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[Cancer Research 59, 4413-4418, September 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 4413-4418, September 1, 1999]
© 1999 American Association for Cancer Research

Tumor Biology

Protein Kinase C Lies on the Signaling Pathway for Vascular Endothelial Growth Factor-mediated Tumor Development and Angiogenesis

Hitoshi Yoshiji1, Shigeki Kuriyama, D. Kirk Ways, Junichi Yoshii, Yoji Miyamoto, Mitsuhiro Kawata, Yasuhide Ikenaka, Hirohisa Tsujinoue, Toshiya Nakatani, Masabumi Shibuya and Hiroshi Fukui

Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Nara 634-8522 Japan; [H. Y., S. K., J. Y., Y. M., M. K., Y. I., H. T., T. N., H. F.] Lilly Laboratories, Indianapolis, Indiana 46285 [D. K. W.] and Department of Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan [M. S.]

The growth of any solid tumor depends on angiogenesis. Among the known angiogenic factors, vascular endothelial growth factor (VEGF) has been shown to play a pivotal role in tumor angiogenesis. However, to date, the signal transduction pathway initiated by VEGF is still not fully understood. It has been suggested that protein kinase C (PKC) plays an important role in the VEGF-induced signal transduction pathway in vitro, although the role of PKC in tumor angiogenesis in vivo still remains to be elucidated. By delivering the VEGF gene within the self-contained tetracycline-regulated retroviral vector (Retro-Tet) into hepatocellular carcinoma (HCC) cells, we manipulated VEGF expression by providing tetracycline in the drinking water to assess the tumor kinetics mediated exclusively by VEGF. In this study, we combined this Retro-tet system and LY333531, an inhibitor of the PKC-ß isoform, to elucidate the role of PKC-ß in tumor development and angiogenesis. Using a syngenic xenograft model, tumor augmentation induced by VEGF overexpression in HCC was markedly suppressed by oral administration of the PKC-ß inhibitor, with an accompanying reduction of neovascularization and p44/42 mitogen-activated protein kinase activation. This inhibitory effect was achieved even after the tumor was fully established. Immunohistochemical analysis revealed that apoptosis increased markedly in the tumor upon PKC-ß inhibitor treatment, whereas tumor cell proliferation itself did not change. Furthermore, with orthotopical transplantation, PKC-ß inhibition suppressed HCC tumor development in the liver. These results suggest that PKC-ß lies on the signal transduction pathway by which VEGF augments development and angiogenesis not only at the initial stage but also after the tumor is fully established.




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Copyright © 1999 by the American Association for Cancer Research.