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. 2009 Nov 17;101(10):1749-57.
doi: 10.1038/sj.bjc.6605368. Epub 2009 Oct 20.

Expression of delta-like ligand 4 (Dll4) and markers of hypoxia in colon cancer

A M Jubb  1 , H Turley, H C Moeller, G Steers, C Han, J-L Li, R Leek, E Y Tan, B Singh, N J Mortensen, I Noguera-Troise, F Pezzella, K C Gatter, G Thurston, S B Fox, A L Harris
Affiliations

Expression of delta-like ligand 4 (Dll4) and markers of hypoxia in colon cancer

A M Jubb et al. Br J Cancer. .

Abstract

Background: Delta-like ligand 4 (Dll4) is a Notch ligand that is upregulated by hypoxia and vascular endothelial growth factor-A (VEGF-A) and is reported to have a role in tumor angiogenesis. Evidence from xenograft studies suggests that inhibiting Dll4-Notch signalling may overcome resistance to anti-VEGF therapy. The aim of this study was to characterise the expression of Dll4 in colon cancer and to assess whether it is associated with markers of hypoxia and prognosis.

Method: In all, 177 colon cancers were represented in tissue microarrays. Immunohistochemistry was performed using validated antibodies against Dll4, VEGF, hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, prolyl hydroxylase (PHD)1, PHD2, PHD3 and carbonic anhydrase 9 (CA9).

Results: The expression of Dll4 was observed preferentially in the endothelium of 71% (125 out of 175) of colon cancers, but not in the endothelium adjacent to normal mucosa (none out of 107, P<0.0001). The expression of VEGF was significantly associated with HIF-2alpha (P<0.0001) and Dll4 (P=0.010). Only HIF-2alpha had a significant multivariate prognostic effect (hazard ratio 1.61, 95% confidence interval 1.01-2.57). Delta-like ligand 4 was also expressed by neoplastic cells, particularly neoplastic goblet cells.

Conclusion: Endothelial expression of Dll4 is not a prognostic factor, but is significantly associated with VEGF. Assessing endothelial Dll4 expression may be critical in predicting response to anti-VEGF therapies.

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Figures

Figure 1
Figure 1
Representative examples of immunohistochemistry in colon cancer showing nuclear HIF-1α (A) and HIF-2α (B) expression, and cytoplasmic VEGF (C), PHD1 (D), PHD2 (E) and PHD3 (F) expression.
Figure 2
Figure 2
Representative examples of immunohistochemistry in colon cancer showing membranous CA9 adjacent necrosis (A) and endothelial Dll4 (B) expression. Immunohistochemistry for Dll4 shows membranous and cytoplasmic endothelial expression in a colon adenoma (C) and epithelial expression associated with goblet cell differentiation in a neoplastic crypt ((D) black arrows indicate Dll4-positive goblet cells, and red arrows indicate Dll4-negative non-goblet cells). Dll4 is also weakly expressed by neoplastic cells without goblet cell differentiation in a colon adenocarcinoma (E). Endothelial cells lining vessels (arrows) adjacent to normal colonic crypts did not express Dll4 by immunohistochemistry (F).
Figure 3
Figure 3
Kaplan–Meier survival curves for colon cancer patients subgrouped according to HIF-2α expression. The patients with cancers who are positive for HIF-2α have a significantly shorter median survival (57 months, 95% confidence interval 36–79 months) than patients with cancers who are negative for HIF-2α (101 months, 95% confidence interval 81–121 months), P=0.027.
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