-
摘要:
细胞焦亡是一种新近发现的促炎程序性死亡方式,细胞焦亡是由半胱天冬氨酸蛋白酶-1(Caspase-1)介导,通过GSDM家族蛋白的剪切活化,令细胞膜上形成小孔,从而使胞膜快速裂解,导致细胞内炎性内容物释放引起炎性反应的过程。细胞焦亡的三种途径分别为Caspase-1作用的经典通路、Caspase-4、5、11作用的非经典通路以及Caspase-3或Hela细胞作用的特殊通路。细胞焦亡在乳腺癌的发生、侵袭和转移方面起着重要的作用,与乳腺癌的预防和治疗有着密切的联系。本文就细胞焦亡的生物学机制及其在乳腺癌中的研究进展作一综述,以期为临床医生治疗乳腺癌提供新的思路。
Abstract:Pyroptosis is a newly discovered way of proinflammatory programmed cell death. Pyroptosis is mediated by caspase-1 (Caspase-1). Through the cleavage and activation of GSDM family proteins, small pores are formed on the cell membrane, thus rapid lysis of the cell membrane process, and then leads to intracellular inflammatory content release thereby causing inflammatory response. The three pyroptosis pathways are the classical pathway of Caspase-1, the non-classical pathway of Caspase-4, 5, and 11, and the special pathway of Caspase-3 or Hela cells. Pyroptosis plays an important role in the occurrence, invasion, and metastasis of breast cancer, and is closely related to the prevention and treatment of breast cancer. This article reviews the biological mechanism of pyroptosis and its research progress in breast cancer, to provide a new idea for clinicians in the treatment of breast cancer.
-
Key words:
- Pyroptosis /
- Caspase /
- Programmed cell death /
- Breast cancer
-
0 引言
宫颈小细胞神经内分泌癌(small cell neuroendocrine carcinoma, SCNEC)是一种较为罕见的原发于宫颈的神经内分泌性肿瘤,约占宫颈恶性肿瘤的1%~2%[1-2]。在各种类型的宫颈癌中,SCNEC是一种侵袭性强的病理类型[3-8]。但因为该类病例较少,目前尚无规范化的治疗。本研究对101例宫颈小细胞神经内分泌癌患者的临床病理资料及生存状况进行分析,旨在探讨SCNEC合理的治疗方案及预后相关因素,为此类患者治疗及预后判断提供临床依据。
1 资料与方法
1.1 临床资料
收集2007年1月—2018年6月在江西省妇幼保健院确诊并完成治疗的101例宫颈小细胞神经内分泌癌患者作为研究对象。患者确诊年龄25~73岁,中位年龄44岁,其中41~50岁者有40例。宫颈局部肿瘤直径 > 4 cm患者34例,≤4 cm患者67例。患者临床资料及年龄分布见表 1。所有患者均知情同意。
表 1 101例SCNEC患者临床病理特征Table 1 Clinical and pathological features of 101 SCNEC patients1.2 方法
1.2.1 研究对象纳入标准
