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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2023, Vol. 43 Issue (6): 54-68    DOI: 10.13523/j.cb.2301036
综述     
肿瘤靶向细菌Escherichia coli Nissle 1917在癌症治疗中的研究进展*
李雨桐,崔天琦,张海林,于广乐,栾霁**(),王海龙**()
山东大学微生物技术国家重点实验室 微生物技术研究院 青岛 266237
Research Advances in Tumor-targeting Bacteria Escherichia coli Nissle 1917 in Cancer Therapy
LI Yu-tong,CUI Tian-qi,ZHANG Hai-lin,YU Guang-le,LUAN Ji**(),WANG Hai-long**()
State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266237, China
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摘要：

传统化疗、放疗等癌症治疗手段存在靶向性差、毒副作用大等问题。肿瘤靶向细菌可以特异性定殖于实体肿瘤微环境,通过基因工程改造可以使其在实体肿瘤内持续合成并释放抗癌药物,提高药物对肿瘤组织的选择性,避免化疗药物对正常组织的伤害,成为近年来癌症靶向治疗的研究热点。Escherichia coli Nissle 1917(EcN)作为一种被广泛研究和应用的益生菌,没有致病性,不产生免疫毒副作用,且具有高效的肿瘤靶向定殖能力,能在正常组织中迅速被清除,因此在癌症细菌疗法中备受关注。针对EcN在癌症靶向治疗研究方面的最新进展进行综述,介绍了通过基因工程提高其靶向性、可控性和安全性的方法,并介绍了EcN在辅助其他癌症治疗方面的应用。随着基因工程和合成生物学技术的进步,人们对细菌功能的设计合成能力不断增强,EcN作为可编程的活体药物,有希望发展成为对抗癌症的有力武器。
关键词： 细菌疗法;  肿瘤靶向治疗;  癌症;  合成生物学;  大肠杆菌Nissle 1917    
Abstract:

Traditional cancer therapies such as chemotherapy and radiotherapy have problems such as poor targeting and high toxic side effects. Tumor-targeting bacteria can specifically colonize in the solid tumor microenvironment, and can be genetically engineered to synthesize anti-cancer drugs, improve the selectivity of drugs for tumor tissues and avoid the damage to normal tissues by chemotherapeutic drugs. These advantages make tumor-targeting bacteria a research hot spot in targeted cancer therapy in recent years. Escherichia coli Nissle 1917(EcN), a probiotic bacterium that has been widely studied and used, has attracted much attention in bacterial cancer therapies. EcN is non-pathogenic and non-immunotoxic and has a highly effective tumor-targeting ability. It can be rapidly cleared in normal tissues. Here, the latest advances in engineering of EcN for tumor-targeting therapy were reviewed. The applications of EcN in adjuvant therapy were also discussed. With the advancement of genetic engineering and synthetic biology, scientists’ ability to design and synthesize bacteria is growing stronger. EcN as a programmable living drug holds the promise of becoming a powerful weapon against cancer.
Key words: Bacteriotherapy    Tumor-targeting therapy    Cancer    Synthetic biology    Escherichia coli Nissle 1917
收稿日期: 2023-01-27 出版日期: 2023-07-04
ZTFLH:  Q819  
基金资助: * 山东省泰山学者(tsqn201812008);高等学校学科创新引智计划(B16030)
通讯作者: **电子信箱:luanji@sdu.edu.cn;wanghailong@sdu.edu.cn   
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李雨桐
崔天琦
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于广乐
栾霁
王海龙

引用本文:

李雨桐, 崔天琦, 张海林, 于广乐, 栾霁, 王海龙. 肿瘤靶向细菌Escherichia coli Nissle 1917在癌症治疗中的研究进展*[J]. 中国生物工程杂志, 2023, 43(6): 54-68.

