VEGF-D expression correlates with colorectal cancer aggressiveness and is downregulated by cetuximab.
OBJECTIVE
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.


CONCLUSIONS
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.
Moehler
Markus
M
1st Department of Medicine, Johannes Gutenberg University, Langenbeckstrasse 1, Mainz 55101, Germany. moehler@mail.uni-mainz.de
Frings
Christian
C
Mueller
Annett
A
Gockel
Ines
I
Schimanski
Carl-C
CC
Biesterfeld
Stefan
S
Galle
Peter-R
PR
Holtmann
Martin-H
MH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000473:pathology; D066246:ErbB Receptors / Q000032:analysis; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D042582:Vascular Endothelial Growth Factor C / Q000032:analysis; D042643:Vascular Endothelial Growth Factor D / Q000032:analysis*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000502:physiology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D066246:ErbB Receptors; D040321:Vascular Endothelial Growth Factor Receptor-3; D000068818:Cetuximab