(1)所有患者接受治疗前均经江西省妇幼保健院病理确诊为宫颈小细胞神经内分泌癌;(2)临床分期盆腔检查均经三位以上有经验的妇科肿瘤专业医师检查确定;(3)治疗前均未接受任何干预性治疗,且初始治疗及后续治疗均在同一机构完成;(4)纳入研究的患者治疗模式均为手术+术后补充放化疗(下文简称手术治疗组)或根治性放化疗,且按计划完成全部治疗;(5)全部患者术后病理检查均在同一医院完成;(6)建立了完整的病历档案,并持续随访,具备完整的住院及门诊复查病历资料。
1.2.2 手术方式
72例手术治疗患者手术方式为广泛子宫切除+盆腔淋巴结切除术±腹主动脉旁淋巴结切除术,其中47例行腹主动脉旁淋巴结切除术。69例行双附件切除,其余3例保留一侧卵巢且进行了保留卵巢的组织活检。
1.2.3 放疗
放疗包括体外照射+腔内后装治疗,体外照射采用全盆腔体外照射+中央遮盖体外照射。体外照射剂量:全盆照射肿瘤剂量30~40 Gy,中央遮盖照射剂量15~25 Gy,放疗频率及强度:每周5次,每次分割剂量2 Gy。腔内后装采用高剂量率后装治疗设备,放射源为铱192。放疗剂量参照点A点累积剂量要求60~70 Gy;B点累积剂量要求54~56 Gy。放疗期间均给予铂类为基础的同步化疗。
1.2.4 随访
通过电话或门诊复查方式进行随访,截止时间为2018年9月。
1.3 统计学方法
采用GraphPad7.0统计软件对不同组间患者生存率进行显著性比较。生存分析采用Kaplan-Meier法,生存率的比较采用Log rank检验。P < 0.05为差异有统计学意义。
2 结果
72例手术组患者中,2例失访,19例死亡,51例生存。19例死亡患者生存时间1~63月,中位生存时间19月,平均生存时间18.5月。51例生存的患者中,生存时间1~139月,中位生存时间39月,平均生存时间47.3月。随访5年以上共33例,生存20例,五年生存率60.6%。
29例根治性放化疗患者中,随访5年以上20例,其中2例失访,死亡15例,生存3例,五年生存率15%。生存时间1~75月,中位生存时间21月。3例生存患者年龄分别为40岁、41岁、46岁,临床分期均为ⅡB期,病理均为单纯的宫颈小细胞神经内分泌癌,化疗方案均为多西他赛+卡铂,放疗给予根治性同步放化疗。ⅠB1期~ⅡA期手术治疗组患者生存率优于ⅡB期~Ⅳ期期根治性放化疗组患者(P=0.0025),见图 1。
72例接受手术治疗的患者均行宫颈癌根治术+盆腔淋巴结切除术,47例行腹主动脉旁淋巴结切除术,其中1例(1/47, 2.12%)腹主动脉旁淋巴结阳性。27例(27/72, 37.5%)盆腔淋巴结阳性。淋巴结阳性与阴性患者生存曲线比较差异有统计学意义,淋巴结阴性患者生存优于淋巴结阳性患者(P=0.0004),见图 2。
72例手术治疗的患者中,按病理类型分,单纯SCNEC例41例,混合其他病理类型者31例,其中混合有腺癌19例,鳞癌9例,腺鳞癌3例。混合型与单纯型SCNEC生存曲线比较差异无统计学意义(P=0.0546),见图 3。
3 讨论
WHO分类将宫颈神经内分泌肿瘤分为低级别神经内分泌肿瘤(包括类癌及非典型类癌)和高级别神经内分泌肿瘤(包括小细胞神经内分泌癌和大细胞神经内分泌癌)。目前无公认的、规范有效的治疗方案,对于宫颈神经内分泌肿瘤多参照常见宫颈癌的分期治疗原则,主张手术、化疗和放疗的综合性治疗,但其治疗是否应有别于宫颈鳞癌需要更大样本、多中心的研究。美国国立综合癌症网络(National Comprehensive Cancer Network, NCCN)指南也将SCNEC列入特殊类型宫颈癌。
关于SCNEC患者生存率及预后方面的研究,Ishikawa等的一项多中心研究显示淋巴血管间隙受侵是患者的总生存率及无进展生存率的重要预后因素,盆腔淋巴结转移是DFS的重要预后影响因素[9]。Cohen等研究发现Ⅰ~ⅡA、ⅡB~ⅣA、ⅣB期5年生存率分别为36.8%、9.8%和0[10],本研究结果显示临床分期与预后密切相关,各期别5年生存率均较以往文献报道略高。FIGO分期是较为公认的影响患者预后的最重要的独立危险因素[11-12]。由于SCNEC侵袭性强,易发生远处转移,有学者认为早期SCNEC患者手术联合化疗的预后优于单纯手术者[13-14]。本研究中ⅠB~ⅡA期患者均采用手术+放化疗综合治疗,5年总生存率60%以上,提示手术联合术后放化疗对此类患者疗效较好。