LI Yu-tong, CUI Tian-qi, ZHANG Hai-lin, YU Guang-le, LUAN Ji, WANG Hai-long. Research Advances in Tumor-targeting Bacteria Escherichia coli Nissle 1917 in Cancer Therapy. China Biotechnology, 2023, 43(6): 54-68.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2301036    或    https://manu60.magtech.com.cn/biotech/CN/Y2023/V43/I6/54

菌株 作用方式 机制 肿瘤类型 参考文献
S. typhimurium
ΔppGpp		 提高安全性 敲除relA和spoT基因,阻断ppGpp的合成 - [9]
L. monocytogenes
ΔactA/ΔinlB		 提高安全性 敲除毒力基因actA和inlB CT26小鼠结肠癌 [10]
E. coli Nissle 1917 提高安全性 通过调节kifC基因表达水平来动态调节细菌表面荚膜多糖的生成 4T1小鼠乳腺癌,CT26小鼠结肠癌 [11]
S. typhimurium SL1344 提高安全性 整合同步裂解回路 MC26小鼠结肠癌 [12]
S. typhimurium A1 提高靶向性 Leu和Arg营养缺陷型 PC-3人前列腺癌 [13]
S. typhimurium SF104 提高靶向性 aroA基因突变,芳香族氨基酸营养缺陷型 CT26小鼠结肠癌,Renca小鼠肾癌 [14]
E. coli Nissle 1917 提高靶向性 胸苷和DAP营养缺陷型 B16-F10小鼠黑色素瘤,EL4小鼠胸腺淋巴瘤,A20小鼠B细胞淋巴瘤,4T1小鼠乳腺癌,CT26小鼠结肠癌 [15]
S. typhimurium YB1 提高靶向性 将调节DAP合成的asd基因置于缺氧诱导的启动子下 MDA-MB-231人乳腺癌 [16]
S. typhimurium
VNP20009		 提高靶向性 表达癌胚抗原(CEA)特异性抗体 MC38小鼠结肠癌 [17]
S. typhimurium
ΔppGpp		 提高靶向性 将RGD序列融合在细菌外膜蛋白A上,以靶向癌细胞表面高表达的整合素αvβ3 MDA-MB-231人乳腺癌,MDA-MB-435人黑色素瘤,U87MG人胶质母细胞瘤,MCF7人乳腺癌,ASPC-1人胰腺癌,CT26小鼠结肠癌,4T1小鼠乳腺癌 [18]
S. typhimurium
VNP20009		 提高靶向性 在细菌表面偶联肿瘤特异性适配体 4T1小鼠乳腺癌,H22小鼠肝细胞癌 [19]
S. typhimurium
VNP20009		 提高安全性和
靶向性		 敲除msbB和purI基因,使LPS中的类脂A豆蔻酰化,嘌呤营养缺陷型 B16-F10小鼠黑色素瘤,LOX人黑色素瘤,DLD-1人结肠癌 [20]
S. typhimurium S636 提高安全性和
靶向性		 aroA基因突变以及参与类脂A修饰的其他突变 CT26小鼠结肠癌,B16-F10小鼠黑色素瘤 [21]
E. coli Nissle 1917 表达细胞毒性
药物		 产生生物丁酸盐,导致细胞周期在G1期停滞,并诱导独立于p53的线粒体凋亡途径 HT29人结肠癌 [22]
E. coli Nissle 1917 表达细胞毒性药物 表达溶血素E,诱导细胞凋亡 HT29人结肠癌,SW620人结肠癌 [23]
S. typhimurium
VNP20009		 表达前药转化酶 表达羧肽酶G2,激活前药并在人肿瘤细胞中诱导细胞毒性 MDA-MB-361人乳腺癌,WiDr人结肠癌,B16-F10小鼠黑色素瘤 [24]
E. coli DH5α 表达前药转化酶 表达β-葡糖醛酸酶,将前药9ACG转化为9AC,增加化疗的敏感性 CL1-5人肺腺癌 [25]
E. coli Nissle 1917 表达前药转化酶 表达黑芥子酶,将硫代葡萄糖苷转化为具抗癌活性的萝卜硫素 HCT116人结肠癌,LoVo人结肠癌,AGS人胃腺癌,MCF7人乳腺癌,CT26小鼠结肠癌 [26]
