This Article Full Text Full Text (PDF) 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clarijs, R. Articles by de Waal, R. M. W. Search for Related Content PubMed PubMed Citation Articles by Clarijs, R. Articles by de Waal, R. M. W.

Induction of Vascular Endothelial Growth Factor Receptor-3 Expression on Tumor Microvasculature as a New Progression Marker in Human Cutaneous Melanoma¹

Department of Pathology, University Medical Centre, 6500 HB Nijmegen, the Netherlands [R. C., L. S., D. J. R., R. M. W. d. W.], and Universitäts-Hautklinik, D-97080 Würzburg, Germany [U. B. H.]

The anatomical relation between a malignant tumor and its vascular and lymphatic bed is an important factor influencing metastasis. Lack of specific markers for the lymphatic endothelium has long hampered a reliable detection of lymphatics. Here, we demonstrate that lymphatic endothelium can reliably be identified in a panel of different normal tissues and of benign and malignant tumors. Application of the previously described PAL-E/CD31 double staining protocol differentiates between blood capillaries and veins on one hand and lymphatic vessels on the other. Blood vessel marker CD34, absent from lymphatics, was used additionally to classify arteries. We found that the lymphatic vascular endothelial growth factor receptor-3 (VEGFR-3, also known as Flt-4) was present on both lymphatic and blood vessels in 76 of 113 malignant tumors [adenocarcinoma of kidney (n = 3), colon (n = 3) and liver (n = 3), breast (n = 9) and squamous cell carcinoma (n = 5), primary (n = 81), and metastatic (n = 9) melanoma]. No evident signs of tumor-induced lymphangiogenesis were observed. Evaluation of a series of 110 melanocytic skin lesions indicated that VEGFR-3 expression is confined to the lymphatic vasculature in benign lesions. However, its expression emerges on the blood neovasculature in malignant lesions as soon as metastatic potential develops. We conclude that induction of VEGFR-3 expression on tumor blood vessels may be a general phenomenon that would make VEGFR-3 a marker for tumor endothelium. In addition, we propose VEGFR-3 expression as a new microvascular progression marker in cutaneous melanoma.

This article has been cited by other articles:

				J. F. Donoghue, F. L. Lederman, B. J. Susil, and P. A.W. Rogers Lymphangiogensis of normal endometrium and endometrial adenocarcinoma Hum. Reprod., June 1, 2007; 22(6): 1705 - 1713. [Abstract] [Full Text] [PDF]

				B. Zhao, G. Smith, J. Cai, A. Ma, and M. Boulton Vascular endothelial growth factor C promotes survival of retinal vascular endothelial cells via vascular endothelial growth factor receptor-2 Br J Ophthalmol, April 1, 2007; 91(4): 538 - 545. [Abstract] [Full Text] [PDF]

				A. Schmeisser, M. Christoph, A. Augstein, R. Marquetant, M. Kasper, R.C. Braun-Dullaeus, and R.H. Strasser Apoptosis of human macrophages by Flt-4 signaling: Implications for atherosclerotic plaque pathology Cardiovasc Res, September 1, 2006; 71(4): 774 - 784. [Abstract] [Full Text] [PDF]

				M-A Brundler, J A Harrison, B de Saussure, M de Perrot, and M S Pepper Lymphatic vessel density in the neoplastic progression of Barrett's oesophagus to adenocarcinoma J. Clin. Pathol., February 1, 2006; 59(2): 191 - 195. [Abstract] [Full Text] [PDF]

				H. Niemela, K. Elima, T. Henttinen, H. Irjala, M. Salmi, and S. Jalkanen Molecular identification of PAL-E, a widely used endothelial-cell marker Blood, November 15, 2005; 106(10): 3405 - 3409. [Abstract] [Full Text] [PDF]

				X. Jimenez, D. Lu, L. Brennan, K. Persaud, M. Liu, H. Miao, L. Witte, and Z. Zhu A recombinant, fully human, bispecific antibody neutralizes the biological activities mediated by both vascular endothelial growth factor receptors 2 and 3 Mol. Cancer Ther., March 1, 2005; 4(3): 427 - 434. [Abstract] [Full Text] [PDF]

				Y. Zeng, K. Opeskin, M. E. Baldwin, L. G. Horvath, M. G. Achen, S. A. Stacker, R. L. Sutherland, and E. D. Williams Expression of Vascular Endothelial Growth Factor Receptor-3 by Lymphatic Endothelial Cells Is Associated with Lymph Node Metastasis in Prostate Cancer Clin. Cancer Res., August 1, 2004; 10(15): 5137 - 5144. [Abstract] [Full Text] [PDF]

				K. Persaud, J.-C. Tille, M. Liu, Z. Zhu, X. Jimenez, D. S. Pereira, H.-Q. Miao, L. A. Brennan, L. Witte, M. S. Pepper, et al. Involvement of the VEGF receptor 3 in tubular morphogenesis demonstrated with a human anti-human VEGFR-3 monoclonal antibody that antagonizes receptor activation by VEGF-C J. Cell Sci., June 1, 2004; 117(13): 2745 - 2756. [Abstract] [Full Text] [PDF]

				Y. Nakamura, H. Yasuoka, M. Tsujimoto, Q. Yang, S. Imabun, M. Nakahara, K. Nakao, M. Nakamura, I. Mori, and K. Kakudo Flt-4-Positive Vessel Density Correlates with Vascular Endothelial Growth Factor-D Expression, Nodal Status, and Prognosis in Breast Cancer Clin. Cancer Res., November 1, 2003; 9(14): 5313 - 5317. [Abstract] [Full Text] [PDF]