Bone marrow-derived endothelial progenitors expressing Delta-like 4 (Dll4) regulate tumor angiogenesis

Area of Science:

• Oncology
• Vascular Biology
• Cell Signaling

Background:

• Tumor growth necessitates angiogenesis, involving endothelial cells (EC) and bone marrow-derived vascular precursor cells (BM-VPC).
• Vascular endothelial growth factor (VEGF) and the Notch pathway, particularly Delta-like 4 (Dll4), are key regulators of tumor angiogenesis.
• The specific role of BM-VPC in Notch pathway-modulated angiogenesis remained unclear.

Purpose of the Study:

• To investigate the role of Dll4 expressed by BM-VPC in tumor angiogenesis.
• To elucidate the mechanisms by which BM-VPC influence endothelial cell activation and vascular stability within tumors.
• To assess the impact of modulating Dll4 expression on BM-VPC in tumor growth.

Main Methods:

• Tumor-secreted factors (SDF-1, VEGF) were analyzed for their effect on Dll4 expression in BM-VPC.
• In vitro co-culture systems assessed Dll4-dependent activation of EC by BM-VPC, measuring ICAM-2 and Fibronectin expression.
• In vivo studies involved transplanting BM-VPC with altered Dll4 levels into tumor-bearing mice to evaluate tumor angiogenesis, vascular stability, hypoxia, and growth.

Main Results:

• Tumor-derived SDF-1 and VEGF upregulate Dll4 expression on recruited BM-VPC.
• BM-VPC activate EC via a Dll4-dependent pathway, inducing ICAM-2 and Fibronectin expression, which is blocked by anti-Dll4 antibodies.
• In vivo, reduced Dll4 on transplanted BM-VPC led to unstable microvessels, impaired angiogenesis, increased tumor hypoxia and apoptosis, and ultimately, reduced tumor growth.

Conclusions:

• Dll4 expression on BM-VPC is critical for their communication with tumor EC, promoting vascular stabilization.
• Modulating Dll4 in BM-VPC significantly impacts tumor angiogenesis and growth by affecting vascular integrity.
• Targeting the Dll4 pathway in BM-VPC represents a potential therapeutic strategy for inhibiting tumor angiogenesis.