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

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。

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.