宫颈小细胞神经内分泌癌早期容易发生转移,但从72例早期患者手术情况发现,仅1例(1.39%)发生卵巢转移。提示对于存在生育要求的年轻SCNEC患者,是否一定要行卵巢切除有待进一步研究证实。研究证实,SCNEC好发转移器官为肺、脑、肝,预后差[15-16]。
此外,几乎所有文献均支持此类肿瘤早期即容易发生远处转移,本研究资料中,死亡病例主要病因为肺转移、全身转移,临床观察也支持上述观点。关于淋巴结转移,有研究认为,即使是早期的SCNEC患者,淋巴结转移也非常普遍,淋巴结转移率为41.6%~57%[17]。本研究中,72例早期SCNEC患者手术后病理提示淋巴结转移22例,转移率37.5%,与文献报道接近,但是对于腹主动脉旁淋巴结,72例患者中47例患者行腹主动脉旁淋巴结活检或切除,仅1例发生腹主动脉旁淋巴结转移,转移率仅为2.13%,远低于盆腔淋巴结转移率。这一研究结果提示我们,即便是早期SCNEC患者,化疗对于控制转移也有重要的临床意义。
与以往报道相比,本研究中手术患者术后均补充了放化疗,且均达到6个疗程,其中49例采用紫杉醇+铂类化疗方案,23例采用顺铂+环磷酰胺+表阿霉素化疗方案,提示手术后放化疗的必要性。
总之,宫颈小细胞神经内分泌癌发病率低、恶性程度高、易发生远处转移和复发,患者预后差、死亡率高、有独特的病理特征,诊断主要依据病理诊断和免疫组织化学结果可提高其诊断的准确率。由于研究样本少,尚需大量的临床资料及多中心研究探索最佳早期诊断及治疗的方法。
Competing interests: The authors declare that they have no competing interests.作者贡献:窦赫:资料的收集与分析、论文设计及撰写马爽:协助论文撰写邾月:文献收集刘宇琪:论文修改肖敏:论文撰写指导 -
[1] Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424. doi: 10.3322/caac.21492
[2] 杨春明. 导言: 乳腺外科手术的发展历程和基本理念[J]. 医学与哲学(B), 2018, 39(11): 17. https://www.cnki.com.cn/Article/CJFDTOTAL-YXZL201811008.htm Yang CM. Introduction: the development process and basic concept of breast surgery[J]. Yi Xue Yu Zhe Xue(B), 2018, 39(11): 17. https://www.cnki.com.cn/Article/CJFDTOTAL-YXZL201811008.htm
[3] Shi J, Gao W, Shao F. Pyroptosis: Gasdermin-mediated programmed necrotic cell death[J]. Trends Biochem Sci, 2017, 42(4): 245-254. doi: 10.1016/j.tibs.2016.10.004
[4] 陈逸钿, 苏良平, 丘晓奕, 等. 细胞焦亡及其在肿瘤疾病中的作用[J]. 中国科学(生命科学), 2020, 50(10): 1042-1054. https://www.cnki.com.cn/Article/CJFDTOTAL-JCXK202010008.htm Chen YT, Su LP, Qiu XY, et al. Molecular mechanism of pyroptosis and its role in cancer[J]. Zhongguo Ke Xue(Sheng Ming Ke Xue), 2020, 50(10): 1042-1054. https://www.cnki.com.cn/Article/CJFDTOTAL-JCXK202010008.htm
[5] Gui R, Chen Q. Molecular Events Involved in Influenza A Virus-Induced Cell Death[J]. Front Microbiol, 2021, 12: 797789.
