Colorectal Cancer
Copyright ©2008 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Jul 14, 2008; 14(26): 4156-4167
Published online Jul 14, 2008. doi: 10.3748/wjg.14.4156
VEGF-D expression correlates with colorectal cancer aggressiveness and is downregulated by cetuximab
Markus Moehler, Christian Frings, Annett Mueller, Ines Gockel, Carl C Schimanski, Stefan Biesterfeld, Peter R Galle, Martin H Holtmann
Markus Moehler, Christian Frings, Annett Mueller, Carl C Schimanski, Peter R Galle, Martin H Holtmann, 1st Department of Medicine, Johannes Gutenberg University, Mainz 55101, Germany
Ines Gockel, Department of General and Abdominal Surgery, Johannes Gutenberg University, Mainz 55101, Germany
Stefan Biesterfeld, Institute of Pathology, Johannes Gutenberg University, Mainz 55101, Germany
Author contributions: Moehler M and Frings C contributed equally to this work; Moehler M, Galle PR and Holtmann MH designed research; Frings C, Mueller A, Gockel I, Schimanski CC and Biesterfeld S performed research; Moehler M, Schimanski CC, Biesterfeld S, Galle PR and Holtmann MH contributed new reagents/analytic tools; Moehler M, Frings C and Mueller A analyzed data; Moehler M, Mueller A, Galle PR and Holtmann MH wrote the paper.
Correspondence to: Dr. Markus Moehler, 1st Department of Medicine, Johannes Gutenberg University, Langenbeckstrasse 1, Mainz 55101, Germany. moehler@mail.uni-mainz.de
Telephone: +49-6131-177276
Fax: +49-6131-176410
Received: March 6, 2008
Revised: April 25, 2008
Accepted: May 2, 2008
Published online: July 14, 2008
Abstract

AIM: To gain mechanistic insights into the role played by epidermal growth factor receptor (EGFR) in the regulation of vascular endothelial growth factors (VEGFs) in colorectal cancer (CRC).

METHODS: The impact of high-level expression of the growth factor receptors EGFR and VEGF receptor (VEGFR)3 and the VEGFR3 ligands VEGF-C and VEGF-D on disease progression and prognosis in human CRC was investigated in 108 patients using immunohistochemistry. Furthermore, the expression of the lymphangiogenic factors in response to the modulation of EGFR signalling by the EGFR-targeted monoclonal antibody cetuximab was investigated at the mRNA and protein level in human SW480 and SW620 CRC cell lines and a mouse xenograft model.

RESULTS: Human CRC specimens and cell lines displayed EGFR, VEGF-C and VEGF-D expression with varying intensities. VEGF-C expression was associated with histological grade. Strong expression of VEGF-D was significantly associated with lymph node metastases and linked to a trend for decreased survival in lymph node-positive patients. EGFR blockade with cetuximab resulted in a significant decrease of VEGF-D expression in vitro and in vivo.

CONCLUSION: In conclusion, the expression of VEGF-D in colorectal tumours is significantly associated with lymphatic involvement in CRC patients and such expression might be blocked effectively by cetuximab.

Keywords: Human colorectal cancer, Lymphangiogenesis, Vascular endothelial growth factor-C, Vascular endothelial growth factor-D, Epidermal growth factor receptor