Young M R, Duffie G P, Lozano Y, Young M E, Wright M A
Department of Research Services, Hines Veterans Administration Hospital, Illinois 60141.
Cancer Res. 1990 May 15;50(10):2973-8.
Cloned Lewis lung carcinoma (LLC) variants were used in an in vitro migration model for dissemination, to determine if prostaglandin E2 (PGE2) produced by nonmetastatic LLC cells could directly stimulate dissemination of metastatic LLC cells and to identify an intracellular mechanism for such an effect. The migration of metastatic LLC clones was stimulated not only by exogenous PGE2 but also by nonmetastatic LLC cells, by their production of a migration-stimulatory factor which was sensitive to indomethacin and anti-PGE2 antibodies. Nonmetastatic LLC clones were unresponsive to migration stimulation by PGE2. The results of in vivo metastasis studies were consistent with those of in vitro migration studies. In vivo lung metastasis was increased by PGE2, as well as by nonmetastatic cells when they were either admixed with the metastatic LLC inoculum, irradiated and injected adjacent to the metastatic LLC tumor, or localized in chambers and implanted s.c. into mice given injections of metastatic LLC cells. Indomethacin blocked metastasis stimulation by nonmetastatic cells. The in vitro PGE2 stimulation of metastatic LLC cells appeared to be linked to a cyclic AMP (cAMP) response, since migration could also be stimulated by dibutyryl-cyclic AMP and blockage of a cAMP response with nicotinic acid ablated the PGE2 stimulation of migration. In vivo metastasis could be stimulated by elevation of cAMP with aminophylline. The differential responsiveness of metastatic versus nonmetastatic LLC cells to PGE2 could not be due to PGE2-adenylate cyclase coupling, since PGE2 increased the cAMP levels in cultures of both metastatic and nonmetastatic LLC cells. There was, however, a difference in the cyclic AMP-dependent protein kinase (PKA) response to PGE2, with PKA activity of metastatic LLC being stimulated by PGE2 and by the adenylate cyclase-stimulator forskolin, whereas PKA of nonmetastatic LLC was not stimulated by these cAMP elevators, suggesting a dysfunction in the cAMP-PKA coupling.
克隆的Lewis肺癌（LLC）变体被用于体外迁移模型以研究肿瘤扩散，目的是确定非转移性LLC细胞产生的前列腺素E2（PGE2）是否能直接刺激转移性LLC细胞的扩散，并确定这种效应的细胞内机制。转移性LLC克隆的迁移不仅受到外源性PGE2的刺激，也受到非转移性LLC细胞的刺激，非转移性LLC细胞产生一种对吲哚美辛和抗PGE2抗体敏感的迁移刺激因子。非转移性LLC克隆对PGE2的迁移刺激无反应。体内转移研究结果与体外迁移研究结果一致。PGE2以及非转移性细胞与转移性LLC接种物混合、照射后并注射到转移性LLC肿瘤附近，或定位在小室中并皮下植入给注射转移性LLC细胞的小鼠体内时，都会增加体内肺转移。吲哚美辛可阻断非转移性细胞对转移的刺激。体外PGE2对转移性LLC细胞的刺激似乎与环磷酸腺苷（cAMP）反应有关，因为迁移也可被二丁酰环磷腺苷刺激，用烟酸阻断cAMP反应可消除PGE2对迁移的刺激。氨茶碱升高cAMP可刺激体内转移。转移性与非转移性LLC细胞对PGE2的不同反应性并非由于PGE2 - 腺苷酸环化酶偶联，因为PGE2增加了转移性和非转移性LLC细胞培养物中的cAMP水平。然而，环磷酸腺苷依赖性蛋白激酶（PKA）对PGE2的反应存在差异，转移性LLC的PKA活性受到PGE2和腺苷酸环化酶刺激剂福斯高林的刺激，而非转移性LLC的PKA则不受这些cAMP升高剂的刺激，这表明cAMP - PKA偶联存在功能障碍。
