工程菌在肿瘤治疗方面的应用进展

doi:10.12211/2096-8280.2022-062

合成生物学 ›› 2023, Vol. 4 ›› Issue (4): 690-702.DOI: 10.12211/2096-8280.2022-062

工程菌在肿瘤治疗方面的应用进展

陈家文¹, 黄建东²^,³^,⁴^,⁵^,⁶, 孙海涛¹^,²

^1.南方医科大学珠江医院神经外科中心，国家临床重点专科，脑血管病诊断与治疗教育部工程研究中心，广东省普通高校脑功能修复与再生重点实验室，广东神经外科研究所，广东广州 510280
^2.南方医科大学珠江医院检验医学部，临床生物样本资源中心，南方医科大学微生物组医学中心，广东广州 510280
^3.香港大学李嘉诚医学院生物医学学院，生物医学学院，香港 999077
^4.中国科学院深圳先进技术研究院，深圳合成生物学创新研究院，中国科学院定量工程生物学重点实验室，广东省合成基因组学重点实验室，广东深圳 518055
^5.香港大学深圳医院临床肿瘤科，深圳市肿瘤转移与个体化治疗重点实验室，广东深圳 518055
^6.粤港RNA医学联合实验室，中山大学，广东广州 510120

收稿日期:2022-11-14 修回日期:2023-04-10 出版日期:2023-08-31 发布日期:2023-09-14
通讯作者: 黄建东,孙海涛
作者简介:陈家文（1996—），男，硕士。研究方向为脑胶质瘤的基础研究。E-mail：1448596298@qq.com
黄建东（1965—），男，博士，教授。研究方向为合成生物学、肿瘤免疫治疗和传染病疫苗。E-mail：jdhuang@hku.hk
孙海涛（1988—），男，博士，副主任医师，副研究员。研究方向为基于肠-脑-轴的重大脑疾病（脑血管病、脑肿瘤）诊断、机制及干预研究；肿瘤微生物组学研究；临床生物样本库的标准化建设与转化应用。E-mail：2009sht@smu.edu.cn
基金资助:
国家重点研发计划(2021YFA0910700);广东省创新创业团队计划(2019BT02Y198);广东省基础应用基础研究基金(2023A1515030045);南方医科大学珠江医院院长基金(yzjj2022ms4)

Current developments in the use of engineered bacteria for cancer therapy

Jiawen CHEN¹, Jiandong HUANG²^,³^,⁴^,⁵^,⁶, Haitao SUN¹^,²

^1.Neurosurgery Center，The National Key Clinical Specialty，The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease，Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration，The Neurosurgery Institute of Guangdong Province，Zhujiang Hospital，Southern Medical University，Guangzhou 510280，Guangdong，China
^2.Department of Laboratory Medicine，Clinical Biobank Center，Microbiome Medicine Center，Zhujiang Hospital，Southern Medical University，Guangzhou 510280，Guangdong，China
^3.School of Biomedical Sciences，Li Ka Shing Faculty of Medicine，The University of Hong Kong，Hong Kong 999077，China
^4.Chinese Academy of Sciences （CAS） Key Laboratory of Quantitative Engineering Biology，Shenzhen Institute of Synthetic Biology，Shenzhen Institutes of Advanced Technology，Chinese Academy of Sciences，Shenzhen 518055，Guangdong，China
^5.Department of Clinical Oncology，Shenzhen Key Laboratory for cancer metastasis and personalized therapy，The University of Hong Kong-Shenzhen Hospital，Shenzhen 518055，Guangdong，China
^6.Guangdong-Hong Kong Joint Laboratory for RNA Medicine，Sun Yat-Sen University，Guangzhou 510120，Guangdong，China

Received:2022-11-14 Revised:2023-04-10 Online:2023-08-31 Published:2023-09-14
Contact: Jiandong HUANG, Haitao SUN

