Carmona-Cortés Javier, Rodríguez-Gómez Isabel, Wangensteen Rosemary, Banegas Inmaculada, García-Lora Ángel M, Quesada Andrés, Osuna Antonio, Vargas Félix
Departamento de Ciencias de la Salud, Universidad de Jaén, Jaén, Spain.
Tumour Biol. 2014 Jun;35(6):5519-26. doi: 10.1007/s13277-014-1726-2. Epub 2014 Feb 20.
This study evaluated the effects of thyroid hormone-NO interaction on tumor development, vascularization, vascular endothelial growth factor (VEGF), and aminopeptidase (AP) activity in a murine model of implanted Lewis's carcinoma. Experiments were performed in male CBA-C57 mice. Animals were untreated (controls) or treated with: T4, the antithyroid drug methimazole, the NO inhibitor L-NAME, T4+L-NAME, methimazole+NAME, the αvß3 integrin antagonist tetrac, T4+tetrac, the iNOS inhibitor aminoguanidine (AG), and T4 + AG; all treatments were for 6 weeks except for tetrac, administered for the last 11 days. Mice were subcutaneously inoculated with 1 × 10(6) exponentially growing Lewis carcinoma 3LL cells into the dorsum. Study variables 9 days later were tumor weight (TW), Hb content, an index of tumor vascularization, VEGF, and AP activity. T4 produced parallel increases in TW and angiogenesis. L-NAME reduced TW and angiogenesis in control, hyperthyroid, and hypothyroid mice, whereas AG had no effect on these variables. Tetrac arrested TW in normal and T4-treated mice but did not decrease angiogenesis in T4-treated animals. Negative correlations were found between TW and AP activity in tumors from control hyper- and hypothyroid groups and an inverse relationship was observed between TW and AP activities in tetrac-treated mice. T4 enhances TW and angiogenesis, in which NO participates, but requires activation of integrin αvß3 to promote carcinogenesis. NO blockade reduces TW, regardless of the thyroid status. Thyroid hormone negatively modulates AP activity in the tumor. Accordingly, blockade of the membrane TH receptor αvß3 integrin reduces TW associated with an increase in AP activity.
本研究在植入Lewis癌的小鼠模型中评估了甲状腺激素与一氧化氮（NO）相互作用对肿瘤发展、血管生成、血管内皮生长因子（VEGF）和氨肽酶（AP）活性的影响。实验在雄性CBA-C57小鼠中进行。动物未接受治疗（对照组）或接受以下治疗：甲状腺素（T4）、抗甲状腺药物甲巯咪唑、NO抑制剂L-精氨酸甲酯（L-NAME）、T4 + L-NAME、甲巯咪唑 + L-NAME、αvβ3整合素拮抗剂替曲膦（tetrac）、T4 + tetrac、诱导型一氧化氮合酶（iNOS）抑制剂氨基胍（AG）以及T4 + AG；除替曲膦给药11天外，所有治疗均持续6周。将1×10⁶指数生长的Lewis癌3LL细胞皮下接种到小鼠背部。9天后的研究变量包括肿瘤重量（TW）、血红蛋白（Hb）含量、肿瘤血管生成指数、VEGF和AP活性。T4使TW和血管生成平行增加。L-NAME降低了对照组、甲状腺功能亢进和甲状腺功能减退小鼠的TW和血管生成，而AG对这些变量无影响。替曲膦使正常和T4处理小鼠的TW停滞，但未降低T4处理动物的血管生成。在对照组甲状腺功能亢进和减退组的肿瘤中，TW与AP活性之间存在负相关，在替曲膦处理的小鼠中，TW与AP活性之间存在相反关系。T4增强TW和血管生成，其中NO参与，但需要激活整合素αvβ3来促进致癌作用。无论甲状腺状态如何，NO阻断均会降低TW。甲状腺激素对肿瘤中的AP活性具有负调节作用。因此，阻断膜甲状腺激素受体αvβ3整合素可降低TW，并伴随AP活性增加。
