This Article Full Text Full Text (PDF) 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 Küsters, B. Articles by Leenders, W. P. J. Search for Related Content PubMed PubMed Citation Articles by Küsters, B. Articles by Leenders, W. P. J.

Differential Effects of Vascular Endothelial Growth Factor A Isoforms in a Mouse Brain Metastasis Model of Human Melanoma¹

Departments of Pathology [B. K., R. M. W. d. W., P. W., K. V., C. M., D. J. R., W. P. J. L.], Radiology [A. H., J. O. B.], and Chemical Endocrinology [F. S.], University Medical Centre St. Radboud, 6500 HB Nijmegen, the Netherlands

We reported previously that vascular endothelial growth factor isoform A (VEGF-A) expression by Mel57 human melanoma cells led to tumor progression in a murine brain metastasis model in an angiogenesis-independent fashion by dilation of co-opted, pre-existing vessels and concomitant enhanced blood supply (B. Kusters et al., Cancer Res., 62: 341–345, 2002). Here, we compare the activities of the 121, 165, and 189 VEGF-A isoforms in this model by transfecting Mel57 cells with the respective cDNAs and by injecting the resulting stably transfected cell lines in the internal carotid arteries of nude mice (n = 10 for each isoform). Although the three isoforms had similar potency to induce endothelial cell proliferation, VEGF₁₂₁ expression did not result in sprouting angiogenesis but rather led to extensive vasodilation and increased permeability of pre-existing, predominantly peritumoral vessels. Sometimes, proliferating endothelial cells accumulated in vessel lumina, giving these a microvascular, glomeruloid, proliferation-like appearance. Expression of VEGF₁₆₅ or VEGF₁₈₉ was associated with induction of an intratumoral neovascular bed. In VEGF₁₆₅-expressing tumors, daughter endothelial cells were distributed among newly formed vessels that were extensively dilated. This also occurred in VEGF₁₈₉ tumors, but there, vasodilation was less pronounced. Using contrast-enhanced magnetic resonance imaging, the different vascular phenotypes were visualized on characteristic radiological images. VEGF₁₆₅ expression was the most unfavorable of the three. Mice carrying VEGF₁₆₅ tumors became moribund earlier than those carrying VEGF₁₂₁-expressing tumors (16 ± 4 days versus 22 ± 3 days). Our data demonstrate that VEGF-A isoforms differ in angiogenic properties that can be visualized by contrast-enhanced magnetic resonance imaging.

This article has been cited by other articles:

				G. M. Tozer, S. Akerman, N. A. Cross, P. R. Barber, M. A. Bjorndahl, O. Greco, S. Harris, S. A. Hill, D. J. Honess, C. R. Ireson, et al. Blood Vessel Maturation and Response to Vascular-Disrupting Therapy in Single Vascular Endothelial Growth Factor-A Isoform-Producing Tumors Cancer Res., April 1, 2008; 68(7): 2301 - 2311. [Abstract] [Full Text] [PDF]

				J. W. Ji, F. Mac Gabhann, and A. S. Popel Skeletal muscle VEGF gradients in peripheral arterial disease: simulations of rest and exercise Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3740 - H3749. [Abstract] [Full Text] [PDF]

				D. Palmieri, A. F. Chambers, B. Felding-Habermann, S. Huang, and P. S. Steeg The Biology of Metastasis to a Sanctuary Site Clin. Cancer Res., March 15, 2007; 13(6): 1656 - 1662. [Abstract] [Full Text] [PDF]

				F. Mac Gabhann, J. W. Ji, and A. S. Popel VEGF gradients, receptor activation, and sprout guidance in resting and exercising skeletal muscle J Appl Physiol, February 1, 2007; 102(2): 722 - 734. [Abstract] [Full Text] [PDF]

				I. Roodink, J. Raats, B. van der Zwaag, K. Verrijp, B. Kusters, H. van Bokhoven, M. Linkels, R. M.W. de Waal, and W. P.J. Leenders Plexin D1 Expression Is Induced on Tumor Vasculature and Tumor Cells: A Novel Target for Diagnosis and Therapy? Cancer Res., September 15, 2005; 65(18): 8317 - 8323. [Abstract] [Full Text] [PDF]

				L. Manenti, E. Riccardi, S. Marchini, E. Naumova, I. Floriani, A. Garofalo, R. Dossi, E. Marrazzo, D. Ribatti, E. Scanziani, et al. Circulating plasma vascular endothelial growth factor in mice bearing human ovarian carcinoma xenograft correlates with tumor progression and response to therapy Mol. Cancer Ther., May 1, 2005; 4(5): 715 - 725. [Abstract] [Full Text] [PDF]

				W. P. J. Leenders, B. Kusters, K. Verrijp, C. Maass, P. Wesseling, A. Heerschap, D. Ruiter, A. Ryan, and R. de Waal Antiangiogenic Therapy of Cerebral Melanoma Metastases Results in Sustained Tumor Progression via Vessel Co-Option Clin. Cancer Res., September 15, 2004; 10(18): 6222 - 6230. [Abstract] [Full Text] [PDF]

				A. Iwasaki, T. Shirakusa, Y. Yoshinaga, S. Enatsu, and M. Yamamoto Evaluation of the treatment of non-small cell lung cancer with brain metastasis and the role of risk score as a survival predictor Eur. J. Cardiothorac. Surg., September 1, 2004; 26(3): 488 - 493. [Abstract] [Full Text] [PDF]

				L. Jensen, H. Pilegaard, P. D. Neufer, and Y. Hellsten Effect of acute exercise and exercise training on VEGF splice variants in human skeletal muscle Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2004; 287(2): R397 - R402. [Abstract] [Full Text] [PDF]