CN114002133B - 血清中ps阳性外泌体作为乳腺癌化疗敏感性标志物的应用 - Google Patents
血清中ps阳性外泌体作为乳腺癌化疗敏感性标志物的应用 Download PDFInfo
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Abstract
本发明公开了血清中ps阳性外泌体作为乳腺癌化疗敏感性标志物的应用。利用磁珠吸附外泌体后构建了对外泌体进行表征分析的流式细胞术。发明人通过流式细胞术分析发现PS阳性的外泌体含量在化疗无效的乳腺癌患者血清中显著高于化疗有效的乳腺癌患者，ROC曲线显示血清中PS阳性的外泌体含量可以有效区分乳腺癌患者化疗敏感还是不敏感，其曲线下面积达到0.9196，可作为检测标志物应用于乳腺癌化疗敏感性的诊断。
Description
技术领域
本发明属于生物技术领域，涉及血清中PS阳性外泌体作为乳腺癌化疗敏感性标志物的应用。
背景技术
细胞外囊泡(EVs)是由几乎所有细胞类型释放的纳米级脂质双层囊泡，包括外泌体、微囊泡(MVs)或微粒，以及凋亡小体。Exosomes即外泌体，直径在30～150nm，主要来源于细胞的内涵体(Endosome)，经由多泡体(MVB)和质膜融合后形成腔内小泡释放到细胞外。外泌体含有大量生物活性物质，如核酸、蛋白质、脂质、氨基酸和代谢产物等，被认为是细胞间通讯的重要介质，在发育，免疫应答，疾病发生等生物学过程中均发挥着重要作用。
磷脂酰丝氨酸(PS)是一种带负电荷的磷脂，其定位通常仅限于质膜的内部小叶。在细胞凋亡时，这种不对称分布被重塑，PS暴露在外小叶上，据信它充当“吃我”信号，促进吞噬细胞识别和摄取凋亡细胞。研究表明，与正常的非致瘤细胞相比，肿瘤细胞在细胞表面暴露PS。有趣的是来自卵巢癌患者腹水和血清的小细胞外囊泡(sEV)已被证明在其表面显示PS，有研究者用ELISA系统将其作为早期恶性肿瘤的诊断标志物。
临床上乳腺癌是女性最常见的恶性肿瘤之一，化疗是治疗侵袭性乳腺癌的有效方法，常常在术前会进行新辅助化疗治疗，缩小肿瘤。而化疗耐受一直是乳腺癌治疗中的难题，外泌体通过参与耐药机制的形成、改变肿瘤微环境、转移内容物等参与乳腺癌的耐药。化疗引发的EVs可能会提供生物标志物，用于预测未达到完全反应的患者与新辅助化疗相关的转移风险。
综上所述，开发血清中外泌体生物标志物可以用于预测化疗敏感性，对临床治疗具有重要的参考价值。在本发明中，我们利用流式细胞术对外泌体进行表征分析，鉴定出血清中ps阳性外泌体可作为乳腺癌化疗敏感性标志物。
发明内容
本发明的目的在于提供与血清中磷脂酰丝氨酸阳性外泌体在制备区分乳腺癌化疗敏感性试剂中的应用。
本发明的另一目的是提供一种通过流式细胞术检测血清中磷脂酰丝氨酸阳性外泌体的方法。
本发明的目的可通过如下技术方案实现：
血清中磷脂酰丝氨酸阳性外泌体在制备区分乳腺癌化疗敏感性试剂中的应用，磷脂酰丝氨酸阳性的外泌体作为区分乳腺癌患者化疗敏感和不敏感的标志物。相比对化疗有效的乳腺癌患者，化疗无效的患者血清外泌体表面PS阳性信号显著增加。
检测血清中磷脂酰丝氨酸的试剂在制备区分乳腺癌化疗敏感性试剂中的应用，磷脂酰丝氨酸阳性的外泌体作为区分乳腺癌患者化疗敏感和不敏感的标志物。
作为本发明的一种优选，所述的检测血清中磷脂酰丝氨酸的试剂为检测血清中磷脂酰丝氨酸的流式细胞术试剂。流式细胞术与传统的外泌体鉴定方法更具便捷性和特异性。
