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Incipient Angiogenesis in Barrett’s Epithelium and Lymphangiogenesis in Barrett’s Adenocarcinoma

From the Cellular Signalling Group, Division of Biochemistry, Department of Biosciences, Viikki BioCenter, University of Helsinki; and Department of Cardiothoracic Surgery, Helsinki University Central Hospital; and Karyon Ltd, Viiki BioCenter, Helsinki, Finland.

Address reprint requests to: Merja Auvinen, PhD, Division of Biochemistry, Department of Biosciences, Viikinkaari 5D, P.O. Box 56, Viikki BioCenter, FIN-00014 University of Helsinki, Finland; email: merja.auvinen{at}astrazeneca.com

PURPOSE: Barrett’s esophagus (BE), a precancerous condition for Barrett’s adenocarcinoma, is classically characterized by flames of salmon-colored mucosa extending into normal pale esophageal mucosa. This flaming is thought to be a consequence of continuous erosis of mucosa caused by chronic reflux. Another characteristic feature of Barrett’s adenocarcinoma patients is the frequent development of lymph node metastases. We addressed whether onset of angiogenesis occurs in BE and if the lymphatic system might provide a route for Barrett’s adenocarcinoma cells to infiltrate regular lymph nodes.

PATIENTS AND METHODS: Fifteen surgically resected Barrett’s dysplasia or adenocarcinoma patients were included. Immunohistochemistry and a modified whole mount analysis were used.

RESULTS: The incipient angiogenesis originates from the pre-existing vascular network in the lamina propria and infiltrates Barrett’s epithelium, giving its ominous salmon-red color. Barrett’s epithelium–specific goblet cells express vascular endothelial growth factor (VEGF)-A. The immature blood vessels show a relative absence of smooth muscle actin (SMA)-positive mural cells and express VEGF receptor (VEGFR)-2 and matrix metalloproteinase (MMP)-9 on their exterior. Coexpression of VEGF-C and its receptor VEGFR-3 on lymphatic vessels is demonstrated.

CONCLUSION: BE is strongly neovascularized not eroded. This novel concept of a molecular mechanism of the origin of BE might emphasize why precancerous BE can give rise to the more cancerous dysplasia and Barrett’s adenocarcinoma stages. In addition, adenocarcinoma cells induce lymphangiogenesis. The new lymphangiogenic vessels might provide a systemic route for adenocarcinoma cells to invade circulation and induce lymph node metastasis.

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