Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
J Pharmacol Exp Ther. 2011 Feb;336(2):516-23. doi: 10.1124/jpet.110.173278. Epub 2010 Nov 9.
It is well known that tumor-surrounding stromal tissues support tumor development through secreting soluble factors such as various cytokines, chemokines, and growth factors. It has also been suggested that tumor-associated fibroblast and immune cells have a high expression of cyclooxygenase-2 (COX-2) and produce and secrete several prostaglandins (PGs) to adjacent cancer tissues. From these findings, we assumed that COX-2 inhibition might have an anticancer effect on cancer cells even without COX-2 expression in COX-2-dependent mechanisms through blocking the effect of stroma-derived PGs. Here, because of the complex involvement of various factors in vivo, we investigated this possibility with an in vivo-mimicking model using a Transwell system. To test our hypothesis, we used COX-2-transfected cell lines as stromal cells in our model. When we cocultured cancer cells (LS174T cells without COX-2 expression) with COX-2-high stromal cells in the Transwell membrane system, we observed that the proliferation of cancer cells was promoted and vascular endothelial growth factor synthesis was up-regulated significantly. These effects were blocked completely by COX-2 inhibitors and phosphoinositide-3-kinase inhibitors and partially by the PG E(2) receptor 4 antagonist. Even if some cancer cells did not express COX-2, they were found to have expression of PG receptors and PG-related downstream signaling molecules associated with cell viability. Our observation suggests that these cells can be influenced by PGs derived from stromal tissues. These findings also suggest that COX-2 inhibitors can be used to control the interaction between cancer and surrounding stromal tissues and suppress the proliferation of cancer cells regardless of the expression of COX-2 in cancer cells.
众所周知，肿瘤周围的基质组织通过分泌各种细胞因子、趋化因子和生长因子等可溶性因子来支持肿瘤的发展。还有研究表明，肿瘤相关成纤维细胞和免疫细胞中环氧合酶-2（COX-2）表达水平较高，并产生和分泌几种前列腺素（PGs）到相邻的癌细胞组织中。从这些发现中，我们假设 COX-2 抑制剂可能通过阻断基质衍生 PG 的作用，即使在 COX-2 依赖性机制中 COX-2 不表达，也对癌细胞具有抗癌作用。在这里，由于体内涉及各种因素的复杂性，我们使用 Transwell 系统的体内模拟模型来研究这种可能性。为了验证我们的假设，我们在模型中使用 COX-2 转染细胞系作为基质细胞。当我们将 COX-2 低表达的癌细胞（LS174T 细胞）与 Transwell 膜系统中的 COX-2 高表达基质细胞共培养时，我们观察到癌细胞的增殖显著促进，血管内皮生长因子的合成也显著上调。这些作用可被 COX-2 抑制剂和磷酯酰肌醇-3-激酶抑制剂完全阻断，部分被 PG E（2）受体 4 拮抗剂阻断。即使一些癌细胞不表达 COX-2，也发现它们表达与细胞活力相关的 PG 受体和 PG 相关的下游信号分子。我们的观察结果表明，这些细胞可能会受到基质组织衍生的 PG 的影响。这些发现还表明，COX-2 抑制剂可用于控制癌症与周围基质组织之间的相互作用，并抑制癌细胞的增殖，而与癌细胞中 COX-2 的表达无关。