作为本发明的进一步优选，外泌体和磁珠孵育结合后标记荧光抗体利用流式细胞术进行PS阳性检测，PS阳性的外泌体可作为乳腺癌化疗敏感性标志物。
作为本发明的进一步优选，外泌体和
magnetic beads孵育结合后利用流式细胞仪更方便对其进行表征分析。由于单独的游离外泌体太小难以通过流式细胞术检测，预富集的外泌体和磁珠(直径为4.5μm)孵育后形成微珠结合外泌体的复合物，通过流式细胞术可获得清晰明确FFC/SSC。
作为本发明的一种优选，磁珠表面包被有Anti-CD63 antibody，可以特异性吸附外泌体，使检测方法更具特异性。
作为本发明的进一步优选，外泌体的PS阳性信号用荧光抗体Annexin V,AlexaFluorTM488conjugate标记后进行流式细胞术检测。
一种通过流式细胞术检测血清中磷脂酰丝氨酸阳性外泌体的方法，外泌体和
magnetic beads孵育结合后形成微珠结合外泌体的复合物，通过流式细胞术获得清晰明确FFC/SSC，对其进行表征分析。
作为本发明的一种优选，磁珠表面包被有Anti-CD63 antibody。
作为本发明的进一步优选，通过对磷脂酰丝氨酸的受体Annexin V标记后利用流式细胞术进行检测。
本发明的有益效果：
发明人首先利用流式细胞术建立检测PS阳性外泌体的方法，接着分离细胞培养上清的外泌体进行流式检测发现，在正常培养和化疗药刺激下乳腺癌细胞耐药株比普通株外泌体释放更多PS阳性的外泌体。进一步分离检测乳腺癌患者血清外泌体发现，PS阳性的外泌体可以区分乳腺癌患者化疗敏感还是不敏感。本发明提供的血清中PS阳性外泌体作为乳腺癌化疗敏感性标志物，具有极重要的临床应用潜力和价值。
附图说明
图1乳腺癌细胞耐药株比普通株释放更多PS阳性的外泌体。A:流程图。B:流式细胞术分析流程。C:乳腺癌细胞化疗药刺激前后外泌体的PS信号统计图。
图2化疗无效的乳腺癌患者血清外泌体的PS阳性信号显著增加。A:检测血清中PS阳性的外泌体流程。B:流式细胞仪鉴定血清中PS阳性的外泌体。C:化疗药物敏感(response)和不敏感(non-response)的乳腺癌患者血清中PS阳性的外泌体含量。D:PS阳性的外泌体含量区分化疗药物敏感(response)和不敏感(non-response)的乳腺癌患者的ROC曲线。
具体实施方式
以下通过实施例对本发明作进一步的阐述。
本发明所用的标本是从南京市鼓楼医院收集的乳腺癌患者血清样品。
实施例1乳腺癌细胞耐药株比普通株释放更多PS阳性的外泌体实例
选取人源乳腺癌细胞系普通株MDA-MB-231及其耐药株MDA-MB-231/DPP(顺铂耐药株)来源的外泌体进行流式检测。
实验具体步骤为：
(1)外泌体提取：细胞培养至80％融合度后换成FBS耗尽的培养基继续培养24h，收集细胞培养上清，进行外泌体提取。培养上清在300g 4℃的条件下离心5min去除残余的细胞，3000g 30min离心去除细胞碎片，加入二分之一体积的外泌体提取试剂(invitrogen,Cat#4478359)混匀4℃孵育过夜。孵育结束后10000g 1h 4℃离心，用1×PBS重悬沉淀。
(2)外泌体和磁珠吸附：磁珠涡旋30秒后取20μL于离心管中，加入200μLIsolation Buffer(PBS with 0.1％BSA,filtered through a 0.2μm filter)清洗磁珠。将离心管在磁力架上放置一分钟，弃掉上清。取下离心管，加入100μL预富集的外泌体溶液，4℃条件下放置在样品混合器上孵育18-22h。孵育结束后加入300μL Isolation Buffer清洗磁珠。再用400μL Isolation Buffer清洗磁珠一次。用合适的Buffer重悬微珠结合的外泌体进行后续实验(Annexin V染色依赖于含Ca2+离子的Binding buffer，其他标记可用Isolation Buffer重悬)。
