Expression of vascular endothelial growth factor receptor-3 by lymphatic endothelial cells is associated with lymph node metastasis in prostate cancer.
OBJECTIVE
The molecular mechanisms underlying lymph node metastasis are poorly understood, despite the well-established clinical importance of lymph node status in many human cancers. Recently, vascular endothelial growth factor (VEGF)-C and VEGF-D have been implicated in the regulation of tumor lymphangiogenesis and enhancement of lymphatic invasion via activation of VEGF receptor-3. The purpose of this study was to determine the expression pattern of the VEGF-C/VEGF-D/VEGF receptor-3 axis in prostate cancer and its relationship with lymph node metastasis.


METHODS
The expression pattern of VEGF-C, VEGF-D, and VEGF receptor-3 in localized prostate cancer specimens (n = 37) was determined using immunohistochemistry.


RESULTS
Widespread, heterogeneous staining for VEGF-C and VEGF-D was observed in all cancer specimens. Intensity of VEGF-C staining was lower in benign prostate epithelium than in adjacent carcinoma, whereas no difference between benign epithelium and carcinoma was observed for VEGF-D staining. VEGF receptor-3 immunostaining was detected in endothelial cells of lymphatic vessels in 18 of 37 tissue samples. The presence of VEGF receptor-3-positive vessels was associated with lymph node metastasis (P = 0.0002), Gleason grade (P < 0.0001), extracapsular extension (P = 0.0382), and surgical margin status (P = 0.0069). In addition, VEGF receptor-3 staining highlighted lymphatic invasion by VEGF-C-positive/VEGF-D-positive carcinoma cells.


CONCLUSIONS
Together, these results suggest that paracrine activation of lymphatic endothelial cell VEGF receptor-3 by VEGF-C and/or VEGF-D may be involved in lymphatic metastasis. Thus the VEGF-C/VEGF-D/VEGF receptor-3 signaling pathway may provide a target for antilymphangiogenic therapy in prostate cancer.
Bernard O'Brien Institute of Microsurgery, Melbourne, Australia.
Yiping
Y
Zeng
Kenneth
K
Opeskin
Megan E
ME
Baldwin
Lisa G
LG
Horvath
Marc G
MG
Achen
Steven A
SA
Stacker
Robert L
RL
Sutherland
Elizabeth D
ED
Williams
D000906:Antibodies / Q000737:chemistry; D000918:Antibody Specificity; D015153:Blotting, Western; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008198:Lymph Nodes / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008297:Male; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000096:biosynthesis*
D000906:Antibodies; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3