VEGF-induced Nrdp1 deficiency in vascular endothelial cells promotes cancer metastasis by degrading vascular basement...

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Vascular endothelial cells (VECs) are crucial in tumor growth and metastasis.
• The precise mechanisms linking VECs and cancer spread are not fully understood.
• Decreased Nrdp1 protein in tumor-associated VECs correlates with higher metastatic potential.

Purpose of the Study:

• To investigate the role of Nrdp1 in VECs concerning tumor metastasis.
• To elucidate the molecular mechanisms by which Nrdp1 influences VEC function and metastasis.
• To explore therapeutic strategies targeting Nrdp1 for anti-metastatic therapies.

Main Methods:

• Investigated Nrdp1 downregulation in VECs induced by hypoxia-conditioned cancer cell medium via VEGF signaling.
• Utilized Nrdp1 knockout VEC mouse models to assess metastasis.
• Examined the interaction between Nrdp1, Fam20C, extracellular matrix degradation, and vascular integrity.
• Evaluated therapeutic efficacy of Nrdp1 restoration using adeno-associated virus and chemical activators in mouse models.

Main Results:

• Hypoxia-conditioned medium downregulates Nrdp1 in VECs through VEGF-CHIP-mediated degradation.
• Nrdp1 deficiency in VECs significantly increases lung metastasis in mice.
• Nrdp1 promotes Fam20C degradation; Nrdp1 deficiency leads to increased Fam20C secretion, extracellular matrix degradation, and disrupted vascular integrity.
• Overexpression or activation of Nrdp1 in VECs effectively mitigates tumor metastasis in vivo.

Conclusions:

• Nrdp1 in VECs is essential for maintaining vascular integrity and suppressing tumor metastasis.
• VEGF enhances metastasis by downregulating Nrdp1 in VECs, leading to Fam20C-mediated vascular disruption.
• Targeting ecNrdp1-mediated pathways presents a promising strategy for anti-metastatic therapies.