This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zeng, Y. Articles by Williams, E. D. Search for Related Content PubMed PubMed Citation Articles by Zeng, Y. Articles by Williams, E. D.

Tumor-Induced Activation of Lymphatic Endothelial Cells via Vascular Endothelial Growth Factor Receptor-2 Is Critical for Prostate Cancer Lymphatic Metastasis

¹ Bernard O'Brien Institute of Microsurgery; Departments of ² Anatomical Pathology and ³ Urology, St. Vincent's Hospital, Fitzroy, Victoria; Departments of ⁴ Surgery and ⁵ Pathology, University of Melbourne, Parkville, Victoria; and ⁶ Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia

Requests for reprints: Elizabeth D. Williams, Monash Institute of Medical Research, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. Phone: 61-3-9594-7164; Fax: 61-3-9594-7114; E-mail: Elizabeth.Williams{at}med.monash.edu.au.

Prostate cancer disseminates initially and primarily to regional lymph nodes. However, the nature of interactions between tumor cells and lymphatic endothelial cells (LEC) is poorly understood. In the current study, we have isolated prostate LECs and developed a series of two-dimensional and three-dimensional in vitro coculture systems and in vivo orthotopic prostate cancer models to investigate the interactions of prostate cancer cells with prostate LECs. In vitro, highly lymph node metastatic prostate cancer cell lines (PC-3 and LNCaP) and their conditioned medium enhanced prostate LEC tube formation and migration, whereas poorly lymph node metastatic prostate cancer cells (DU145) or normal prostate epithelial cells (RWPE-1) or their conditioned medium had no effect. In vivo, the occurrence of lymphatic invasion and lymph node metastasis was observed in PC-3 and LNCaP xenografts but not in DU145 xenografts. Furthermore, vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 is expressed by prostate LECs, and its ligands VEGF-A, VEGF-C, and VEGF-D are up-regulated in highly lymph node metastatic prostate cancer cells. Recombinant VEGF-A and VEGF-C, but not VEGF-C156S, potently promoted prostate LEC tube formation, migration, and proliferation in vitro, indicating that signaling via VEGFR-2 rather than VEGFR-3 is involved in these responses. Consistent with this, blockade of VEGFR-2 significantly reduced tumor-induced activation of LECs. These results show that the interaction of prostate tumor cells with LECs via VEGFR-2 modulates LEC behavior and is related to the ability of tumor cells to form lymph node metastases. (Cancer Res 2006; 66(19): 9566-75)