Cooke Niamh M, Spillane Cathy D, Sheils Orla, O'Leary John, Kenny Dermot
Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland.
The Biomedical Diagnostics Institute, Dublin City University, Dublin, Ireland.
BMC Cancer. 2015 Sep 9;15:627. doi: 10.1186/s12885-015-1634-x.
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.
血小板与癌细胞的相互作用在成功的血行转移中起关键作用。播散性恶性肿瘤是卵巢癌患者死亡的主要原因。不同的卵巢癌为何具有不同的转移表型尚不清楚。为了研究血小板与癌细胞的相互作用是否起作用，我们在功能和分子水平上对卵巢癌细胞系对血小板的反应进行了表征。
将59 M和SK-OV-3细胞系用作转移性卵巢癌的体外模型系统。通过流式细胞术对每个细胞系的血小板包被情况进行定量。使用基质胶侵袭小室试验评估细胞系的侵袭能力。通过形态学分析和使用TaqMan RT-PCR对一组11种上皮-间质转化（EMT）标志物进行基因表达分析来评估EMT的诱导情况。
SK-OV-3细胞比59 M细胞黏附并激活更多的血小板（p = 0.0333）。血小板仅显著促进了SK-OV-3细胞的侵袭能力（p≤0.0001）。形态学和转录组分析表明，血小板在两种细胞系中均诱导上皮-间质转化表型，在SK-OV-3细胞中的反应更为明显。接下来，我们研究了抗血小板药物是否可以消除血小板诱导的SK-OV-3细胞的侵袭性表型。阿司匹林（p≤0.05）和2-甲硫基腺苷5'-单磷酸三乙铵盐水合物（P2Y12抑制剂；p≤0.01）均显著降低了它们的侵袭能力，并有效地将侵袭恢复到与单独的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抗癌保护作用，但本研究表明P2Y12抑制也可能起作用。了解血小板与癌细胞之间的这些复杂相互作用最终可能有助于建立针对抑制转移的治疗方法，从而显著降低癌症发病率。
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