ArticleClinical & experimental metastasis2019
Metastasis is impaired by endothelial-specific Dll4 loss-of-function through inhibition of epithelial-to-mesenchymal transition and reduction of cancer stem cells and circulating tumor cells.
Article in Clinical & experimental metastasis, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 30 citations in OpenAlex.
- Conservation of Epithelial-to-Mesenchymal Transition Process in Neural Crest Cells and Metastatic Cancer.Cells, tissues, organs · 2021Pooled it
- Angiocrine factors in tumor microenvironment: bidirectional crosstalk, mechanistic insights, and therapeutic strategies.Journal of translational medicine · 2026Review
- IFNγ-dependent metabolic reprogramming restrains an immature, pro-metastatic lymphatic state in melanoma.Cancer cell · 2026Article
- Effects of Tumor Microenvironment on Lung Cancer Stem Cells: Bidirectional Regulatory Mechanisms.Cancer medicine · 2026Review
- Breast cancer stem cells and circulating tumor cells: Dual drivers of progression and relapse.World journal of stem cells · 2025Review
- DLL4-targeted CAR-T therapy sensitizes neoadjuvant chemotherapy via eliminating cancer stem cells and reshaping immune microenvironment in HER2Journal for immunotherapy of cancer · 2024Article
- Colorectal cancer tumor stem cells mediate bevacizumab resistance through the signal IL-22-STAT3 signaling pathway.3 Biotech · 2023Article
- Systemic Reprogramming of Endothelial Cell Signaling in Metastasis and Cachexia.Physiology (Bethesda, Md.) · 2023Review
- The ADAM17 sheddase complex regulator iTAP/Frmd8 modulates inflammation and tumor growth.Life science alliance · 2023Article
- Tumor cell stemness in gastrointestinal cancer: regulation and targeted therapy.Frontiers in molecular biosciences · 2023Review
- Notch Signaling in Vascular Endothelial and Mural Cell Communications.Cold Spring Harbor perspectives in medicine · 2022Article
- The Prognostic Role and Significance of Dll4 and Toll-like Receptors in Cancer Development.Cancers · 2022Review
- Exosomal microRNA-125a-3p from human adipose-derived mesenchymal stem cells promotes angiogenesis of wound healing through inhibiting PTEN.Molecular and cellular biochemistry · 2022Article
- Delta-like ligand 4 level in colorectal cancer is associated with tumor aggressiveness and clinical outcome.Cancer biomarkers : section A of Disease markers · 2022Article
- The role of calcium oscillations in the phenotype selection in endothelial cells.Scientific reports · 2021Article
- Dll4/Notch1 signalling pathway is required in collective invasion of salivary adenoid cystic carcinoma.Oncology reports · 2021Article
- Review
- The complexity of tumour angiogenesis based on recently described molecules.Contemporary oncology (Poznan, Poland) · 2021Review
- A New Antitumor Direction: Tumor-Specific Endothelial Cells.Frontiers in oncology · 2021Review
- Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Systemic inhibition of Dll4 has been shown to thoroughly reduce cancer metastasis. The exact cause of this effect and whether it is endothelial mediated remains to be clarified. Therefore, we proposed to analyze the impact of endothelial Dll4 loss-of-function on metastasis induction on three early steps of the metastatic process, regulation of epithelial-to-mesenchymal transition (EMT), cancer stem cell (CSC) frequency and circulating tumor cell (CTC) number. For this, Lewis Lung Carcinoma (LLC) cells were used to model mouse tumor metastasis in vivo, by subcutaneous transplantation into endothelial-specific Dll4 loss-of-function mice. We observed that endothelial-specific Dll4 loss-of-function is responsible for the tumor vascular regression that leads to the reduction of tumor burden. It induces an increase in tumoral blood vessel density, but the neovessels are poorly perfused, with increased leakage and reduced perivascular maturation. Unexpectedly, although hypoxia was increased in the tumor, the number and burden of macro-metastasis was significantly reduced. This is likely to be a consequence of the observed reduction in both EMT and CSC numbers caused by the endothelial-specific Dll4 loss-of-function. This multifactorial context may explain the concomitantly observed reduction of the circulating tumor cell count. Furthermore, our results suggest that endothelial Dll4/Notch-function mediates tumor hypoxia-driven increase of EMT. Therefore, it appears that endothelial Dll4 may constitute a promising target to prevent metastasis.
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