[6] Yang J, Hu S, Bian Y, et al. Targeting Cell Death: Pyroptosis, Ferroptosis, Apoptosis and Necroptosis in Osteoarthritis[J]. Front Cell Dev Biol, 2021, 9: 789948.
[7] Zhang F, Deng Y, Wang D, et al. Construction and validation of a pyroptosis-related gene signature associated with the tumor microenvironment in uveal melanoma[J]. Sci Rep, 2022, 12(1): 1640. doi: 10.1038/s41598-022-05599-9
[8] Simpson DS, Pang J, Weir A, et al. Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway[J]. Immunity, 2022, 55(3): 423-441. e9. doi: 10.1016/j.immuni.2022.01.003
[9] Galluzzi L, Vitale I, Aaronson SA, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018[J]. Cell Death Differ, 2018, 25(3): 486-541. doi: 10.1038/s41418-017-0012-4
[10] Zhang Y, Chen X, Gueydan C, et al. Plasma membrane changes during programmed cell deaths[J]. Cell Res, 2018, 28(1): 9-21. doi: 10.1038/cr.2017.133
[11] Lee Y, Reilly B, Tan C, et al. Extracellular CIRP Induces Macrophage Extracellular Trap Formation Via Gasdermin D Activation[J]. Front Immunol, 2021, 12: 780210. doi: 10.3389/fimmu.2021.780210
[12] Broz P, Pelegrín P, Shao F. The gasdermins, a protein family executing cell death and inflammation[J]. Nat Rev Immunol, 2020, 20(3): 143-157. doi: 10.1038/s41577-019-0228-2
[13] 杨羽依, 刘秀萍. Gasdermin E诱导细胞焦亡的研究进展[J]. 中华病理学杂志, 2021, 50(4): 421-424. doi: 10.3760/cma.j.cn112151-20200724-00589 Yang YY, Liu XP. Research process of Gasdermin E in inducing cell pyroptosis[J]. Zhonghua Bing Li Xue Za Zhi, 2021, 50(4): 421-424. doi: 10.3760/cma.j.cn112151-20200724-00589
[14] Zhao Y, Shi J, Shao F. Inflammatory caspases: activation and cleavage of gasdermin-D in vitro and during pyroptosis[J]. Methods Mol Biol, 2018, 1714: 131-148.
[15] Platnich JM, Muruve DA. Nod-like receptors and inflammasomes: A review of their canonical and non-canonical signaling pathways[J]. Arch Biochem Biophys, 2019, 670: 4-14. doi: 10.1016/j.abb.2019.02.008
[16] 朱潇雨, 李杰. 诱导细胞焦亡抑制恶性肿瘤的新策略研究进展[J]. 肿瘤防治研究, 2021, 48(4): 393-399. doi: 10.3971/j.issn.1000-8578.2021.20.0983 Zhu XY, Li J. New strategies of inhibiting malignant tumor based on inducing pyroptosis[J]. Zhong Liu Fang Zhi Yan Jiu, 2021, 48(4): 393-399. doi: 10.3971/j.issn.1000-8578.2021.20.0983
[17] 林文, 曹珈琪, 张燕, 等. 细胞焦亡的分子机制及研究进展[J]. 中国当代医药, 2020, 27(27): 25-29. doi: 10.3969/j.issn.1674-4721.2020.27.008 Lin W, Cao JQ, Zhang Y, et al. Molecular mechanism and research progress of cell pyroptosis[J]. Zhongguo Dang Dai Yi Yao, 2020, 27(27): 25-29. doi: 10.3969/j.issn.1674-4721.2020.27.008
[18] Lyu Z, Li Q, Yu Z, et al. Yi-Zhi-Fang-Dai Formula Exerts Neuroprotective Effects Against Pyroptosis and Blood-Brain Barrier-Glymphatic Dysfunctions to Prevent Amyloid-Beta Acute Accumulation After Cerebral Ischemia and Reperfusion in Rats[J]. Front Pharmacol, 2021, 12: 791059. doi: 10.3389/fphar.2021.791059
[19] Aglietti RA, Dueber EC. Recent Insights into the Molecular Mechanisms Underlying Pyroptosis and Gasdermin Family Functions[J]. Trends Immunol, 2017, 38(4): 261-271. doi: 10.1016/j.it.2017.01.003
[20] Wang YP, Gao WQ, Shi X, et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin[J]. Nature, 2017, 547(7661): 99-103. doi: 10.1038/nature22393
[21] Shen X, Wang H, Weng C, et al. Caspase 3/GSDME-dependent pyroptosis contributes to chemotherapy drug-induced nephrotoxicity[J]. Cell Death Dis, 2021, 12(2): 186. doi: 10.1038/s41419-021-03458-5
[22] Kambara H, Liu F, Zhang X, et al. Gasdermin D exerts anti-inflammatory effects by promoting neutrophil death[J]. Cell Rep, 2018, 22(11): 2924-2936. doi: 10.1016/j.celrep.2018.02.067
[23] Sarhan J, Liu BC, Muendlein HI, et al. Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during infection[J]. Proc Natl Acad Sci USA, 2018, 115(46): E10888-E10897.
