The Prostate 58:193 ^199 (2004) Expression of Vascular Endothelial Growth Factor Receptor-3 (VEGFR-3) in Human Prostate Rile Li, 1 Mamoun Younes, 1 Thomas M. Wheeler, 1,2 Peter Scardino, 3 Makato Ohori, 3 Anna Frolov, 2 and Gustavo Ayala 1,2 * 1 Department of Pathology, Baylor College of Medicine, Houston,Texas 2 Scott Department of Urology, Baylor College of Medicine, Houston,Texas 3 Department of Urology, Memorial Sloan Kettering Cancer Center, NewYork, NewYork BACKGROUND. The growth and dissemination of tumors has been associated with angio- genesis, which is regulated by a group of polypeptide factors including vascular endothelial growth factor-C (VEGF-C). VEGF-C binds its receptor, vascular endothelial growth factor receptor-3 (VEGFR-3) to promote growth of tumor-associated lymphatic vessels. METHODS. In this study, microarray technology was used to build tissue arrays of normal prostate, benign prostate hyperplasia (BPH) and prostate carcinomas (PCa) using tissues from 640 patients. Slides were sectioned and stained with a polyclonal antibody to VEGFR-3 using a standard immunoperoxidase method and digitized. Immunoreactivity was scored using a 0–3þ semiquantitation scoring system for both intensity and percentage. The sum index was obtained by totaling the scores. RESULTS. VEGFR-3 is expressed in normal prostate, BPH, and PCa, but VEGFR-3 expression is up-regulated in PCa. We also found that VEGFR-3 is correlated with pre-operative prostate- specific antigen (Pre-PSA), Gleason score, and lymph node metastasis. The recurrence-free 5-year survival in cases with lower sum index (0 – 3) was significantly higher than that in cases with higher sum index (4–6) (77.3, 69.6%, respectively, P ¼ 0.037) by Kaplan–Meier actuarial model. CONCLUSIONS. Our data suggest that VEGFR-3 expression is associated with tumor progression and may play an important role in facilitating lymphatic spread of PCa; high-level of VEGFR-3 expression in prostate cancer cells increases the risk of biochemical recurrence in prostate cancer patients treated by radical prostatectomy. Prostate 58: 193–199, 2004. # 2003 Wiley-Liss, Inc. KEY WORDS: lymphangiogenesis; vascular endothelial growth factor receptor; metas- tasis; prostate carcinoma INTRODUCTION Metastasis is the most prominent feature of malig- nant tumors and the principal cause of cancer deaths. Metastasis may occur along different pathways by means of local tissue invasion, direct seeding of body cavities or surfaces, hematogenous metastasis, or lym- phatic spread. Of those possibilities, transport of tumor cells via lymphatics is thought to be the most common route of initial dissemination in many carcinomas [20]. Lymphatic dissemination of cancer cells is believed to occur either through preexisting lymphatics and/or via newly formed lymphatic capillaries (lymphangiogen- esis) [27]. It has been suggested that production of lymphangiogenic factors in tumors may promote lymphatic metastases by increasing the number of Grant sponsor: Specialized Programs of Research Excellence in Prostate Cancer; Grant number: P50 CA58204. *Correspondence to: Gustavo Ayala, MD, Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: gayala@bcm.tmc.edu Received 13 January 2003; Accepted 16 April 2003 DOI 10.1002/pros.10321 ß 2003 Wiley-Liss, Inc.