Tamoxifen Directly Inhibits Platelet Angiogenic Potential and Platelet-Mediated Metastasis.
Tamoxifen Directly Inhibits Platelet Angiogenic Potential and Platelet-Mediated Metastasis.
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DOI：
10.1161/atvbaha.116.308791
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发表时间：
2017-04
期刊：
影响因子：
--
通讯作者：
Battinelli EM
中科院分区：
文献类型：
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作者：
Johnson KE;Forward JA;Tippy MD;Ceglowski JR;El-Husayni S;Kulenthirarajan R;Machlus KR;Mayer EL;Italiano JE Jr;Battinelli EM
血小板主要以其在止血中的作用而闻名，现在已知其在转移中发挥着至关重要的作用。他莫昔芬是一种选择性雌激素受体调节剂，广泛用于治疗乳腺癌。他莫昔芬及其代谢物已被证明可直接影响血小板功能，表明该药物具有其他作用机制。本研究的目的是确定他莫昔芬是否通过直接抑制血小板发挥抗肿瘤作用。这项研究发现，他莫昔芬预处理可显着抑制血小板活化。暴露于他莫昔芬的血小板释放的促血管生成调节剂 VEGF 的量显着降低。体外血管生成测定证实他莫昔芬预处理导致毛细管形成减少和内皮迁移减少。他莫昔芬及其代谢物4-Hydroxytamoxifen在体外也显着抑制血小板促进转移的能力。使用基于膜的阵列，我们鉴定了几种与血管生成转移相关的蛋白质，这些蛋白质从他莫昔芬处理的血小板中活化释放较低，包括血管生成素、CXCL1、CCL5、EGF、CXCL5和PDGF-BB，而抗血管生成血管生成素-1则升高。从接受他莫昔芬维持治疗的患者身上分离的血小板也被发现具有降低的激活反应、减少的 VEGF 释放以及较低的血管生成和转移潜力。我们证明他莫昔芬及其代谢物 4-羟基他莫昔芬直接改变血小板功能，导致血管生成和转移潜力降低。此外，这项研究支持利用靶向血小板疗法来抑制血小板在血管生成和恶性肿瘤中的作用的想法。
Platelets, which are mainly known for their role in hemostasis, are now known to play a crucial role in metastasis. Tamoxifen is a selective estrogen receptor modulator that is widely used for the treatment of breast cancer. Tamoxifen and its metabolites have been shown to directly impact platelet function suggesting that this drug has additional mechanisms of action. The purpose of this study was to determine whether tamoxifen exerts anti-tumor effects through direct platelet inhibition. This study found that pretreatment with tamoxifen leads to a significant inhibition of platelet activation. Platelets exposed to tamoxifen released significantly lower amounts of pro-angiogenic regulator VEGF. In vitro angiogenesis assays confirmed that tamoxifen pretreatment led to diminished capillary tube formation and decreased endothelial migration. Tamoxifen and its metabolite, 4-Hydroxytamoxifen, also significantly inhibited the ability of platelets to promote metastasis in vitro. Using a membrane based array, we identified several proteins associated with angiogenesis metastasis that were lower in activated releasate from tamoxifen treated platelets including angiogenin, CXCL1, CCL5, EGF, CXCL5 and PDGF-BB while anti-angiogenic angiopoietin-1 was elevated. Platelets isolated from patients on tamoxifen maintenance therapy were also found to have decreased activation responses, diminished VEGF release and lower angiogenic and metastatic potential. We demonstrate that tamoxifen and its metabolite 4-Hydroxytamoxifen directly alters platelet function leading to decreased angiogenic and metastatic potential. Furthermore, this study supports the idea of utilizing targeted platelet therapies to inhibit the platelet’s role in angiogenesis and malignancy.