[24] Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. doi: 10.3322/caac.21660
[25] 石瑛, 任静静, 梁晨, 等. GSDME通过调控细胞焦亡影响乳腺癌MCF-7细胞对紫杉醇的敏感性[J]. 中国肿瘤生物治疗杂志, 2019, 26(2): 146-151. https://www.cnki.com.cn/Article/CJFDTOTAL-ZLSW201902002.htm Shi Y, Ren JJ, Liang C, et al. GSDME influences sensitivity of breast cancer MCF-7 cells to paclitaxel by regulating cell pyroptosis[J]. Zhongguo Zhong Liu Sheng Wu Zhi Liao Za Zhi, 2019, 26(2): 146-151. https://www.cnki.com.cn/Article/CJFDTOTAL-ZLSW201902002.htm
[26] Jiao Y, Zhao H, Chen G, et al. Pyroptosis of mcf7 cells induced by the secreted factors of hucmscs[J]. Stem Cells Int, 2018, 2018: 5912194.
[27] Huang QF, Fang DL, Nong BB, et al. Focal pyroptosis-related genes AIM2 and ZBP1 are prognostic markers for triple-negative breast cancer with brain metastases[J]. Transl Cancer Res, 2021, 10(11): 4845-4858. doi: 10.21037/tcr-21-2182
[28] Pizato N, Luzete BC, Kiffer LFMV, et al. Omega-3 docosahexaenoic acid induces pyroptosis cell death in triple-negative breast cancer cells[J]. Sci Rep, 2018, 8(1): 1952. doi: 10.1038/s41598-018-20422-0
[29] Elion DL, Jacobson ME, Hicks DJ, et al. Therapeutically Active RIG-I Agonist Induces Immunogenic Tumor Cell Killing in Breast Cancers[J]. Cancer Res, 2018, 78(21): 6183-6195.
[30] Li Y, Wang W, Li A, et al. Dihydroartemisinin induces pyroptosis by promoting the AIM2/caspase-3/DFNA5 axis in breast cancer cells[J]. Chem Biol Interact, 2021, 340: 109434.
[31] Li Z, Huang Z, Zhang H, et al. Moderate-intensity exercise alleviates pyroptosis by promoting autophagy in osteoarthritis via the P2X7/AMPK/mTOR axis[J]. Cell Death Discov, 2021, 7(1): 346.
[32] Cheng R, Billet S, Liu C, et al. Periodontal inflammation recruits distant metastatic breast cancer cells by increasing myeloid-derived suppressor cells[J]. Oncogene, 2020, 39(7): 1543-1556.
[33] Faria SS, Costantini S, de Lima VCC, et al. NLRP3 inflammasome-mediated cytokine production and pyroptosis cell death in breast cancer[J]. J Biomed Sci, 2021, 28(1): 26.