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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Wong, S. Y. Articles by Hynes, R. O. Search for Related Content PubMed PubMed Citation Articles by Wong, S. Y. Articles by Hynes, R. O.

Tumor-Secreted Vascular Endothelial Growth Factor-C Is Necessary for Prostate Cancer Lymphangiogenesis, but Lymphangiogenesis Is Unnecessary for Lymph Node Metastasis

¹ Howard Hughes Medical Institute, Center for Cancer Research; ² Department of Biology, Massachusetts Institute of Technology, Cambridge; and ³ Department of Biomedical Sciences, Tufts University School of Veterinary Medicine, North Grafton, Massachusetts

Requests for reprints: Richard O. Hynes, E17-227, Massachusetts Institute of Technology, Cambridge, MA 02139. Phone: 617-253-6422; Fax: 617-253-8357; E-mail: rohynes{at}mit.edu.

Dissemination to draining lymph nodes is a frequent first step in prostate cancer metastasis. Although tumors metastasize to lymph nodes via the lymphatics, the importance of lymphangiogenesis in mediating the process remains controversial. Here, we inhibit intratumoral lymphangiogenesis in s.c. and surgical orthotopic implantation mouse models of human prostate cancer using several strategies. Stable expression of small interfering RNAs (siRNA) targeted against human vascular endothelial growth factor-C (VEGF-C) in PC-3 cells reduced intratumoral lymphatics by 99% in s.c. tumors, indicating that tumor-secreted VEGF-C is necessary for lymphangiogenesis. Expression of siRNAs against human VEGF-A somewhat reduced tumor lymphangiogenesis. Secretion of a soluble VEGF receptor-3/Flt4 fusion protein by PC-3 cells reduced intratumoral lymphatics by 100% in s.c. tumors. Combination of soluble Flt4 and VEGF-C siRNA yielded >92% reduction of intratumoral lymphatics in orthotopic prostate tumors. However, metastasis to lymph nodes was not significantly affected regardless of intratumoral lymphatic vessel density. The abundance of marginal lymphatics at the tumor-stromal interface was unchanged in orthotopic tumors whose intratumoral lymphatics were inhibited, suggesting that these marginal vessels could be sufficient for lymph node metastasis. Hematogenous metastasis (blood tumor burden, lung metastasis) correlated with degree of lymph node invasion. We also analyzed the lymphatics in spontaneous transgenic adenocarcinomas of the mouse prostate which metastasize to lymph nodes. Progression from well-differentiated prostate intraepithelial neoplasia to metastatic, undifferentiated adenocarcinoma was accompanied by loss of lymphatics. These results suggest that tumor-secreted VEGF-C and, to a lesser extent, VEGF-A, are important for inducing prostate cancer intratumoral lymphangiogenesis but are unnecessary for lymph node metastasis.

This article has been cited by other articles:

				J. B. Burton, S. J. Priceman, J. L. Sung, E. Brakenhielm, D. S. An, B. Pytowski, K. Alitalo, and L. Wu Suppression of Prostate Cancer Nodal and Systemic Metastasis by Blockade of the Lymphangiogenic Axis Cancer Res., October 1, 2008; 68(19): 7828 - 7837. [Abstract] [Full Text] [PDF]

				H. Koyama, N. Kobayashi, M. Harada, M. Takeoka, Y. Kawai, K. Sano, M. Fujimori, J. Amano, T. Ohhashi, R. Kannagi, et al. Significance of Tumor-Associated Stroma in Promotion of Intratumoral Lymphangiogenesis: Pivotal Role of a Hyaluronan-Rich Tumor Microenvironment Am. J. Pathol., January 1, 2008; 172(1): 179 - 193. [Abstract] [Full Text] [PDF]

				S. S. Sundar and T. S. Ganesan Role of Lymphangiogenesis in Cancer J. Clin. Oncol., September 20, 2007; 25(27): 4298 - 4307. [Abstract] [Full Text] [PDF]

				S. Y. Wong, H. Haack, J. L. Kissil, M. Barry, R. T. Bronson, S. S. Shen, C. A. Whittaker, D. Crowley, and R. O. Hynes Protein 4.1B suppresses prostate cancer progression and metastasis PNAS, July 31, 2007; 104(31): 12784 - 12789. [Abstract] [Full Text] [PDF]

				M. I. Harrell, B. M. Iritani, and A. Ruddell Tumor-Induced Sentinel Lymph Node Lymphangiogenesis and Increased Lymph Flow Precede Melanoma Metastasis Am. J. Pathol., February 1, 2007; 170(2): 774 - 786. [Abstract] [Full Text] [PDF]

				G. Azzali Tumor Cell Transendothelial Passage in the Absorbing Lymphatic Vessel of Transgenic Adenocarcinoma Mouse Prostate Am. J. Pathol., January 1, 2007; 170(1): 334 - 346. [Abstract] [Full Text] [PDF]

				Y. Zeng, K. Opeskin, J. Goad, and E. D. Williams Tumor-Induced Activation of Lymphatic Endothelial Cells via Vascular Endothelial Growth Factor Receptor-2 Is Critical for Prostate Cancer Lymphatic Metastasis Cancer Res., October 1, 2006; 66(19): 9566 - 9575. [Abstract] [Full Text] [PDF]

				N. E. Tobler and M. Detmar Tumor and lymph node lymphangiogenesis--impact on cancer metastasis J. Leukoc. Biol., October 1, 2006; 80(4): 691 - 696. [Abstract] [Full Text] [PDF]

				T. Hoshida, N. Isaka, J. Hagendoorn, E. di Tomaso, Y.-L. Chen, B. Pytowski, D. Fukumura, T. P. Padera, and R. K. Jain Imaging Steps of Lymphatic Metastasis Reveals That Vascular Endothelial Growth Factor-C Increases Metastasis by Increasing Delivery of Cancer Cells to Lymph Nodes: Therapeutic Implications Cancer Res., August 15, 2006; 66(16): 8065 - 8075. [Abstract] [Full Text] [PDF]