Nat Med:心脏病或促进乳腺癌转移!心脏病会重编程免疫系统,导致免疫力下降,促进乳腺癌进展和转移

2020-07-16 奇点糕 奇点网

随着新疗法的不断涌现,乳腺癌患者的5年生存率越来越高了。

随着新疗法的不断涌现,乳腺癌患者的5年生存率越来越高了。

据统计,在2019年,仅美国就有380万浸润性乳腺癌幸存者。如果从全球来看的话,这一数据恐怕在千万以上。

今天,来自美国纽约大学医学院的Kathryn J. Moore教授和她领衔的研究团队,在著名医学期刊《自然·医学》上发表重要研究论文。

这项研究成果给广大的乳腺癌幸存者提了个醒:要照顾好自己的心脏,警惕心脏病发作。

Moore团队回顾性分析了两个大型前瞻性研究的数据,意外发现,与确诊乳腺癌之后没有出现心脏病的患者相比,确诊后发生心脏病的患者,乳腺癌复发风险增加59%,因乳腺癌死亡的风险增加60%。

她们还在小鼠模型中研究了心脏病促进乳腺癌进展的可能机制:心肌梗死(MI)会导致免疫细胞重编程,诱使一些免疫细胞变成免疫抑制表型,引发全身性免疫稳态失衡,加速乳腺癌的进展和转移。

“心脏病发作似乎通过钝化免疫系统对癌细胞的攻击,给肿瘤提供了一个有利的生长环境,”Moore说。

一直以来,科学家们已经发现,乳腺癌患者由于治疗的毒性和生活习惯的改变,患血管疾病的风险显著增加[4,5]。而且,随着治疗手段的改进升级,患者的存活时间越来越长,出现心血管并发症的风险也越来越高。

不过,乳腺癌患者出现心脏病,对癌症的发展有何影响目前仍未可知。

Moore是心脏病领域的专家,也是纽约大学医学院心血管研究中心主任,几年前她也注意到乳腺癌患者群体心脏病的发病率不低。“我想知道心脏病发作是否会影响她们的癌症,”Moore说,“让我吃惊的是,竟然没有人做过相关的研究。”

Kathryn J. Moore教授

虽然我们常说癌症是一种基因病,但是癌症的发生和发展也不全是基因决定的,肿瘤微环境和患者自身的免疫能力,也是影响肿瘤发生和发展的重要因素。

实际上,已经有研究发现,心肌梗死导致的缺血性心肌损伤等,会在一定程度上影响外周循环和骨髓中的免疫细胞形态,尤其是单核细胞。

而单核细胞是肿瘤微环境的关键调控因子,外周循环中单核细胞水平升高又与多种癌症的不良临床结局相关。

基于以上信息,Moore教授推测心脏病对乳腺癌的发展应该是有一定的影响,有必要做深入的研究。

该图片由Raman Oza在Pixabay上发布

Moore和她的同事首先对早期乳腺癌的两项前瞻性病例队列研究进行了回顾性分析,以评估新发的、诊断后的心血管事件(如心肌梗死或卒中)与癌症结果(复发和癌症特异性死亡)之间的关系。

研究人员排除了癌症诊断时已有心血管疾病或心血管危险因素的患者,并对剩余1724名患者进行多重协变量调整。

在诊断后平均11.7年的随访时间里,与没有出现心血管事件的患者相比,乳腺癌诊断后发生心血管事件与调整后的癌症复发风险增加59%,和乳腺癌特异性死亡率增加60%相关。

Moore团队得到的数据和之前心力衰竭与全癌种发病率增加相关的研究相吻合。

 

乳腺癌患者复发和死亡曲线图,以及相关数据

那么这背后的作用机制究竟是什么呢?

为了解答这个问题,Moore和她的同事转向了模式小鼠。她们先将乳腺癌细胞注射到小鼠体内,然后将小鼠分成两组,一组通过手术的方式阻断心脏的两条冠状动脉,模拟心肌梗死,另一组小鼠做了一个假手术,作为对照组。

20天之后,研究人员发现模拟心梗组的小鼠身上长了巨大的肿瘤,体积和重量是假手术组小鼠的2倍左右。

很明显,心肌梗死提升了肿瘤的生长速度

小鼠肿瘤体积和重量变化

为了搞清楚心梗后肿瘤生长速度加快的原因,Moore和她的同事分析了肿瘤中的免疫细胞变化。总的来说,抑制T细胞浸润和抗肿瘤反应的免疫抑制性细胞水平显著增加,尤其是CD11b+Ly6G-Ly6Chi单核细胞(或者叫单核细胞型髓系来源的抑制性细胞,M-MDSCs)。而且后续的研究表明,Ly6Chi单核细胞增多确实是心梗引起的。

