The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells.
Flt-4, a VEGF receptor, is activated by its specific ligand, VEGF-C. The resultant signaling pathway promotes angiogenesis and/or lymphangiogenesis. This report provides evidence that the VEGF-C/Flt-4 axis enhances cancer cell mobility and invasiveness and contributes to the promotion of cancer cell metastasis. VEGF-C/Flt-4-mediated invasion and metastasis of cancer cells were found to require upregulation of the neural cell adhesion molecule contactin-1 through activation of the Src-p38 MAPK-C/EBP-dependent pathway. Examination of tumor tissues from various types of cancers revealed high levels of Flt-4 and VEGF-C expression that correlated closely with clinical metastasis and patient survival. The VEGF-C/Flt-4 axis, through upregulation of contactin-1, may regulate the invasive capacity in different types of cancer cells.
Su
Jen-Liang
JL
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Yang
Pan-Chyr
PC
Shih
Jin-Yuan
JY
Yang
Ching-Yao
CY
Wei
Lin-Hung
LH
Hsieh
Chang-Yao
CY
Chou
Chia-Hung
CH
Jeng
Yung-Ming
YM
Wang
Ming-Yang
MY
Chang
King-Jen
KJ
Hung
Mien-Chie
MC
Kuo
Min-Liang
ML
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002465:Cell Movement; D058967:Contactin 1; D058966:Contactins; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
C548669:CNTN1 protein, human; D015816:Cell Adhesion Molecules, Neuronal; C548670:Cntn1 protein, mouse; D058967:Contactin 1; D058966:Contactins; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3; D020928:Mitogen-Activated Protein Kinases