Aspirin and P2Y12 inhibition attenuate platelet-induced ovarian cancer cell invasion.
Aspirin and P2Y12 inhibition attenuate platelet-induced ovarian cancer cell invasion.
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DOI：
10.1186/s12885-015-1634-x
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发表时间：
2015-09-09
期刊：
影响因子：
3.8
通讯作者：
Kenny D
中科院分区：
文献类型：
--
作者：
Cooke NM;Spillane CD;Sheils O;O'Leary J;Kenny D
血小板与癌细胞的相互作用在成功的血源性转移中起着关键作用。播散性恶性肿瘤是卵巢癌患者的主要死亡原因。目前尚不清楚为什么不同的卵巢癌有不同的转移表型。为了研究血小板与癌细胞的相互作用是否起作用，我们从功能和分子水平描述了卵巢癌细胞系对血小板的反应。用59-M和SK-OV-3细胞系作为转移性卵巢癌体外模型系统。用流式细胞仪测定各细胞系的血小板覆盖率。采用Matrigel侵袭小室实验评价细胞株的侵袭能力。通过形态分析和TaqMan RT-PCR对一组11个EMT标志物的基因表达分析来评估EMT的诱导。SK-OV-3细胞黏附和激活的血小板多于59个M细胞(p = 0.0333)。血小板显著促进了只有SK-OV-3细胞的侵袭能力(p ≤ 0.0001)。形态学和跨临界体学分析表明，在两种细胞系中，血小板都能诱导上皮细胞向间充质细胞的转化，其中SK-OV-3细胞的反应更为夸张。接下来，我们研究了抗血小板药物能否消除SK-OV-3细胞中由血小板诱导的侵袭性表型。阿司匹林(p ≤ 0.0 5)和2-甲基硫代腺苷5‘-单乙基铵盐水合物(p ≤ 0.0 1)均显著降低细胞的侵袭能力，并有效地将侵袭能力恢复到与SK-OV-3细胞相当的水平。虽然越来越多的证据表明阿司匹林具有防癌作用，但这项研究表明，抑制P2Y12也可能起到一定作用。了解了血小板和癌细胞之间的这些复杂的相互作用，最终可以建立针对抑制转移的治疗方法，从而显著降低癌症发病率。
Platelet-cancer cell interactions play a key role in successful haematogenous metastasis. Disseminated malignancy is the leading cause of death among ovarian cancer patients. It is unknown why different ovarian cancers have different metastatic phenotypes. To investigate if platelet-cancer cell interactions play a role, we characterized the response of ovarian cancer cell lines to platelets both functionally and at a molecular level. Cell lines 59 M and SK-OV-3 were used as in vitro model systems of metastatic ovarian cancer. Platelet cloaking of each cell line was quantified by flow cytometry. Matrigel invasion chamber assays were used to assess the invasive capacity of the cell lines. The induction of an EMT was assessed by morphology analysis and by gene expression analysis of a panel of 11 EMT markers using TaqMan RT-PCR. SK-OV-3 cells adhered to and activated more platelets than 59 M cells (p = 0.0333). Platelets significantly promoted the ability of only SK-OV-3 cells to invade (p ≤ 0.0001). Morphology and transcritpome analysis indicated that platelets induce an epithelial-to-mesenchymal transition phenotype in both cells lines, with a more exaggerated response in SK-OV-3 cells. Next, we investigated if antiplatelet agents could abrogate the platelet-induced aggressive phenotype in SK-OV-3 cells. Both aspirin (p ≤ 0.05) and 2-methylthioadenosine 5′-monophosphate triethylammonium salt hydrate (P2Y12 inhibitor; p ≤ 0.01) significantly decreased their invasion capacity, and effectively reverted invasion to levels comparable to SK-OV-3 cells alone. While there is increasing evidence for the cancer-protective effect of aspirin, this study suggests P2Y12 inhibition may also play a role. Understanding these complex interactions between platelets and cancer cells could ultimately allow the establishment of therapies tailored to inhibiting metastasis, thus significantly reducing cancer morbidity.