Vascular endothelial growth factor C disrupts the endothelial lymphatic barrier to promote colorectal cancer invasion

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metastasis

Background:

• Colorectal cancer (CRC) is a highly metastatic disease.
• The role of lymphangiogenesis in CRC progression is not fully understood.
• Vascular Endothelial Growth Factor C (VEGFC) signaling via VEGFR3 is implicated in lymphangiogenesis and metastasis.

Purpose of the Study:

• To investigate the role of VEGFC signaling and lymphatic barriers in colorectal cancer progression.
• To determine the impact of VEGFC and VEGFR3 on lymphangiogenesis and metastasis in CRC.
• To evaluate therapeutic strategies targeting VEGFR3 for CRC metastasis.

Main Methods:

• Analysis of human colorectal tumor tissues and healthy controls using immunohistochemistry, immunoblot, and real-time PCR.
• Orthotopic implantation of CT26 CRC cells in mice, followed by treatment with anti-VEGFR3 antibody or VEGFC-encoding adenovirus.
• Evaluation of lymphatic vessel density, metastasis, and endothelial barrier integrity (CDH5 expression) in tumor tissues and relevant organs.

Main Results:

• Increased levels of podoplanin, VEGFC, and VEGFR3 were observed in CRC tissues compared to controls.
• VEGFC expression led to increased lymphatic vessel density and enhanced metastasis to lymph nodes, lungs, and liver in mice.
• VEGFC compromised lymphatic endothelial barrier integrity, increasing permeability and CRC cell migration, while VEGFR3 blockade reversed these effects.

Conclusions:

• VEGFC signaling through VEGFR3 promotes lymphangiogenesis and metastasis in colorectal cancer.
• VEGFC signaling reduces lymphatic endothelial barrier integrity, facilitating cancer cell spread.
• Targeting VEGFR3 presents a potential therapeutic strategy to inhibit colorectal cancer metastasis.