Genetically modified "obligate" anaerobic Salmonella typhimurium as a therapeutic strategy for neuroblastoma.
BACKGROUND
Neuroblastoma currently has poor prognosis, therefore we proposed a new strategy by targeting neuroblastoma with genetically engineered anaerobic Salmonella (Sal-YB1).


METHODS
Nude and nonobese diabetic-severe combined immunodeficiency (NOD-SCID) orthotopic mouse models were used, and Sal-YB1 was administered via tail vein. The therapeutic effectiveness, bio-safety, and mechanisms were studied.


RESULTS
No mice died of therapy-related complications. Tumor size reduction was 70 and 30% in nude and NOD-SCID mice, respectively. No Salmonella was detected in the urine; 75% mice had positive stool culture if diaminopimelic acid was added, but all turned negative subsequently. Tumor tissues had more Sal-YB1 infiltration, necrosis, and shrinkage in Sal-YB1-treated mice. Significantly higher expression of TLR4, TNF-stimulated gene 6 protein (TSG6), and cleaved caspase 1, 3, 8, and 9 was found in the tumor masses of the Sal-YB1-treated group with a decrease of interleukin 1 receptor-associated kinase (IRAK) and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα). There was a high release of TNFα both in human macrophages and mouse tumor tissues with Sal-YB1 treatment. The antitumor effect of the supernatant derived from macrophages treated with Sal-YB1 could be reversed with TNFα and pan-caspase inhibitors.


CONCLUSIONS
This new approach in targeting neuroblastoma by bio-engineered Salmonella with the assistance of macrophages indirectly may have a clinical therapeutic impact in the future.
Department of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, SAR, People's Republic of China. guochenyan07@gmail.com.
Zhu-Ling
ZL
Guo
Department of Biochemistry, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, SAR, People's Republic of China. yubin1982@msn.com.|Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, People's Republic of China. yubin1982@msn.com.
Bin
B
Yu
Department of Hematology & Oncology of Children's Hospital, Zhejiang Key Laboratory for Diagnosis and Treatment of Neonatal Diseases, Zhejiang University School of Medicine, Hangzhou, People's Republic of China. ningbotao@126.com.
Bo-Tao
BT
Ning
Department of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, SAR, People's Republic of China. schan88@hku.hk.
Shing
S
Chan
Department of Biochemistry, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, SAR, People's Republic of China. lqiubin@gmail.com.
Qiu-Bin
QB
Lin
Department of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, SAR, People's Republic of China. jamesli@hku.hk.
James Chun-Bong
JC
Li
Department of Biochemistry, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, SAR, People's Republic of China. jdhuang@hku.hk.|HKU-SIRI, the University of Hong Kong, Hong Kong, SAR, People's Republic of China. jdhuang@hku.hk.
Jian-Dong
JD
Huang
Department of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, SAR, People's Republic of China. gcfchan@hku.hk.
Godfrey Chi-Fung
GC
Chan
D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009447:Neuroblastoma / Q000628:therapy*; D012486:Salmonella typhimurium / Q000378:metabolism*