves the prevention of signal transduction for perineural invasion using HSG cells. NCAM mRNA and protein expression was found to decrease in a dose-dependent manner upon treatment with the anti-NCAM antibody (MAb NCAM) for 24 h. The MTT assay showed a significant reduction in the number of viable HSG cells. Confocal laser microscopy showed that HSG cells underwent apoptosis after treatment with MAb NCAM. The activation of caspases 3, 7 and 9 was observed in HSG cells after treatment with MAb NCAM, thus confirming that apoptosis was induced by the activated caspases. Apaf-1 activity was also detected in HSG cells in a dose-dependent manner after treatment with MAb NCAM. The up-regulation of TGF-beta1-mediated NCAM expression appeared to lead to the activation of homophilic NCAM binding, further accelerating HSG cell proliferation. In addition, the localization of NCAM in adenoid cystic carcinomas (ACCs) was examined using an immunohistochemical method. NCAM was slightly to moderately positive in 9 of 13 cases (69.2%) of ACC. These findings suggest that NCAM is associated not only with a cell-to-cell adhesion mechanism, but also with tumorigenesis, including growth, development and perineural invasion in human salivary gland tumors.     

OPN在胆管腺癌组织中的表达及其与预后的关系

目的:检测OPN在胆管腺癌、癌旁胆管组织中的表达,了解OPN在胆管腺癌组织中的表达及其与预后的关系.方法:采用免疫组化SP法检测OPN在44例胆管腺癌、44例癌旁胆管组织中的表达情况,分析OPN与胆管癌临床病理参数的关系,并对患者进行随访.结果:OPN在胆管腺癌、癌旁胆管组织中表达阳性率分别为68.2%(30/44)、27.3%(12/44),在胆管腺癌组织中表达阳性率明显高于癌旁胆管组织(P<0.05).OPN在胆管腺癌组织中的表达与胆管癌浸润深度、淋巴结转移相关(P<0.05),差异有统计学意义.OPN阳性表达患者术后5年总体生存率明显低于阴性患者(P=0.015).结论:OPN在胆管腺癌组织中高表达,与胆管癌的侵袭、转移及预后密切相关,可作为胆管腺癌的参考指标,对胆管腺癌的诊断和预后评估具有重要意义.     

Clinical significance of extrahepatic bile duct resection for advanced gallbladder cancer

BACKGROUND AND OBJECTIVES: The aim of this study was to determine the clinical significance of extrahepatic bile duct (EHBD) resection during surgery for advanced gallbladder cancer. METHODS: Among 110 patients with pT2 or higher grade gallbladder cancer, 58 patients without microscopic invasion to the EHBD were reviewed. Prognostic factors of the 58 patients were evaluated by multivariate analysis. The impact of EHBD resection on survival was assessed in relation to two prognostic determinants: (i) lymph node metastasis: positive (n = 23) and negative (n = 35); (ii) perineural invasion: positive (n = 25) and negative (n = 33). RESULTS: Hepatic metastasis and perineural invasion were found to be independently significant prognostic factors. (i) No survival benefit of additional EHBD resection could be confirmed in each group of patients with or without nodal metastasis. (ii) In 25 patients with perineural invasion, 14 patients who underwent EHBD resection showed better survival as compared to the 11 patients who did not undergo EHBD resection (5-year survival rate, 46% vs. 0%, P = 0.009). In the remaining 33 patients without perineural invasion, the additional EHBD resection did not yield significant improvement of survival (P = 0.28). CONCLUSIONS: Resection of EHBD may offer prognostic advantage when perineural invasion exists, even in the absence of biliary infiltration.     

前列腺干细胞抗原在人胰腺癌神经浸润转移中作用的研究

目的探讨前列腺干细胞抗原(PSCA)在人胰腺癌神经浸润中的作用.方法80例胰腺癌手术标本切片行HE染色,观察记数小血管、小淋巴管、神经纤维浸润数.用鼠抗人PSCA单抗行免疫组化(Elivison二步法)染色,观察肿瘤细胞的阳性情况.结果肿瘤细胞神经浸润阳性与小血管、小淋巴管的浸润呈正相关(P<0.01);肿瘤细胞PSCA表达阳性(53例)与神经浸润阳性(66例)呈正相关(P<0.01);肿瘤的恶性程度与PSCA表达呈正相关;PSCA表达与小血管、小淋巴管浸润无关.结论PSCA可能是胰腺癌的特征性分子之一,可引导胰腺癌细胞向神经纤维趋化和黏附,即起"导航"和"停泊"作用.     