摘要/Abstract

摘要：

肿瘤的细菌治疗最早可以追溯到19世纪，人们第一次利用链球菌（Streptococcus pyogenes）成功治疗了患有无法手术切除的肉瘤患者。此后，细菌在肿瘤治疗上的研究越来越多，并取得了令人期待的结果。与其他肿瘤治疗方法相比，细菌治疗肿瘤具有许多独特的优点。随着合成生物学的发展，人们对细菌进行改造后大大增强了其在肿瘤治疗中的运用。本文介绍了细菌改造策略和应用进展，特别是鼠伤寒沙门氏菌治疗肿瘤的研究。在动物模型中，工程菌可以选择性定植到肿瘤组织中并抑制肿瘤的生长。此外，介绍了工程菌治疗肿瘤的新策略——表达抗肿瘤分子来提高肿瘤治疗的效果。最后，讨论了工程菌治疗肿瘤运用于临床还有一些需要解决的问题，如何平衡细菌毒力和抗肿瘤能力是一个关键点，需要设计更精巧的基因线路来对细菌进行改造。在减弱细菌毒力的同时，还要增强细菌靶向到肿瘤组织的能力，以减少对其他正常组织的影响。细菌的遗传不稳定性也是一个潜在的问题，因为突变可能会产生无效或有害的表型。但是，随着合成生物学的发展，在不久的将来，上述问题将会得到解决，细菌治疗将会是一种具有巨大潜力的肿瘤治疗的方法。

关键词: 工程菌, 递送载体, 肿瘤, 治疗

Abstract:

Bacterial therapy has a long history, which originated at the end of the 19th century when bacteria were used for the first time to treat cancer. William B. Coley, a bone sarcoma surgeon, used heat-killed Streptococcus pyogenes to treat patients with unresectable sarcomas and found that the cancer had disappeared spontaneously. Over the next 40 years, he injected more than 1000 cancer patients with heat-killed bacteria Streptococcus pyogenes and Serratia marcescens, which are now known as Coley's toxins. However, owing to criticism from the medical community, rare reproducibility of the results and the emergence of radiotherapy and chemotherapy, bacterial therapy gradually disappeared from medical practice. With the development of immunology and synthetic biology, bacterial therapy has once again gained importance. Over the past 20 years, bacterial therapy has become a major focus area for research, and several types of bacteria have been used in clinical and preclinical studies. Therefore, bacterial therapy is considered an innovative and ideal strategy to treat cancer. In this review, we summarized the recent progress in the treatment of tumours with genetically engineered bacteria. Various bacteria include Salmonella, Escherichia coli, Bifidobacterium and Streptococcus pyogenes, which can accumulate, especially in tumours, and suppress their growth. However, in order to improve bacterial tumour-targeting ability and reduce bacterial virulence, various bacterial species have been genetically engineered through molecular biology techniques, thus forming different genetically engineered strains by using Clostridium novyi-NT, Listeria monocytogenes and Salmonella typhimurium. These genetically engineered bacteria can be selectively colonized in tumours and can inhibit cancer growth. In addition, they can also be used as live delivery carriers for cancer treatment, which can overcome the limitations of conventional antitumour therapies, such as high toxicity to normal tissue cells and the inability to treat deep tumour tissues. Potential targets including cytokines, cytotoxic agents, regulatory factors, prodrug-converting enzymes and small interfering RNAs (siRNAs) can be delivered via genetically engineered bacteria to treat cancer. However, various problems remain to be overcome before bacterial therapy can be used for clinical cancer treatment. The balance between bacterial virulence and anti-tumor ability is a key point, and more sophisticated genetic circuits need to be designed to modify the bacteria. While reducing the virulence of the bacteria, it is also important to enhance the ability of the bacteria to target to the tumor tissue to reduce the impact on other normal tissues. Genetic instability of bacteria is also a potential problem, as mutations may produce ineffective or deleterious phenotypes. However, with the development of synthetic biology, the above problems would be solved in the future, and bacterial therapy will be an approach with great potential for tumor treatment. {L-End}

Key words: genetically engineered bacteria, delivery carriers, tumor, therapy

中图分类号:

Q816

陈家文, 黄建东, 孙海涛. 工程菌在肿瘤治疗方面的应用进展[J]. 合成生物学, 2023, 4(4): 690-702.

Jiawen CHEN, Jiandong HUANG, Haitao SUN. Current developments in the use of engineered bacteria for cancer therapy[J]. Synthetic Biology Journal, 2023, 4(4): 690-702.

