High delta-like ligand 4 expression correlates with a poor clinical outcome in gastric cancer

Youjin Kim, Sun-Ju Byeon, Joonyoung Hur, Kangkook Lee, Dongin Kim, Jin-Hyung Ahn, Sang Hoon Lee, Weon-Kyoo You, Seung Tae Kim, Se Hoon Park, Won Ki Kang, Kyoung-Mee Kim, Jeeyun Lee, Youjin Kim, Sun-Ju Byeon, Joonyoung Hur, Kangkook Lee, Dongin Kim, Jin-Hyung Ahn, Sang Hoon Lee, Weon-Kyoo You, Seung Tae Kim, Se Hoon Park, Won Ki Kang, Kyoung-Mee Kim, Jeeyun Lee

Abstract

Background: Emerging evidence suggests that delta-like ligand 4 (DLL4) and other members of the Notch pathway may offer new targets for development of anti-angiogenesis drugs for the treatment of several tumor types. However, the role of DLL4 in gastric cancer (GC) remains unclear. In this study, we investigated the impact of DLL4 overexpression on recurrence and survival in gastric cancer (GC) patients. Methods: DLL4 expression levels were evaluated by immunohistochemistry in tissue samples from 336 GC patients. Samples were classified into high and low DLL4 expression according to a cut-off of 50% positively stained cells. The correlation between DLL4 expression and clinicopathological parameters, disease-free survival (DFS), and overall survival (OS) were statistically analyzed. Results: High DLL4 expression was observed in 67 (19.9%) of the 336 GC patients. After a median follow-up duration of 54.97 months [95% confidence interval (CI), 52.40-57.55 months), patients at stage II-IV with high DLL4 expression showed significantly poorer DFS compared with those at the same stage but with low DLL4 expression [not reached (NR) for both cohorts, hazard ratio (HR) 0.73 (95% CI, 0.38-1.40); p = 0.007]. Likewise, GC patients with high DLL4 expression had a significantly shorter OS following curative surgery compared to those with low DLL4 expression [NR for both groups, HR 0.56 (95% CI, 0.32-0.96; p = 0.002]. High DLL4 expression had a greater influence on DFS in stage IIIb/IV patients than in patients at early stages [34.87 vs. 10.1 months; HR, 0.44 (95% CI, 0.19-0.96); p = 0.004]. Moreover, stage IIIb/IV patients with high DLL4 expression had a significantly shorter OS after surgery than those with low DLL4 expression [58.87 vs. 16.93 months, HR 0.39 (95% CI, 0.16-0.99), p = 0.001). Conclusion: High DLL4 expression was observed in 19.9% of GC patients and was significantly associated with poor survival following curative surgery. Given its prevalence in the GC cohort with a poor prognosis, DLL4 is a potential therapeutic target.

Keywords: DLL4; Gastric cancer; anti-angiogenesis.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Representative microphotographs of DLL4 immunohistochemistry. (A) low DLL4 expression, intestinal-type; (B) high DLL4 expression, intestinal-type; (C) low DLL4 expression, diffuse-type; and (D) high DLL4 expression, diffuse-type gastric adenocarcinomas
Figure 2
Figure 2
Kaplan-Meier survival analysis according to the clinical stage of gastric cancer (GC). (A) Disease-free survival (DFS) in stage II-IV GC, (B) overall survival (OS) in stage II-IV GC, (C) DFS in stage II-IIIa GC, (D) OS in stage II-IIIa GC, (E) DFS in stage IIIb-IV GC, and (F) OS in stage IIIB-IV GC

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