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Blood, 1 February 2007, Vol. 109, No. 3, pp. 1010-1017. Prepublished online as a Blood First Edition Paper on October 10, 2006; DOI 10.1182/blood-2006-05-021758. This Article Full Text (PDF) All Versions of this Article: blood-2006-05-021758v1 109/3/1010    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hirakawa, S. Articles by Detmar, M. Search for Related Content PubMed PubMed Citation Articles by Hirakawa, S. Articles by Detmar, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 8, 2006 Accepted September 14, 2006 VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites Satoshi Hirakawa, Lawrence F. Brown, Shohta Kodama, Karri Paavonen, Kari Alitalo, and Michael Detmar* Department of Dermatology, Ehime University School of Medicine, Ehime, Japan Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA Department of Immunobiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland * Corresponding author; email: michael.detmar{at}pharma.ethz.ch. The mechanisms by which tumors metastasize to sentinel and distant lymph nodes, and beyond, are poorly understood. We developed transgenic mice that overexpress vascular endothelial growth factor-C (VEGF-C) and green fluorescent protein specifically in the skin and studied the effects of chemically-induced skin carcinogenesis in this model. We found that in contrast to VEGF-A, VEGF-C does not increase the growth of primary tumors, but instead induces expansion of lymphatic networks within sentinel lymph nodes, even before the onset of metastasis. Once the metastatic cells arrived at the sentinel lymph nodes, the extent of lymphangiogenesis at these sites increased. Importantly, in mice with metastasis-containing sentinel lymph nodes, tumors that expressed VEGF-C were more likely to metastasize to additional organs, such as distal lymph nodes and lungs. No metastases were observed in distant organs in the absence of lymph node metastases. These findings indicate an important role of VEGF-C-induced lymph node lymphangiogenesis in the promotion of cancer metastasis beyond the sentinel lymph nodes. VEGF-C is therefore a good target to slow or even prevent the onset of metastasis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Hirakawa, M. Detmar, D. Kerjaschki, S. Nagamatsu, K. Matsuo, A. Tanemura, N. Kamata, K. Higashikawa, H. Okazaki, K. Kameda, et al. Nodal Lymphangiogenesis and Metastasis: Role of Tumor-Induced Lymphatic Vessel Activation in Extramammary Paget's Disease Am. J. Pathol., November 1, 2009; 175(5): 2235 - 2248. [Abstract] [Full Text] [PDF] D. Vitoux, S. Mourah, D. Kerob, O. Verola, N. Basset-Seguin, M. Baccard, N. Schartz, L. Ollivaud, A. Archimbaud, J.-M. Servant, et al. Highly Sensitive Multivariable Assay Detection of Melanocytic Differentiation Antigens and Angiogenesis Biomarkers in Sentinel Lymph Nodes With Melanoma Micrometastases Arch Dermatol, October 1, 2009; 145(10): 1105 - 1113. [Abstract] [Full Text] [PDF] R. E. Kalin, N. E. Banziger-Tobler, M. Detmar, and A. W. 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