图/表 2

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抗肿瘤分子	描述	种类
细胞因子
白介素-12（IL-2）	一种信号分子，调节淋巴细胞的活性	梭状芽孢杆菌^[55] 沙门氏菌^[51-52,54]
淋巴细胞趋化因子	一种趋化因子，控制T细胞、树突状细胞和NK细胞的迁移	沙门氏菌^[56]
白介素-18（IL-18）	一种信号分子，刺激NK细胞和T细胞释放IFN-γ	沙门氏菌^[57]
白介素-12（IL-12）	一种信号分子，刺激活化的NK和T细胞的增殖，并诱导这些细胞产生IFN-γ	梭状芽孢杆菌^[53]
细胞毒性药物
肿瘤坏死因子相关的细胞凋亡诱导配体（TRAIL）	一种促凋亡分子，通过死亡受体途径诱导肿瘤细胞凋亡	沙门氏菌^[58-59]
血管内皮抑制素（Endostatin）	一种血管生成抑制剂	沙门氏菌^[60-61]
细胞溶素A （CytolysinA）	在大肠杆菌和沙门氏菌、伤寒和副伤寒中发现的一种成孔的溶血性蛋白	沙门氏菌^[62] 大肠杆菌^[6]
死亡受体配体（FasL）	一种属于TNF蛋白家族的膜蛋白，与Fas受体结合后，诱导Fas表达细胞凋亡	沙门氏菌^[63]
抗肿瘤蛋白
天青蛋白Laz	一种抗肿瘤蛋白，可以诱导肿瘤细胞凋亡	沙门氏菌^[64]
金属蛋白酶的组织抑制剂TIMP-2	MMP的一个同源抑制剂家族，通过抑制MMP来控制细胞外基质的降解	沙门氏菌^[65]
肿瘤抑制素Tum-5	抑制肿瘤血管的生成	大肠杆菌^[66]
肿瘤抑制蛋白p53	一种与肿瘤发生和发展有关的肿瘤抑制蛋白	大肠杆菌^[67]
前药物酶
胞嘧啶脱氨酶	一种可以将无毒的5-氟胞嘧啶(5-FC)转化为抗癌的5-氟尿嘧啶(5-FU)的酶	沙门氏菌^[69-70]
羧肽酶G2	一种依赖Zn²⁺的83 kDa同型二聚体、可以激活一系列双功能烷基化剂和抗生素前药的酶	沙门氏菌^[71]
嘌呤核苷磷酸化酶	一种可以将6-甲基嘌呤-2′-脱氧核糖苷(MePdR)转化为6-甲基嘌呤的酶	沙门氏菌^[72]
硝基还原酶	一种可以激活新型DNA交联剂PR-104的酶	梭状芽孢杆菌^[73]
siRNA
程序性死亡受体-1（PD-1）	一种重要的免疫检查点分子，可以帮助癌细胞逃脱宿主的免疫反应	沙门氏菌^[79]
缺氧诱导因子-1	一个关键的转录因子，可以激活蛋白质的表达	沙门氏菌^[77]
抗凋亡蛋白（Bcl-2）	可显著延长细胞存活，对抗经典凋亡刺激	沙门氏菌^[83]
信号转导和转录激活因子3（STAT3）	在人类肿瘤中，STAT3的激活在促进癌细胞增殖和存活中起着重要作用	沙门氏菌^[84]
氨基胺2,3-双加氧酶1（IDO）	色氨酸分解代谢酶可在肿瘤微环境中引起免疫耐受	沙门氏菌^[86]
其他
PD-L1纳米抗体	一种重要的免疫检查点分子受体，可以帮助肿瘤细胞逃脱宿主的免疫反应	大肠杆菌^[89]
CTLA-4纳米抗体	细胞毒性T淋巴细胞相关蛋白-4可以使肿瘤细胞逃脱宿主的免疫反应	大肠杆菌^[89]
L-精氨酸	可以有效增强抗肿瘤T细胞反应	大肠杆菌^[23]

