S48 SURGERY EARLY TUMOR DETECTION, appropriate adjuvant therapy, and standardized surgical treatment, including lymph node dissection, have all led to an extended survival time for patients with gastric cancer. 1 However, some patients in whom there are distant metastases or recurrences can have a variety of disease forms that may involve different organs. 2,3 About a quarter of all the patients who underwent a curative resection died with recur- rence. 3 Although various regimens and anticancer drugs with strong cytotoxic effects are available, 4,5 chemotherapy itself has limitations. A better understanding of molecular mechanisms that reg- ulate complex interactions between the metastatic cells and host factors could lead to new strategies for therapies. Under normal physiologic conditions, angio- genesis, the sprouting of new capillaries from a pre-existing vascular bed, is tightly regulated by both positive effectors and natural inhibitors. 6 Angiogenesis provides nutrients but also provides a route for metastasis. 7 Therefore interest has been directed toward the development of drugs that will inhibit tumor angiogenesis. Tumor endothelial cells can divide up to 50 times more frequently than normal endothelial cells and may also show many different biochemical features, thus making them potential therapeutic targets. 8 On the basis of research by our teams, studies on angiogenesis in gastric cancer were reviewed. TUMOR ANGIOGENESIS AND METASTASIS It is now widely accepted that the growth of solid tumors and the formation of metastases depend on angiogenesis. 9,10 Primary solid tumors go through a prolonged state of avascular and apparently dormant growth, with the maximum size being approximately 1 to 2 mm in diameter. Up to this size, tumor cells can obtain the neces- sary oxygen and nutrients they require for growth and survival by means of simple passive diffusion. These microscopic tumor masses can eventually switch on angiogenesis by recruiting surrounding mature host blood vessels to begin sprouting new blood vessel capillaries that grow toward and infil- trate the tumor mass, setting in motion the poten- tial for expansion of the tumor mass and hematogenous metastatic spread as well. A high degree of tumor vascularization increases the like- lihood that tumor cells will enter the circulatory system and metastasize. 11 Both tumor and host cells secrete a variety of Angiogenesis as a target for gastric cancer Yoshihiro Kakeji, MD, Yoshihiko Maehara, MD, Yasushi Sumiyoshi, MD, Shinya Oda, MD, and Yasunori Emi, MD, Fukuoka, Japan Background. The growth of solid tumors and the formation of metastases depend on angiogenesis. Both tumor cells and host cells secrete a variety of factors to stimulate angiogenesis. Methods. We investigated the expression of angiogenic factors in gastric cancer in vitro and in vivo. Results. The expression of one of the angiogenic factors, vascular endothelial growth factor antigen, in gastric cancer cells can thus serve as a pertinent predictive factor for hematogenous invasion or metasta- sis, in addition to having prognostic value. The presence of micrometastasis in bone marrow was closely related to vascular endothelial growth factor positivity and microvessel density in the primary gastric cancer. In in vivo experiments antiangiogenic agents with cytotoxic anticancer drugs formed a highly effective modulator combination for the treatment of the Lewis lung carcinoma against primary and metastatic disease. Conclusions. Antiangiogenic agents may thus be valuable for long-term administration to maintain tumor dormancy because drug resistance does not develop, and these agents have a sustained effect. As a target, antiangiogenic therapy may therefore be potentially able to prolong survival time of patients with gastric cancer. (Surgery 2002;131:S48-54.) From the Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Reprint requests: Yoshihiro Kakeji, MD, Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. Copyright © 2002 by Mosby, Inc. 0039-6060/2002/$35.00 + 0 11/0/119304 doi:10.1067/msy.2002.119304