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. 2011 Sep 21;17(35):4023-30.
doi: 10.3748/wjg.v17.i35.4023.

Clinicopathological significance of altered Notch signaling in extrahepatic cholangiocarcinoma and gallbladder carcinoma

Hyun Ah Yoon  1 , Myung Hwan Noh, Byung Geun Kim, Ji Sun Han, Jin Seok Jang, Seok Ryeol Choi, Jin Sook Jeong, Jin Ho Chun
Affiliations

Clinicopathological significance of altered Notch signaling in extrahepatic cholangiocarcinoma and gallbladder carcinoma

Hyun Ah Yoon et al. World J Gastroenterol. .

Abstract

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.

Keywords: Cholangiocarcinoma; Delta-like ligand-4; Gallbladder carcinoma; Immunohistochemistry; Notch receptors.

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Figures

Figure 1
Figure 1
Notch receptor expression in cholangiocarcinomas (Immunohistochemistry). A, E: Notch receptor 1; B, F: Notch receptor 2; C, G: Notch receptor 3; D, H: Notch receptor 4; A-D: Non-neoplastic tissue (x 40); E-H: Cholangiocarcinomas (CCS) (x 100). Non-neoplastic biliary glandular or surface epithelial cells show weak cytoplasmic staining. High grade expression of Notch receptors is detected in cytoplasm of cancer cells of CCs.
Figure 2
Figure 2
Cytoplasmonuclear localization of Notch receptor 3 in moderately differentiated cholangiocarcinoma (immunohistochemistry, × 200). Brown-colored positive immunostaining of cholangiocarcinoma cells in both cytoplasm and nuclei is frequently observed.
Figure 3
Figure 3
Delta-like ligand-4 expression in cholangiocarcinomas (immunohistochemistry, × 100). A: Non-neoplastic biliary tissue; B-D: Cholangiocarcinomas. Non-neoplastic biliary epithelial cells (weak) and stromal inflammatory cells (strong) show cytoplasmic staining. Brown-colored expression of delta-like ligand-4 in cholangiocarcinoma cells is located at cytoplasm (B-D), coexisting nuclei (C), and luminal border (D).
Figure 4
Figure 4
Overall survival curve using the Kaplan-Meier method by log rank test. Median survival is 34.1 mo.
Figure 5
Figure 5
Survival curves of Cholangiocarcinomas with Delta-like ligand-4 expression with or without coexistent cytoplasmonuclear localization using the Kaplan-Meier method by log rank test. 0: Without nuclear localization; 1: With coexistent cytoplasmonuclear localization. Cases of coexistent cytoplasmonuclear localization of Delta-like ligand-4 expression show poor survival (P = 0.002).
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