抗肿瘤分子	描述	种类
细胞因子
白介素-12（IL-2）	一种信号分子，调节淋巴细胞的活性	梭状芽孢杆菌^[55] 沙门氏菌^[51-52,54]
淋巴细胞趋化因子	一种趋化因子，控制T细胞、树突状细胞和NK细胞的迁移	沙门氏菌^[56]
白介素-18（IL-18）	一种信号分子，刺激NK细胞和T细胞释放IFN-γ	沙门氏菌^[57]
白介素-12（IL-12）	一种信号分子，刺激活化的NK和T细胞的增殖，并诱导这些细胞产生IFN-γ	梭状芽孢杆菌^[53]
细胞毒性药物
肿瘤坏死因子相关的细胞凋亡诱导配体（TRAIL）	一种促凋亡分子，通过死亡受体途径诱导肿瘤细胞凋亡	沙门氏菌^[58-59]
血管内皮抑制素（Endostatin）	一种血管生成抑制剂	沙门氏菌^[60-61]
细胞溶素A （CytolysinA）	在大肠杆菌和沙门氏菌、伤寒和副伤寒中发现的一种成孔的溶血性蛋白	沙门氏菌^[62] 大肠杆菌^[6]
死亡受体配体（FasL）	一种属于TNF蛋白家族的膜蛋白，与Fas受体结合后，诱导Fas表达细胞凋亡	沙门氏菌^[63]
抗肿瘤蛋白
天青蛋白Laz	一种抗肿瘤蛋白，可以诱导肿瘤细胞凋亡	沙门氏菌^[64]
金属蛋白酶的组织抑制剂TIMP-2	MMP的一个同源抑制剂家族，通过抑制MMP来控制细胞外基质的降解	沙门氏菌^[65]
肿瘤抑制素Tum-5	抑制肿瘤血管的生成	大肠杆菌^[66]
肿瘤抑制蛋白p53	一种与肿瘤发生和发展有关的肿瘤抑制蛋白	大肠杆菌^[67]
前药物酶
胞嘧啶脱氨酶	一种可以将无毒的5-氟胞嘧啶(5-FC)转化为抗癌的5-氟尿嘧啶(5-FU)的酶	沙门氏菌^[69-70]
羧肽酶G2	一种依赖Zn²⁺的83 kDa同型二聚体、可以激活一系列双功能烷基化剂和抗生素前药的酶	沙门氏菌^[71]
嘌呤核苷磷酸化酶	一种可以将6-甲基嘌呤-2′-脱氧核糖苷(MePdR)转化为6-甲基嘌呤的酶	沙门氏菌^[72]
硝基还原酶	一种可以激活新型DNA交联剂PR-104的酶	梭状芽孢杆菌^[73]
siRNA
程序性死亡受体-1（PD-1）	一种重要的免疫检查点分子，可以帮助癌细胞逃脱宿主的免疫反应	沙门氏菌^[79]
缺氧诱导因子-1	一个关键的转录因子，可以激活蛋白质的表达	沙门氏菌^[77]
抗凋亡蛋白（Bcl-2）	可显著延长细胞存活，对抗经典凋亡刺激	沙门氏菌^[83]
信号转导和转录激活因子3（STAT3）	在人类肿瘤中，STAT3的激活在促进癌细胞增殖和存活中起着重要作用	沙门氏菌^[84]
氨基胺2,3-双加氧酶1（IDO）	色氨酸分解代谢酶可在肿瘤微环境中引起免疫耐受	沙门氏菌^[86]
其他
PD-L1纳米抗体	一种重要的免疫检查点分子受体，可以帮助肿瘤细胞逃脱宿主的免疫反应	大肠杆菌^[89]
CTLA-4纳米抗体	细胞毒性T淋巴细胞相关蛋白-4可以使肿瘤细胞逃脱宿主的免疫反应	大肠杆菌^[89]
L-精氨酸	可以有效增强抗肿瘤T细胞反应	大肠杆菌^[23]

[1]	马孟丹, 尚梦宇, 刘宇辰. CRISPR-Cas9系统在肿瘤生物学中的应用及前景[J]. 合成生物学, 2023, 4(4): 703-719.
[2]	谢君鸿, 何晶晶, 周鹏辉. 合成生物学与工程化T细胞治疗[J]. 合成生物学, 2023, 4(2): 373-393.
[3]	吴晓昊, 廖荣东, 李飞云, 欧阳中天, 冉怡, 公维远, 曲明灏, 陈明珏, 林荔军, 肖国芝. 合成生物学在疾病诊疗中的应用[J]. 合成生物学, 2023, 4(2): 244-262.
[4]	陈青黎, 童贻刚. 工程噬菌体的合成生物学“智造”[J]. 合成生物学, 2023, 4(2): 283-300.
[5]	于袁欢, 周阳, 王欣怡, 孔德强, 叶海峰. 光遗传学照进生物医学研究进展[J]. 合成生物学, 2023, 4(1): 102-140.
[6]	林思思, 潘超, 张一帆, 刘尽尧. 基于表面涂层益生菌的肿瘤抗原口服递送系统[J]. 合成生物学, 2022, 3(4): 810-820.
[7]	许仕琳, 许海燕. 双特异性抗体及纳米技术在肿瘤免疫治疗中的应用进展[J]. 合成生物学, 2022, 3(2): 352-368.
[8]	宋斐, 刘宇辰, 蔡志明, 黄卫人. 基于CRISPR/Cas工具的肿瘤基因线路构建及应用[J]. 合成生物学, 2022, 3(1): 53-65.
[9]	袁盛建, 马迎飞. 噬菌体合成生物学研究进展和应用[J]. 合成生物学, 2020, 1(6): 635-655.

工程菌在肿瘤治疗方面的应用进展

Current developments in the use of engineered bacteria for cancer therapy

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