Roles of cell surface membrane and nuclear prostaglandin receptors in growth factor production during colon carcinogenesis

各种研究表明，非类固醇抗炎药(NSAIDs)可预防结肠癌的形成。然而，这些步骤的机制尚未阐明，而环氧合酶(COX-2)已被证明在这一现象中起着重要作用。我们利用细胞系研究了COX-2在人胃肿瘤中的定位及其可能的作用。结果如下：1.COX-2在人结肠腺瘤中表达于上皮下层的间充质细胞。2.COX-2在增生性胃息肉的上皮下层间充质细胞中也有表达，而在胃腺瘤中不表达。3.前列腺素E通过前列腺素受体EP_2和EP_4诱导人巨噬细胞表达血管内皮生长因子。4.前列环素受体的特异性配体西卡前列素和伊洛前列素也能刺激这些细胞产生血管内皮生长因子。5.PPARγ的特异性配基PgJ_2类似物，而PPARδ的特异性配基PgI_2类似物无此作用。6.在结肠癌细胞系中，PPARγ的配体和PPARδ的配体，而不是PGE受体或PGI受体的配体，都能模拟血管内皮生长因子的产生。7.抗溃疡药物瑞巴匹特可抑制膜PG受体介导的巨噬细胞产生的血管内皮生长因子，但不能抑制核受体介导的巨噬细胞产生的血管内皮生长因子。

Various studies have demonstrated that Non-steroidal anti-inflammatory drugs (NSAIDs) prevent colon cancer formation. However, the mechanisms of these steps have not been elucidated yet while cyclooxygenase (COX-2) has been demonstrated to play an important role in this phenomenon. We investigated the localization of COX-2 in human gastric tumors and possible roles using cell lines. What we found was described below: 1. COX-2 was expressed in mesenchymal cells located at sub-epithelial layer of human colonic adenomas. 2. COX-2 was also expressed in mesenchymal cells located at sub-epithelial layer of human hyperplastic gastric polyps but not in human gastric adenomas. 3. Prostaglandin (PG) E induced vascular endothelial growth factor (VEGF) expression by human macrophages through EP_2 and EP_4 prostaglandin receptors. 4. Cicaprost and iloprost, specific ligands for PGI receptors, also stimulated VEGF production by these cells. 5. A PGJ_2 analogue, a specific ligand for PPARγ, but not a PGI_2 analogue, a specific ligand for PPARδ, showed similar effects. 6. Both a ligand for PPARγ and a ligand for PPARδ but not ligands for PGE receptors or PGI receptors simulated VEGF production by colon cancer cell lines. 7. Rebamipide, an anti-ulcer drug, suppressed membrane PG receptor-mediated but not nuclear receptor-mediated increase of VEGF production by macrophages.