随后Moore团队用一种方法消除了血液中90%和骨髓中55%的Ly6Chi单核细胞,奇迹出现了,心肌梗死组小鼠的肿瘤体积缩小了56%;而做假手术组小鼠的肿瘤体积没有发生变化。

 

消除Ly6Chi单核细胞,小鼠肿瘤体积的变化

从心肌梗死组小鼠体内的免疫细胞变化来看,消除Ly6Chi单核细胞后,免疫抑制性T细胞比例降低,活化的细胞毒性T细胞比例增加

消除Ly6Chi单核细胞,免疫细胞的变化

那么心肌梗死究竟是如何调节免疫系统的呢?研究人员又从转录组的角度分析了骨髓和血液中的Ly6Chi单核细胞,以及肿瘤中M-MDSCs的情况。

她们发现,与对照组小鼠相比,心肌梗死组小鼠的235个基因的表达模式发生了改变,其中与肿瘤生长相关的基因表达上调,而促使免疫系统激活的基因表达则被下调。而且心肌梗死对转录组的这种影响,是通过表观遗传学调控完成

转录组数据分析

由于小鼠骨髓中的免疫细胞也发生了类似的变化,研究人员认为当单核细胞还在骨髓中时,心肌梗死就对Ly6Chi单核细胞完成了重编程,导致大量的单核细胞变成免疫抑制型免疫细胞。研究人员还通过骨髓移植,进一步证实了她们的这一猜想。

最后,Moore团队还在原发性乳腺癌小鼠模型身上研究了心肌梗死对乳腺癌肺转移的影响。她们发现,心肌梗死确实增加了乳腺癌的肺转移

基于以上数据,Moore和她的同事认为,她们的研究结果表明,心肌梗死作为一种急性病理应激事件,可加速乳腺癌的进展和转移。从机制上讲,心肌梗死通过表观遗传学手段导致先天性免疫细胞的变化,形成一个全身性免疫抑制环境,促进肿瘤的生长和转移。

下一步需要研究心梗导致的表观遗传学变化究竟是如何发生的,以便找到降低患者癌症复发和死亡风险的方法。

不过,在研究成果出现之前,Moore建议,乳腺癌患者可以更加积极地控制心血管疾病的发生风险,例如多运动等。实际上,运动已经与癌症死亡风险下降联系在一起了。

原始出处:Graeme J. Koelwyn, Alexandra A. C. Newman, Milessa S. Afonso, et al. Myocardial infarction accelerates breast cancer via innate immune reprogramming. Nature Medicine (2020)

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    2020-10-29 Jessica

    Moore建议,乳腺癌患者可以更加积极地控制心血管疾病的发生风险,例如多运动等。

    0

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    2021-04-24 liye789132251
  3. 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  4. 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  5. 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  6. 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, beContent=null, objectType=article, channel=null, level=null, likeNumber=83, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20220519/c2ab253484ee4527a2d4e9589a4821ac/45de9bf494a54becb2ea4369c9d11e85.jpg, createdBy=7a3710, createdName=lovetcm, createdTime=Fri Jul 17 08:39:25 CST 2020, time=2020-07-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=803060, encodeId=d2c980306044, content=人体就是一个整体啊, beContent=null, objectType=article, channel=null, level=null, likeNumber=97, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=43a21971117, createdName=njwbhuang, createdTime=Fri Jul 17 06:22:51 CST 2020, time=2020-07-17, status=1, ipAttribution=)]
    2020-07-17 lovetcm

    #肿瘤心脏病学#一门新学科

    0

  7. 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, beContent=null, objectType=article, channel=null, level=null, likeNumber=83, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20220519/c2ab253484ee4527a2d4e9589a4821ac/45de9bf494a54becb2ea4369c9d11e85.jpg, createdBy=7a3710, createdName=lovetcm, createdTime=Fri Jul 17 08:39:25 CST 2020, time=2020-07-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=803060, encodeId=d2c980306044, content=人体就是一个整体啊, beContent=null, objectType=article, channel=null, level=null, likeNumber=97, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=43a21971117, createdName=njwbhuang, createdTime=Fri Jul 17 06:22:51 CST 2020, time=2020-07-17, status=1, ipAttribution=)]
    2020-07-17 lovetcm

