Inhibitory effect of cyclooxygenase-2 inhibitor on the metastasis of gastrointestinal tumor.

背景。本研究旨在探讨环氧化酶-2 （COX-2）在肝脏转移中的作用以及COX-2抑制剂对胃肠道肿瘤转移的影响。人结肠癌TK-4被皮下（SC）、腹膜（PI）或原位（盲肠表面；CI）植入。植入8周后处死动物，切除生长中的肿瘤进行检查。Northem Blotting法检测COX-1、cox -2、VEGF mRNA水平，并检测微血管密度（MVD）和凋亡指数。此外，我们还对76例结直肠癌患者进行了临床病理分析，以阐明COX-2在转移中的作用。肝转移以CI组发生率最高，TUNEL染色的凋亡指数以CI组最低。COX-2的高表达与er - mp12阳性肿瘤微血管的密度无关。39例（51%）结直肠癌患者COX-2过表达，其发生肝转移的频率高于未过表达者（p<0.05）。但在组织学分型、淋巴结转移及腹膜播散方面无明显差异。这些结果表明，COX-2在肝转移中起重要作用，COX-2的高表达可能会损害结肠癌细胞凋亡的诱导，但可能不会诱导血管生成。COX-2是预防肝转移的靶分子之一。

Background. This study was designed to investigate the role of cyclooxygenase-2 (COX-2) in the liver metastasis and the effect of COX-2 inhibitor on metastasis of gastrointestinal tumor.Methods. Human colon cancer TK-4 was implanted subcutaneously (SC), peritoneally (PI) or orthotopically (on the surface of the cecum ; CI). The animals were sacrified 8 weeks after implantation and growing tumors were removed and examined. COX-1, -2 and VEGF mRNA level were determined by Northem Blotting analysis, and microvessel density (MVD) and apoptotic index were also examined. In addition, clinicopathological analysis was performed in 76 patients with colorectal cancer to clarify the role of COX-2 in the metastasis.Results. Liver metastasis developed most frequently in CI groups and the apoptotic index assessed by TUNEL staining was lowest in the CI group among the three groups. High expression of COX-2 had no connection with the density of ER-MP12-positive tumor microvesseles. Thirty-nine (51%) patients with colorectal cancer showed COX-2 over-expression, in whom liver metastasis developed more frequently than in those without overexpression (p<0.05). However, there was no significant difference in histological types, lymph node metastasis and peritoneal dissemination.Conclusions. These results suggest that COX-2 plays an important role in liver metastasis, and that high COX-2 expression may impair induction of apoptosis, but may not induce angiogenesis in colon cancer. COX-2 is one of target molecules for prevention of liver metastasis.