工程菌在肿瘤治疗方面的应用进展

陈家文; 黄建东; 孙海涛

doi:10.12211/2096-8280.2022-062

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工程菌在肿瘤治疗方面的应用进展

特约评述 | 更新时间：2025-03-20

- 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
- 合成生物学 2023年4卷第4期页码：690-702
- 作者机构：
  
  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
- 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" ]
- 基金信息：
  
  国家重点研发计划(2021YFA0910700;2018YFA0902701);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)
- DOI：10.12211/2096-8280.2022-062
  中图分类号： Q816
- 收稿：2022-11-14，
  
  修回：2023-04-10，
  
  纸质出版：2023-08-31
- 稿件说明：
移动端阅览
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

CHEN Jiawen， HUANG Jiandong， SUN Haitao. Current developments in the use of engineered bacteria for cancer therapy［J］. Synthetic Biology Journal， 2023， 4（4）： 690-702
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 DOI： 10.12211/2096-8280.2022-062.

CHEN Jiawen， HUANG Jiandong， SUN Haitao. Current developments in the use of engineered bacteria for cancer therapy［J］. Synthetic Biology Journal， 2023， 4（4）： 690-702 DOI： 10.12211/2096-8280.2022-062.

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。

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 b

e 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.

关键词

Keywords

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