异常 Notch 信号在肝外胆管癌和胆囊癌中的临床病理意义。
Clinicopathological significance of altered Notch signaling in extrahepatic cholangiocarcinoma and gallbladder carcinoma.
机构信息
Department of Gastroenterology, Dong-A University Hospital, 3-1, Dong dae shin-dong, Seo-gu, Busan 602-715, South Korea.
出版信息
World J Gastroenterol. 2011 Sep 21;17(35):4023-30. doi: 10.3748/wjg.v17.i35.4023.
AIM
To investigate the role and clinicopathological significance of aberrant expression of Notch receptors and Delta-like ligand-4 (DLL4) in extrahepatic cholangiocarcinoma and gallbladder carcinoma.
METHODS
One hundred and ten patients had surgically resected extrahepatic cholangiocarcinoma (CC) and gallbladder carcinoma specimens examined by immunohistochemistry of available paraffin blocks. Immunohistochemistry was performed using anti-Notch receptors 1-4 and anti-DLL4 antibodies. We scored the immunopositivity of Notch receptors and DLL4 expression by percentage of positive tumor cells with cytoplasmic expression and intensity of immunostaining. Coexistent nuclear localization was evaluated. Clinicopathological parameters and survival data were compared with the expression of Notch receptors 1-4 and DLL4.
RESULTS
Notch receptor proteins showed in the cytoplasm with or without nuclear expression in cancer cells, as well as showing weak cytoplasmic expression in non-neoplastic cells. By semiquantitative evaluation, positive immunostaining of Notch receptor 1 was detected in 96 cases (87.3%), Notch receptor 2 in 97 (88.2%), Notch receptor 3 in 97 (88.2%), Notch receptor 4 in 103 (93.6), and DLL4 in 84 (76.4%). In addition, coexistent nuclear localization was noted [Notch receptor 1; 18 cases (18.8%), Notch receptor 2; 40 (41.2%), Notch receptor 3; 32 (33.0%), Notch receptor 4; 99 (96.1%), DLL4; 48 (57.1%)]. Notch receptor 1 expression was correlated with advanced tumor, node, metastasis (TNM) stage (P = 0.043), Notch receptor 3 with advanced T stage (P = 0.017), tendency to express in cases with nodal metastasis (P = 0.065) and advanced TNM stage (P = 0.052). DLL4 expression tended to be related to less histological differentiation (P = 0.095). Coexistent nuclear localization of Notch receptor 3 was related to no nodal metastasis (P = 0.027) and Notch receptor 4 with less histological differentiation (P = 0.036), while DLL4 tended to be related inversely with T stage (P = 0.053). Coexistent nuclear localization of DLL4 was related to poor survival (P = 0.002).
CONCLUSION
Aberrant expression of Notch receptors 1 and 3 play a role during cancer progression, and cytoplasmic nuclear coexistence of DLL4 expression correlates with poor survival in extrahepatic CC and gallbladder carcinoma.
目的
研究 Notch 受体和 Delta 样配体 4（DLL4）在肝外胆管癌和胆囊癌中的异常表达的作用和临床病理意义。
方法
用免疫组化方法检测 110 例手术切除的肝外胆管癌（CC）和胆囊癌标本的石蜡块。用抗 Notch 受体 1-4 和抗 DLL4 抗体进行免疫组化。通过细胞质表达的阳性肿瘤细胞百分比和免疫染色强度对 Notch 受体和 DLL4 的免疫阳性进行评分。评估共存的核定位。比较 Notch 受体 1-4 和 DLL4 的表达与临床病理参数和生存数据的关系。
结果
Notch 受体蛋白在癌细胞的细胞质中表达，有或无核表达，在非肿瘤细胞中也表现出弱的细胞质表达。通过半定量评价， Notch 受体 1 的阳性免疫染色在 96 例（87.3%）中检测到， Notch 受体 2 在 97 例（88.2%）中检测到， Notch 受体 3 在 97 例（88.2%）中检测到， Notch 受体 4 在 103 例（93.6%）中检测到， DLL4 在 84 例（76.4%）中检测到。此外，还观察到共存的核定位[Notch 受体 1：18 例（18.8%）， Notch 受体 2：40 例（41.2%）， Notch 受体 3：32 例（33.0%）， Notch 受体 4：99 例（96.1%）， DLL4：48 例（57.1%）]。 Notch 受体 1 的表达与晚期肿瘤、淋巴结、转移（TNM）分期相关（P = 0.043）， Notch 受体 3 与晚期 T 分期相关（P = 0.017），与淋巴结转移（P = 0.065）和晚期 TNM 分期（P = 0.052）的倾向相关。 DLL4 的表达倾向于与组织学分化程度较低有关（P = 0.095）。 Notch 受体 3 的共存核定位与无淋巴结转移相关（P = 0.027）， Notch 受体 4 与组织学分化程度较低有关（P = 0.036），而 DLL4 则与 T 分期呈负相关（P = 0.053）。 DLL4 共存核定位与不良生存相关（P = 0.002）。
结论
Notch 受体 1 和 3 的异常表达在癌症进展中起作用， DLL4 的细胞质核共存表达与肝外 CC 和胆囊癌的不良生存相关。
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