(3)PS阳性的外泌体流式细胞术：用100μL 1×Binding buffer重悬上步得到的微珠结合的外泌体，加入5μL Annexin V(Alexa FluorTM488conjugate)和1μL APC anti-human CD63抗体，室温下避光在样品摇床上孵育60分钟。孵育结束后加300μL 1×Bindingbuffer清洗微珠结合的外泌体两遍。最后将微珠结合的外泌体重悬在300μL 1×Bindingbuffer中以进行流式细胞术分析。
检测结果：
首先我们利用流式细胞术建立检测PS阳性外泌体的方法(图1A)，对分离的外泌体进行荧光标记后，利用流式细胞术检测外泌体的PS阳性信号(图1B)。检测结果发现相比于普通株MDA-MB-231，在正常培养和顺铂药物刺激下耐药株MDA-MB-231/DDP释放的外泌体的PS阳性信号均显著增加(图1C)。
实施例2化疗无效的乳腺癌患者血清外泌体的PS阳性信号显著增加实例
从南京市鼓楼医院经过化疗的乳腺癌患者的血清样本90例，对照病例信息分为对顺铂药物有效和无效两种类型，其中化疗无效的乳腺癌患者血清样本40例，化疗有效的乳腺癌患者血清样本50例。
实验具体步骤为：
(1)外泌体提取：血清样本首先2000g 30min离心去除细胞碎片，取100μL血清样本加入0.2倍体积的外泌体提取试剂(invitrogen,Cat#4478360)混匀4℃孵育30min。孵育结束后室温条件下10000g 10min离心，用1×PBS重悬沉淀。
(2)外泌体和磁珠吸附及流式细胞术同实施例1。
检测结果：
基于对细胞上清来源的外泌体能够检测到PS阳性信号，我们利用同样的方法对对乳腺癌患者血清外泌体进行检测(图2A-B)。结果显示PS阳性的外泌体含量在化疗无效的乳腺癌患者血清中显著高于化疗有效的乳腺癌患者(图2C)，通过ROC曲线分析发现，血清中PS阳性的外泌体含量可以区分乳腺癌患者化疗敏感还是不敏感，其曲线下面积达到0.9196(p<0.01,95％CI：0.8060to 1.000)，准确性为91.25％,灵敏度为86.34％。
Claims (6)
1.血清中磷脂酰丝氨酸阳性外泌体在制备区分乳腺癌化疗敏感性试剂中的应用，其特征在于磷脂酰丝氨酸阳性的外泌体作为区分乳腺癌患者化疗敏感和不敏感的标志物。
2.检测血清中磷脂酰丝氨酸的试剂在制备区分乳腺癌化疗敏感性试剂中的应用，其特征在于磷脂酰丝氨酸阳性的外泌体作为区分乳腺癌患者化疗敏感和不敏感的标志物。
3.根据权利要求2所述的应用，其特征在于所述的检测血清中磷脂酰丝氨酸的试剂为检测血清中磷脂酰丝氨酸的流式细胞术试剂。
4.根据权利要求3所述的应用，其特征在于外泌体和磁珠孵育结合后形成微珠结合外泌体的复合物，通过流式细胞术获得清晰明确 FFC/SSC，对其进行表征分析。
5.根据权利要求4所述应用，其特征在于磁珠表面包被有Anti-CD63 antibody。
6.根据权利要求3所述的应用，通过对磷脂酰丝氨酸的受体Annexin V标记后利用流式细胞术进行检测。
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