前列腺干细胞抗原在人胰腺癌神经浸润转移中作用的研究

目的探讨前列腺干细胞抗原(PSCA)在人胰腺癌神经浸润中的作用.方法80例胰腺癌手术标本切片行HE染色,观察记数小血管、小淋巴管、神经纤维浸润数.用鼠抗人PSCA单抗行免疫组化(Elivison二步法)染色,观察肿瘤细胞的阳性情况.结果肿瘤细胞神经浸润阳性与小血管、小淋巴管的浸润呈正相关(P<0.01);肿瘤细胞PSCA表达阳性(53例)与神经浸润阳性(66例)呈正相关(P<0.01);肿瘤的恶性程度与PSCA表达呈正相关;PSCA表达与小血管、小淋巴管浸润无关.结论PSCA可能是胰腺癌的特征性分子之一,可引导胰腺癌细胞向神经纤维趋化和黏附,即起"导航"和"停泊"作用.     

前列腺干细胞抗原在人胰腺癌神经浸润转移中作用的研究

目的探讨前列腺干细胞抗原(PSCA)在人胰腺癌神经浸润中的作用.方法80例胰腺癌手术标本切片行HE染色,观察记数小血管、小淋巴管、神经纤维浸润数.用鼠抗人PSCA单抗行免疫组化(Elivison二步法)染色,观察肿瘤细胞的阳性情况.结果肿瘤细胞神经浸润阳性与小血管、小淋巴管的浸润呈正相关(P<0.01);肿瘤细胞PSCA表达阳性(53例)与神经浸润阳性(66例)呈正相关(P<0.01);肿瘤的恶性程度与PSCA表达呈正相关;PSCA表达与小血管、小淋巴管浸润无关.结论PSCA可能是胰腺癌的特征性分子之一,可引导胰腺癌细胞向神经纤维趋化和黏附,即起"导航"和"停泊"作用.     

aPKC-ι和E-cadherin在胆管癌组织中的表达及意义

背景与目的:研究表明,极化调节蛋白非典型蛋白激酶C(atypical protein kinase C,aPKC)亚型aPKC-ι和E-cadherin在一些恶性肿瘤中异常表达对肿瘤的发生、发展起着重要作用.本研究分析aPKC-ι和E-cadherin在胆管癌组织中的表达与临床病理的关系,探讨胆管癌侵袭转移的分子机制.方法:采用免疫组化EnVision法检测9例非癌胆管疾病组织及35例胆管癌组织中aPKC-ι和E-cadherin表达,分析两者与胆管癌临床病理特征、侵袭性的关系.结果:aPKC-ι在胆管癌组织中的阳性高表达率为68.6%明显高于非癌胆管疾病组织的11.1%(P=0.006),E-cadherin在胆管癌中的高表达率为37.1%明显低于非癌胆管疾病组织的88.9%(P=0.016),且两者间呈负相关(r=-0.287,P＜0.05);胆管癌组织分化程度、侵袭性与aPKC-ι表达呈正相关(P＜0.05),与E-cadherin表达呈负相关(P＜0.05).结论:aPKC-ι和E-cadherin的表达与胆管癌分化程度和侵袭性相关,aPKC-ι可能作为一种极化调节相关蛋白在胆管癌侵袭、转移中发挥作用.     

Expression of neural cell adhesion molecules (polysialylated form of neural cell adhesion molecule and L1-cell adhesion molecule) on resected small cell lung cancer specimens: in relation to proliferation state

BACKGROUND AND OBJECTIVES: Alteration of homotypic cell-cell adhesion has been suggested to play an important role in tumor progression. The present study examined the relationship between neural cell adhesion molecules and state of proliferation of small cell lung cancer (SCLC) cells. METHODS: Seventeen surgically resected specimens of SCLC were immunohistochemically examined, by using monoclonal antibodies against neural cell adhesion molecule (NCAM) and its polysialic acid side chains, and L1 cell adhesion molecule (L1-CAM). Ki-67 labeling indices were also determined immunohistochemically. RESULTS: All patients were positive for L1-CAM. Fifteen patients (88.2%) were positive for NCAM. Among the fifteen patients, nine (60.0%) were positive for NCAM PSA side chain. The probability of survival of the NCAM without PSA side chain group was significantly higher than that of the NCAM with PSA side chain group (log-rank test; P = 0.500). CONCLUSIONS: The expression of NCAM with PSA side chains might be a prognostic factor and NCAM a marker for SCLC. L1-CAM may be synthesized independent of state of proliferation of individual tumor cell and may affect clinical feature of SCLC.     

