Clinical implications of DLL4 expression in gastric cancer

Sumiya Ishigami,Hiroshi Kurahara,Yuka Nishizono,Shinichi Ueno,Yuko Kijima,Yoshikazu Uenosono,Tetsuro Setoyama,Shoji Natsugoe,Takaaki Arigami,Hiroshi Okumura,Yasuto Uchikado,Akihiro Nakajo,Yoshiaki Kita,Tetsuro Owaki

doi:10.1186/1756-9966-32-46

Sumiya Ishigami, Hiroshi Kurahara + Show 12 more

Open Access

https://doi.org/10.1186/1756-9966-32-46

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Abstract

BackgroundDelta-like ligand 4 (DLL4)-Notch signaling plays a key role in tumor neovascular development and angiogenesis during tumor growth. The clinical significance of DLL4 expression in gastric cancer has not been clarified.MethodsGastric cancer cell lines and 180 gastric cancer patients were enrolled. DLL4 expression in gastric cancer cells and stroma was identified and evaluated immunohistochemically. The association between DLL4 and clinicopathological factors was also assessed.ResultsDLL4 expression was identified in the cellular membrane and cytoplasm of gastric cancer cells by immunoblotting and immunohistochemical staining. DLL4 positivity in cancer cells and stroma was found in 88 (48%) and 41 (22%) of the 180 gastric cancer patients respectively. Both cancer and stromal DLL4 expression significantly correlated with more advanced tumor depth, nodal involvement, and lymphatic and venous invasion. A strongly positive association between cancerous and stromal DLL4 expression was identified (p < 0.01). Both cancerous and stromal DLL4 expression were prognostic markers in gastric cancer as determined by univariate analysis.ConclusionsCancerous and stromal DLL4 expression was found in 48% and 22% in gastric cancer, and significantly affected postoperative clinical outcomes. Cancerous and stromal DLL4 expression may be an effective target of anti-DLL4 treatment in gastric cancer.

Highlights

Gastric cancer is one of the major causes of cancerrelated deaths worldwide, especially in East Asia [1,2,3]
Delta-like ligand 4 (DLL4) expression in gastric cancer tissues DLL4 positivity was identified in brain tissue as a positive control of DLL4 (Figure 1)
DLL4 expression was primarily identified in the membranes and cytoplasm of cancer cells, regardless of tumor histology (Figure 2), as well as infiltrative cells in cancer stroma (Figure 3). 88 (49%) patients were classified as DLL4 positive (10% of DLL4 positive) group in cell lines; 41 (23%) were positive in the stroma

Summary

Introduction

Gastric cancer is one of the major causes of cancerrelated deaths worldwide, especially in East Asia [1,2,3]. When gastric cancer is diagnosed and treated in the early stages, the prognosis is good. Some patients have an unfavorable postoperative outcome, despite receiving curative surgery. Gastric cancer patients with distant metastases cannot undergo curative surgery. The recent development of novel anticancer agents in unresectable gastrointestinal cancer has improved clinical outcomes. Antiangiogenetic agents are promising for treating advanced, refractory tumors. As angiogenesis directly affects tumor growth and metastasis, it may be an important target for control of tumor. Delta-like ligand 4 (DLL4)-Notch signaling plays a key role in tumor neovascular development and angiogenesis during tumor growth. The clinical significance of DLL4 expression in gastric cancer has not been clarified

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Conclusion