DLL4 overexpression increases gastric cancer stem/progenitor cell self‐renewal ability and correlates with poor clinical outcome via Notch‐1 signaling pathway activation

Abstract

Gastric cancer is one of the most common malignant diseases, and poses a serious threat to the quality of human life. Gastric cancer stem/progenitor cells (GCSPCs) have critical effects on tumor formation, affecting specific features of self‐renewal and differentiation and playing a critical role in metastasis. The Notch‐1 pathway is crucially important to GCSPCs and is regulated by DLL4. In this study, DLL4 and Nestin levels were measured in 383 gastric cancer tissue samples by immunohistochemistry, and the clinico‐pathological features of patients assessed. After DLL4 silencing in selected gastric cancer cell lines, the expression of GCSPC markers and colony formation ability were analyzed and the self‐renewal and differentiation capacities of the cells were evaluated. The relationship between DLL4 levels and Notch‐1 signaling pathway effector amounts was assessed via Western blotting and immunofluorescence. Finally, the tumor formation ability of the gastric cancer cells was evaluated with different levels of DLL4 and multiple cell densities in vivo. Our results indicate that DLL4 expression is associated with TNM stage and cancer metastasis, with high amounts of DLL4 leading to poor outcome. DLL4 silencing inhibited the self‐renewal ability of GCSPCs and increased their multidifferentiation capacity, resulting in reduced GCSPC ratios. DLL4 knockdown also blocked the Notch‐1 pathway, weakening invasion ability and resistance to 5‐FU chemotherapy. In vivo, DLL4 silencing inhibited the tumor formation ability of GCSPCs. In conclusion, DLL4 affects GCSPC stemness, altering their pathological behavior. DLL4 silencing inhibits GCSPC metastatic potential both in vitro and in vivo by impeding Notch‐1 signaling pathway activation, indicating that DLL4 may be a new potential therapeutic target.

Synergistic antitumor activity of a DLL4/VEGF bispecific therapeutic antibody in combination with irinotecan in gastric cancer

“…ABL001 competitively inhibited the binding of ligands to their corresponding receptors, including that of DLL4 to Notch1 and VEGF to VEGFR2 ( 12 ). DLL4 is a Notch ligand that regulates the activity of the Notch pathway and its expression highly correlates with tumor angiogenesis and metastasis ( 10 , 24 , 25 ). VEGFR2 belongs to the receptor type tyrosine kinase gene family, and is involved in tumor angiogenesis, chemoresistance, and aorta survival ( 26 ).…”

“…DLL4, one of the major factors involved in Notch signaling, was shown to be responsible for tumor formation, EMT, and self-renewal as CSCs ( 8 ). Targeting DLL4 expression may be a feasible approach to interfere with angiogenesis, tumorigenesis, and metastasis for anti-cancer effect ( 9 , 10 ). However, the clinical significance of DLL4 expression in GC is associated with poor prognosis ( 9 ) but mechanistic details remain unresolved ( 11 ).…”

Targeting cancer stem cell pathways for cancer therapy

“…194 Similarly, abundant Delta-like ligand 4 (DLL4) also promotes tumor angiogenesis and metastasis in gastric CSCs. 195 Delta-like 1 activation of Notch1 signaling requires the assistance of the actin-related protein 2/3 complex to maintain the stem cell phenotype of glioma-initiating cells. 196 Additionally, some intracellular genes also regulate the Notch signaling pathway.…”

Identification of Prognostic Model and Biomarkers for Cancer Stem Cell Characteristics in Glioblastoma by Network Analysis of Multi-Omics Data and Stemness Indices

“…Cancer stem cell models derived from 16 acute myeloid leukemia (AML) samples demonstrated an extraordinary ability to predict the clinical outcome of AML (Eppert et al, 2011). Similarly, in breast cancer, colon cancer, gastric cancer, and non-small cell lung cancer, the stem cell gene profile model holds promise in redefining clinical outcome stratification and identifying reduced risk (Giampieri et al, 2013;Miao et al, 2017;Codony-Servat et al, 2019;Neckmann et al, 2019). Moreover, three miRNAs (miR-23a, miR-9-3p, and miR-27a) derived from the analysis of GSCs by gene expression profiling, grouped mesenchymal and proneural GBM patients into two different categories with significant survival differences (Marziali et al, 2017).…”