Tetsuji Sawada

Contribution of Colon Cancer Cells to Mesenchymal Cells in the Formation of Hepatic Metastasis

Proliferations of cancer cells and mesenchymal cells are necessary for the formation of hepatic metastasis. Endothelial cells and hepatic stellate cells (HSCs), which exist in the extrasinusoidal space and produce extracellular matrix, are present in hepatic lobules as mesenchymal cells. In this study we investigated the contribution of colon cancer cells to endothelial cells and HSCs in the formation of hepatic metastasis. We collected serum-free conditioned medium (SFCM) of LM-H cells, which are highly liver metastatic colon cancer cells. The SFCM of LM-H cells significantly enhanced proliferation and migration of human umbilical vein endothelial cells (HUVECs) and enhanced the proliferation and migration of HSCs derived from rats. On investigating the growth factors in the SFCM of LM-H cells, we found vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). The proliferation of HUVECs was inhibited by anti-VEGF antibody, and that of HSCs was inhibited by anti-PDGF antibody. The angiogenesis inhibitor TNP-470 significantly decreased the number of hepatic metastases of LM-H cells in nude mice. In conclusion, the VEGF and PDGF that colon cancer cells produce are important factors in the structural reorganization of hepatic metastasis. The angiogenesis inhibitor TNP-470 seems to be a potent agent for inhibiting hepatic metastasis of colon cancer.

Analysis of Factors associated with Peritoneal Metastatic Ability of Scirrrhous Gastric Cancer Cells.

胃癌腹膜播種転移の形成過程には, 癌細胞の胃壁深層への浸潤, 漿膜面からの剥離, 腹膜への接着・浸潤というステップが必要である. 今回, 腹膜播種転移の各ステップに関与する因子を, 教室で樹立されたスキルス胃癌由来の高腹膜播種転移株, 腹膜中皮細胞株, 腹膜線維芽細胞株を用い, 分子生物学的な観点からin vivo, in vitro で検討し, 以下の結論を得た. すなわち, 癌細胞の原発巣からの離脱には, MMP-1産生亢進やE-Cadherin発現低下が関与し, さらに腹腔内に遊離した癌細胞が腹膜に着床するには, 癌細胞の発現する接着分子CD44Hや, α2β1-, α3β1-integrinが関与していることが示された. また, 癌細胞により, 腹膜に線維芽細胞増生がおこり, この増生が癌細胞の浸潤能や中皮細胞形態に影響を及ぼし, 癌細胞の転移に有利に働いていることが示唆された.

Role of ELAM-1 Binding and Cytokines in Liver Metastasis of Pancreatic Cancer and Possible Therapeutic Application of a Glycosylation Inhibitor.

膵癌細胞を用い, 肝転移における糖鎖抗原発現, ELAM-1接着との関連, サイトカインの関与ならびに糖鎖合成阻害剤 (BZN) による転移抑制の可能性を検討した.SW1990は約90%と高率に肝転移をきたし, sialyl-Lea, Lex発現およびヒト臍帯血管内皮細胞 (HUVECs) ならびにELAM-1への接着性と相関した. 末梢血単核球とSW1990との混合培養にて, サイトカイン (TNF-α, IL-1β) の上澄み中への強い産生がみられ, 同上澄みにてHUVECs上にELAM-1の発現が誘導された.SW1990のBZN処理にて, 糖鎖抗原発現およびELAM-1接着, さらにヌードマウス脾内注射による肝転移は有意に抑制され, BZNの新しい転移抑制法としての応用の可能性が示唆された.