Molecular target based combinational therapeutic approaches in thyroid cancer.
Molecular target based combinational therapeutic approaches in thyroid cancer.
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DOI：
10.1186/1479-5876-10-81
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发表时间：
2012-05-01
影响因子：
7.4
通讯作者：
Tiwari RK
中科院分区：
文献类型：
--
作者：
Rajoria S;Suriano R;George AL;Kamat A;Schantz SP;Geliebter J;Tiwari RK
甲状腺癌与其他类型的癌症一样，依赖于血管生成来持续生长和发展。有趣的是，雌激素已被证明有助于体外甲状腺癌的侵袭性，这完全支持观察到的女性甲状腺癌发病率高于男性。如果已经观察到雌激素有助于雌激素反应性乳腺癌的血管生成增加，则可以想象推测雌激素也有助于雌激素反应性甲状腺癌的血管生成。在这项研究中，三个人甲状腺癌细胞（B-CPAP，CGTH-W-1，ML-1）与雌激素单独或雌激素和抗雌激素（氟维司群和3，3 ′-二吲哚甲烷，一种天然的饮食化合物）处理24小时。然后将细胞培养基加入人脐静脉内皮细胞（HUVEC）中并测定血管生成相关事件。还定量了条件培养基中的血管内皮生长因子（VEGF）水平，以评估其是否是参与这些观察的关键因素。来自雌激素处理的甲状腺癌细胞的条件培养基增强了通常在血管生成期间观察到的内皮细胞的表型变化（增殖、迁移和小管形成）。在HUVEC中观察到的这些表型变化被确定受到雌激素诱导的癌细胞分泌VEGF的调节。最后，我们发现抗雌激素、氟维司群和3，3 ′-二吲哚甲烷抑制了VEGF的分泌，这导致HUVEC中血管生成相关事件减少。我们的数据证实雌激素是甲状腺细胞中VEGF分泌/表达的关键调节因子，其增强甲状腺癌中血管生成的过程。这些发现还表明抗雌激素作为抗血管生成化合物的临床效用可用作治疗甲状腺癌的治疗手段。我们还观察到，3，3 ′-二吲哚甲烷是一种很有前途的天然抗雌激素，可用作治疗甲状腺癌的治疗方案的一部分。
Thyroid cancer, as with other types of cancer, is dependent on angiogenesis for its continued growth and development. Interestingly, estrogen has been shown to contribute to thyroid cancer aggressiveness in vitro, which is in full support of the observed increased incidence of thyroid cancer in women over men. Provided that estrogen has been observed to contribute to increased angiogenesis of estrogen responsive breast cancer, it is conceivable to speculate that estrogen also contributes to angiogenesis of estrogen responsive thyroid cancer. In this study, three human thyroid cancer cells (B-CPAP, CGTH-W-1, ML-1) were treated with estrogen alone or estrogen and anti-estrogens (fulvestrant and 3,3′-diindolylmethane, a natural dietary compound) for 24 hours. The cell culture media was then added to human umbilical vein endothelial cell (HUVECs) and assayed for angiogenesis associated events. Vascular endothelial growth factor (VEGF) levels were also quantified in the conditioned media so as to evaluate if it is a key player involved in these observations. Conditioned medium from estrogen treated thyroid cancer cells enhanced phenotypical changes (proliferation, migration and tubulogenesis) of endothelial cells typically observed during angiogenesis. These phenotypic changes observed in HUVECs were determined to be modulated by estrogen induced secretion of VEGF by the cancer cells. Lastly, we show that VEGF secretion was inhibited by the anti-estrogens, fulvestrant and 3,3′-diindolylmethane, which resulted in diminished angiogenesis associated events in HUVECs. Our data establishes estrogen as being a key regulator of VEGF secretion/expression in thyroid cells which enhances the process of angiogenesis in thyroid cancer. These findings also suggest the clinical utility of anti-estrogens as anti-angiogenic compounds to be used as a therapeutic means to treat thyroid cancer. We also observed that 3,3′-diindolylmethane is a promising naturally occurring anti-estrogen which can be used as a part of therapeutic regimen to treat thyroid cancer.