    #乳腺癌#与心梗关联起来了

    0

  8. [GetPortalCommentsPageByObjectIdResponse(id=895448, encodeId=9ef4895448ad, content=Moore建议,乳腺癌患者可以更加积极地控制心血管疾病的发生风险,例如多运动等。 , beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20211019/df01a4bfb64246379ddfef3370d04115/e1274c8eb5e440918f56f83bcfea9031.jpg, createdBy=3a345397082, createdName=Jessica, createdTime=Thu Oct 29 16:33:05 CST 2020, time=2020-10-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1884462, encodeId=51d11884462d7, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Sat Apr 24 02:34:50 CST 2021, time=2021-04-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1307716, encodeId=8e66130e7166a, content=<a href='/topic/show?id=85d2289e188' target=_blank style='color:#2F92EE;'>#免疫力#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=28971, encryptionId=85d2289e188, topicName=免疫力)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=3547346, createdName=dongjia2010, createdTime=Sat Jul 18 14:34:50 CST 2020, time=2020-07-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1590354, encodeId=fe0e1590354e7, content=<a href='/topic/show?id=2c17e154824' target=_blank style='color:#2F92EE;'>#癌转移#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=71548, encryptionId=2c17e154824, topicName=癌转移)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=2dc017794099, createdName=linagood, createdTime=Sat Jul 18 14:34:50 CST 2020, time=2020-07-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1610573, encodeId=84fa16105e3a5, content=<a href='/topic/show?id=eb6b1145939' target=_blank style='color:#2F92EE;'>#Med#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11459, encryptionId=eb6b1145939, topicName=Med)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=552a19396740, createdName=ms3994565386320060, createdTime=Sat Jul 18 14:34:50 CST 2020, time=2020-07-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=803071, encodeId=487d8030e1dc, content=<a href='/topic/show?id=df1582921da' target=_blank style='color:#2F92EE;'>#肿瘤心脏病学#</a>一门新学科, beContent=null, objectType=article, channel=null, level=null, likeNumber=104, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=82921, encryptionId=df1582921da, topicName=肿瘤心脏病学)], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20220519/c2ab253484ee4527a2d4e9589a4821ac/45de9bf494a54becb2ea4369c9d11e85.jpg, createdBy=7a3710, createdName=lovetcm, createdTime=Fri Jul 17 08:41:29 CST 2020, time=2020-07-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=803070, encodeId=501c8030e01c, content=<a href='/topic/show?id=73c423e2572' target=_blank style='color:#2F92EE;'>#乳腺癌#</a>与心梗关联起来了, beContent=null, objectType=article, channel=null, level=null, likeNumber=136, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=23725, encryptionId=73c423e2572, topicName=乳腺癌)], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20220519/c2ab253484ee4527a2d4e9589a4821ac/45de9bf494a54becb2ea4369c9d11e85.jpg, createdBy=7a3710, createdName=lovetcm, createdTime=Fri Jul 17 08:41:03 CST 2020, time=2020-07-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=803069, encodeId=cfe380306929, content=BNP作用? , beContent=null, objectType=article, channel=null, level=null, likeNumber=83, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20220519/c2ab253484ee4527a2d4e9589a4821ac/45de9bf494a54becb2ea4369c9d11e85.jpg, createdBy=7a3710, createdName=lovetcm, createdTime=Fri Jul 17 08:39:25 CST 2020, time=2020-07-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=803060, encodeId=d2c980306044, content=人体就是一个整体啊, beContent=null, objectType=article, channel=null, level=null, likeNumber=97, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=43a21971117, createdName=njwbhuang, createdTime=Fri Jul 17 06:22:51 CST 2020, time=2020-07-17, status=1, ipAttribution=)]
    2020-07-17 lovetcm

    BNP作用?

    0

  9. 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, beContent=null, objectType=article, channel=null, level=null, likeNumber=83, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20220519/c2ab253484ee4527a2d4e9589a4821ac/45de9bf494a54becb2ea4369c9d11e85.jpg, createdBy=7a3710, createdName=lovetcm, createdTime=Fri Jul 17 08:39:25 CST 2020, time=2020-07-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=803060, encodeId=d2c980306044, content=人体就是一个整体啊, beContent=null, objectType=article, channel=null, level=null, likeNumber=97, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=43a21971117, createdName=njwbhuang, createdTime=Fri Jul 17 06:22:51 CST 2020, time=2020-07-17, status=1, ipAttribution=)]
    2020-07-17 njwbhuang

    人体就是一个整体啊

    0

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