DLL4 expression is a prognostic marker and may predict gemcitabine benefit in resected pancreatic cancer

Abstract

Background:There is an increasing interest for Notch signalling pathway and particularly Delta-like ligand 4 (DLL4) as potential therapeutic target to improve outcome for patients with pancreatic ductal adenocarcinoma (PDAC).Methods:Using immunohistochemistry (IHC) and tissue microarray (TMA), we assessed the expression patterns of DLL4, Notch1 and Notch3 in 151 patients from two independent cohorts of resected PDAC. We investigated the prognostic and the predictive significance of these proteins.Results:High IHC DLL4 expression in cancer cells was associated with worse overall survival (OS) and disease-free survival (DFS) than low DLL4 expression (median OS: 12.9 vs 30.4 months, P=0.004 and median DFS: 8.8 vs 17.4 months, P=0.02). High DLL4 expression remained a significant negative prognostic factor in multivariate analysis (HR for OS: 2.1, P=0.02 and HR for DFS: 2.0, P=0.02). Low DLL4 abundance was associated with a longer OS–only for patients who received an adjuvant gemcitabine-based chemotherapy (P<0.001) but not for patients who did not receive gemcitabine (P=0.72). Furthermore, the interaction test for adjuvant gemcitabine therapy was statistically significant (P<0.001). The validating cohort recapitulated the findings of the training cohort.Conclusions:Low DLL4 abundance in tumour cells may predict the benefit from adjuvant gemcitabine therapy after PDAC resection.

CXCL9 promotes prostate cancer progression through inhibition of cytokines from T�cells

“…Subsequently, the sections were blocked with 2% BSA at 4°C for 15 min (D3308; Beyotime Institute of Biotechnology) and incubated with CD4+ (AF1792) and CD8+ (AF1417) primary antibodies (1:100; Beyotime Institute of Biotechnology) overnight at 4°C, and stained with a fluorescein-conjugated secondary antibody anti-CD4+-FITC antibody (F1773) and anti-CD8+-FITC antibody (F0772; 1:100; Sigma-Aldrich; Merck KGaA) for 2 h at room temperature. Finally, images were captured with Leica SP5 AOBS confocal microscope (Leica Microsystems GmbH, Wetzlar, Germany), and the number of positive cells and field area ratio were calculated with Image J software version 1.48 (National Institutes of Health, Bethesda, MD, USA) ( 14 ).…”

<p>The Role of DLLs in Cancer: A Novel Therapeutic Target</p>

“…Overexpressed DLL4 is the main ligand that activates oncogenic Notch signaling and is wildly reported to predict a poor clinical outcome in pancreatic cancer (PC), gastric cancer (GC) and clear cell renal cell cancer (ccRCC). [83][84][85][86][87][88][89][90][91][92] Pre-clinical studies show that blockade of endothelial DLL4 (mDLL4) by anti-mouse DLL4 antibodies (anti-mDLL4) HMD4-2 or 21R30 inhibits neovascularization and the growth of PC in vivo, suggesting DLL4-Notch signaling is a potential target for PC treatment. 93,94 In GC, DLL4 is mainly expressed in the membranes of tumor cells as opposed to the tumor stroma.…”

Anti-DLL4 VNAR targeted nanoparticles for targeting of both tumour and tumour associated vasculature

“…32,34 This overexpression of DLL4 in the tumour bulk and vasculature presents an opportunity for selective localisation of DLL4-binding NPs, and any associated cargo, at the tumour site. High DLL4 expression in PDAC correlates with poor prognosis [31][32][33][34] suggesting a pro-carcinogenic role. DLL4 blockade is found to induce excessive sprouting of vasculature and to inhibit tumour growth, 35,36 while not causing the gastrointestinal toxicity observed with other Notch pathway inhibitors.…”