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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 546-553
Involvement of vascular endothelial growth factor receptor-3 in
maintenance of integrity of endothelial cell lining during tumor
angiogenesis
Hajime Kubo,
Takashi Fujiwara,
Lotta Jussila,
Hiroyuki Hashi,
Minetaro Ogawa,
Kenji Shimizu,
Masaaki Awane,
Yoshiharu Sakai,
Arimichi Takabayashi,
Kari Alitalo,
Yoshio Yamaoka, and
Shin-Ichi Nishikawa
From the Departments of Gastroenterological Surgery and Molecular
Genetics, Graduate School of Medicine, Kyoto University, Kyoto, and the
Laboratory Animal Center, Ehime University School of Medicine, Ehime,
Japan; and the Molecular/Cancer Biology Laboratory, Haartman Institute,
University of Helsinki, Helsinki, Finland.
Vascular endothelial growth factor (VEGF) plays a major role in
tumor angiogenesis. VEGF-C, however, is thought to stimulate the growth
of lymphatic vessels because an expression of its specific receptor,
VEGF receptor-3 (VEGFR-3), was demonstrated to be restricted to
lymphatic vessels. Here we demonstrate that the inactivation of VEGFR-3
by a novel blocking monoclonal antibody (mAb) suppresses tumor growth
by inhibiting the neo-angiogenesis of tumor-bearing tissues. Although
VEGFR-3 is not expressed in adult blood vessels, it is induced in
vascular endothelial cells of the tumor-bearing tissues. Hence, VEGFR-3
is another receptor tyrosine kinase involved in tumor-induced
angiogenesis. Micro-hemorrhage in the tumor-bearing tissue was the most
conspicuous histologic finding specific to AFL4 mAb-treated mice.
Scanning microscopy demonstrated disruptions of the endothelial lining
of the postcapillary venule, probably the cause of micro-hemorrhage and
the subsequent collapse of the proximal vessels. These findings suggest
the involvement of VEGFR-3 in maintaining the integrity of the
endothelial lining during angiogenesis. Moreover, our results suggest
that the VEGF-C/VEGFR-3 pathway may serve another candidate target for
cancer therapy.
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M. S. Gordon, K. Margolin, M. Talpaz, G. W. Sledge Jr, E. Holmgren, R. Benjamin, S. Stalter, S. Shak, and D. C. Adelman
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M. E. Baldwin, B. Catimel, E. C. Nice, S. Roufail, N. E. Hall, K. L. Stenvers, M. J. Karkkainen, K. Alitalo, S. A. Stacker, and M. G. Achen
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M. J. Karkkainen, A. Saaristo, L. Jussila, K. A. Karila, E. C. Lawrence, K. Pajusola, H. Bueler, A. Eichmann, R. Kauppinen, M. I. Kettunen, et al.
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