S. typhimurium S636 抑制肿瘤血管生成 递送抗血管生成剂内皮抑素 CT26小鼠结肠癌,B16-F10小鼠黑色素瘤 [21]
E. coli Nissle 1917 抑制肿瘤血管生
成/提高可控性		 利用缺氧诱导启动子控制Tum-5表达 B16-F10小鼠黑色素瘤 [27]
E. coli Nissle 1917 递送化疗药物 使用酸不稳定接头将化疗药物DOX连接在细菌表面 4T1小鼠乳腺癌 [28]
S. typhimurium LT2 递送化疗药物 将装载DOX的纳米脂质体递送到肿瘤组织 4T1小鼠乳腺癌 [29]
S. typhimurium
SHJ2037		 递送化疗药物 将装载紫杉醇的脂质体递送到肿瘤组织 4T1小鼠乳腺癌 [30]
S. typhimurium
BRD509		 调节免疫微环境 表达重组IFN-γ,即IFN-γ融合到SipB的N端区域(残基1~160) B16-F10小鼠黑色素瘤 [31]
S. typhimurium
BRD509		 调节免疫微环境 表达细胞因子LIGHT CT26小鼠结肠癌,D2F2小鼠乳腺癌,LLC小鼠肺癌 [32]
S. typhimurium GIDIL2 调节免疫微环境 在厌氧诱导的启动子下控制表达细胞因子IL-2 B16-F1小鼠黑色素瘤 [33]
E. coli Nissle 1917 调节免疫微环境 使用同步裂解回路,表达并局部释放CD47纳米抗体 A20小鼠B细胞淋巴瘤,4T1小鼠乳腺癌,B16-F10小鼠黑色素瘤 [34]
E. coli Nissle 1917 调节免疫微环境 使用同步裂解回路,表达并局部释放PD-L1和CTLA-4纳米抗体 CT26小鼠结肠癌,A20小鼠B细胞淋巴瘤 [35]
E. coli Nissle 1917 调节免疫微环境 表达STING激动剂CDA,激活抗原呈递细胞和肿瘤抗原呈递 B16-F10小鼠黑色素瘤,EL4小鼠淋巴细胞瘤,A20小鼠B细胞淋巴瘤,4T1小鼠乳腺癌,CT26小鼠结肠癌 [15]
L. rhamnosus
Probio-M9		 调节免疫微环境 恢复被抗生素破坏的肠道微生物菌群,与PD-1阻断疗法协同作用 CT26小鼠结肠癌 [36]
L. monocytogenes 调节免疫微环境 通过递送破伤风类毒素重新激活先前存在的记忆T细胞以杀死肿瘤细胞 Panc-02小鼠胰腺癌细胞,4T1小鼠乳腺癌 [37]
S. typhimurium YB1 光热疗法 在YB1表面共价连接负载有吲哚菁绿的纳米颗粒INPs,将INPs递送到缺氧肿瘤核心后其光热效应可以杀死肿瘤细胞 MB49小鼠膀胱癌 [38]
E. coli MG1655 调节免疫微环
境/光热疗法		 通过细菌上修饰的生物矿化金纳米颗粒AuNPs的光热效应控制TNF-α在肿瘤部位表达 4T1小鼠乳腺癌 [39]
S. typhimurium
VNP20009		 调节免疫微环
境/光热疗法		 在细菌表面涂覆聚多巴胺,并局部接种含有PD-1的基于磷脂的相分离凝胶 B16-F10小鼠黑色素瘤 [40]
E. coli Nissle 1917 调节免疫微环
境/光热疗法		 在细菌表面偶联基于PDA纳米颗粒与OVA抗原和α-PD-1抗体的三重免疫纳米激活剂 CT26小鼠结肠癌,MC38小鼠结肠癌 [41]
E. coli BL21(DE3) 调节免疫微环
境/光热疗法		 表达产生黑色素,通过多巴胺的原位聚合将αPD-1锚定在细菌表面 4T1小鼠乳腺癌 [42]
Synechococcus 7942 光动力疗法 光敏剂附着在Syne表面,实现肿瘤靶向光敏剂递送和原位光催化制氧 4T1小鼠乳腺癌 [43]
E. coli MG1655 光动力疗法/
递送化疗药物		 通过仿生矿化在细菌上装载了含有光敏剂Ce6和化疗药物DOX的ZIF-8涂层 4T1小鼠乳腺癌 [44]
表1  已用于肿瘤治疗的菌株及其作用方式
图1  提高EcN可控性的三种策略
图2  EcN在辅助治疗肿瘤方面的应用
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