Gap junction coupling is required for tumor cell migration through lymphatic endothelium.

Area of Science:

• Oncology
• Cell Biology
• Vascular Biology

Background:

• Lymphatic vasculature is a key route for cancer metastasis.
• Mechanisms of tumor cell interaction with lymphatic endothelial cells (LECs) are not fully understood.
• Adrenomedullin, a lymphangiogenic peptide, is elevated in tumors and promotes metastasis.

Purpose of the Study:

• To investigate how adrenomedullin facilitates tumor cell transendothelial migration through lymphatic vessels.
• To identify specific molecular events induced by adrenomedullin in LECs and tumor cells.

Main Methods:

• Utilized a tumor cell-LEC coculture system.
• Assessed tumor cell adhesion to LECs.
• Measured gap junction intercellular communication using Lucifer yellow and Calcein dyes.
• Investigated the role of connexins and β-catenin signaling.
• Pharmacologically blocked gap junction communication.

Main Results:

• Adrenomedullin enhanced tumor cell adhesion to LECs.
• Adrenomedullin promoted both homocellular and heterocellular gap junction coupling between tumor cells and LECs.
• Connexin-mediated gap junction communication was essential for tumor cell transendothelial migration.
• Adrenomedullin induced nuclear translocation of β-catenin and increased C-MYC transcription.
• Blocking gap junction communication inhibited β-catenin nuclear translocation.

Conclusions:

• Cell-cell communication, specifically gap junction intercellular communication, is vital for tumor cell migration through lymphatic endothelium.
• Adrenomedullin drives a cascade of events involving gap junctions and β-catenin signaling to facilitate metastasis.