Tumor-Induced Activation of Lymphatic Endothelial Cells via Vascular Endothelial Growth Factor Receptor-2 Is Critical for Prostate Cancer Lymphatic Metastasis
Open Access
- 1 October 2006
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 66 (19), 9566-9575
- https://doi.org/10.1158/0008-5472.can-06-1488
Abstract
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)Keywords
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This publication has 39 references indexed in Scilit:
- Inhibition of Lymphogenous Metastasis Using Adeno-Associated Virus-Mediated Gene Transfer of a Soluble VEGFR-3 Decoy ReceptorCancer Research, 2005
- Bi‐directional interactions of prostate cancer cells and bone marrow endothelial cells in three‐dimensional cultureThe Prostate, 2005
- Upregulation of matrix metalloproteinases (MMPs) in breast cancer xenografts: A major induction of stromal MMP‐13International Journal of Cancer, 2004
- VEGF‐A promotes tissue repair‐associated lymphatic vessel formation via VEGFR‐2 and the α1β1 and α2β1 integrinsThe FASEB Journal, 2004
- Ligand-induced Vascular Endothelial Growth Factor Receptor-3 (VEGFR-3) Heterodimerization with VEGFR-2 in Primary Lymphatic Endothelial Cells Regulates Tyrosine Phosphorylation SitesJournal of Biological Chemistry, 2003
- Gene Therapy of Prostate Cancer with the Soluble Vascular Endothelial Growth Factor Receptor Fk1Cancer Biology & Therapy, 2002
- A Mechanism for Modulation of Cellular Responses to VEGF Activation of the IntegrinsMolecular Cell, 2000
- ANGIOGENESIS IN TWO HUMAN PROSTATE CANCER CELL LINES WITH DIFFERING METASTATIC POTENTIAL WHEN GROWING AS SOLID TUMORS IN NUDE MICEJournal of Urology, 1998
- ANGIOGENESIS IN TWO HUMAN PROSTATE CANCER CELL LINES WITH DIFFERING METASTATIC POTENTIAL WHEN GROWING AS SOLID TUMORS IN NUDE MICEJournal of Urology, 1998
- Lymphatic Mapping and Sentinel Lymphadenectomy for Breast CancerAnnals of Surgery, 1994