Clinicopathological review of 61 patients with early bile duct cancer

AimsThe concept of early cancer is already established in the hollow viscus. However, there is no broadly accepted concept of early bile duct cancer. We aimed to assess whether early bile duct cancer patients have characteristic clinicopathological features and a better prognosis compared with patients with advanced bile duct cancer.Materials and methodsBetween June 1996 and December 2004, 614 patients were histologically confirmed with primary bile duct cancers after resection. Extrahepatic early bile duct cancers are defined as carcinoma where invasion is confined within the fibromuscular layer of the extrahepatic bile duct. Intrahepatic early bile duct cancers arising from intrahepatic large bile ducts are also defined as carcinoma confined within the fibromuscular layer. We retrospectively reviewed medical records to obtain demographic, laboratory, radiological and pathological data.ResultsSixty-one (10%) patients were categorised with early bile duct cancers. They were frequently detected at asymptomatic (39%) or non-icteric (84%) stages. The most common gross type was the intraductal-growing type (58%). Not otherwise specified adenocarcinoma was only 67%, whereas papillary carcinoma was 31% of cancers. No lymph node metastasis and no lymphovascular/perineural invasions were noted in 89% of patients. The 5-year survival rate for early bile duct cancer was excellent (80%).ConclusionsAlthough early bile duct cancer is not a common disease, it is not a very rare entity either. The clinicopathological features of early bile duct cancer patients differ from those of advanced bile duct cancer patients, with asymptomatic clinical presentation, different macroscopic and microscopic findings, and excellent prognosis.     

肝外胆管癌组织MMP-2表达及其临床意义

目的 MMP-2是基质金属蛋白酶(matrixmetalloproteinase,MMPs)家族中最主要的家族成员,因其可以降解细胞外基质,使癌细胞能够顺利穿透细胞外基质和基底膜组成的屏障,浸润其临近的纤维结缔组织,进而发生远处转移.本研究探讨MMP-2在肝外胆管癌及正常胆管组织中的表达水平及其临床意义.方法 收集济宁医学院附属湖西医院2005-11-01-2010-04-30肝外胆管癌手术切除蜡块标本共61例为研究对象,选取同期胆管正常组织标本35例作为对照.采用免疫组化方法检测61例肝外胆管癌及35例胆管正常组织中MMP-2蛋白的表达情况,统计分析MMP-2蛋白和患者临床病理特征及预后相关性.结果 肝外胆管癌组中MMP-2阳性表达率73.77%(45/61),显著高于胆管正常组织的5.71%(2/35),差异有统计学意义,P<0.001.不同性别、年龄、肿瘤分化程度、淋巴结转移和TNM分期肝外胆管癌组织中MMP-2表达水平差异有统计学意义,均P值<0.05.MMP-2阴性肝外胆管癌患者术后1、3和5年生存率分别为82.00%、55.00%和25.00%,MMP-2阳性肝外胆管癌患者术后1、3和5年生存率分别为33.00%、9.00%和0,两组生存率差异有统计学意义,χ2=16.556,P<0.001.结论 MMP-2的表达与肝外胆管癌发生、发展和浸润转移相关,可能在肝外胆管癌的浸润转移中发挥重要作用.MMP-2有望成为新的肝外胆管癌的肿瘤标志物,为预后判断和制定相应的治疗方案提供依据.     

GRK6在胆管癌组织中的表达及对胆管癌细胞增殖和侵袭的影响

目的:检测GRK6在胆管癌组织及相应癌旁正常胆管上皮组织内的表达情况,并探究抑制GRK6的表达对胆管癌细胞克隆增殖及侵袭的影响.方法:通过qRT-PCR及免疫组织化学染色检测GRK6在胆管癌及癌旁正常组织中的表达情况,并分析其与不同临床病理因素之间的关系.通过RNA干扰技术抑制QBC939细胞中GRK6的表达,检测si...     

Expression of cadherin and NCAM in human small cell lung cancer cell lines and xenografts.

Tumour cell adhesion, detachment and aggregation seem to play an important part in tumour invasion and metastasis, and numerous cell adhesion molecules are expressed by tumour cells. Several families of cell-cell adhesion molecules have been described, of which two groups are particularly well characterised, the cadherin family and the Ig superfamily member, neural cell adhesion molecule (NCAM). We investigated expression of these two adhesion molecule families in small cell lung cancer (SCLC) cell lines and xenografts by immunoblotting. Nineteen tumours established from 15 patients with SCLC were examined. All tumours but one expressed both cadherin and NCAM. The tumours expressed one, two or rarely three cadherin bands, and different combinations of two major isoforms of NCAM with M(r)'s of approximately 190,000 and 135,000. Polysialylation of NCAM, a feature characteristic of NCAM during embryonic development, which may play a role in connection with tumour invasion and metastasis, was found in 14/18 NCAM expressing SCLC tumours. Individual tumours grown as cell lines and as nude mouse xenografts showed no qualitative differences in cadherin or NCAM expression.