J Cancer 2017; 8(9):1609-1618. doi:10.7150/jca.18776
Treatment of Neuroblastoma with an Engineered “Obligate” Anaerobic Salmonella typhimurium Strain YB1
1. Pediatric Intensive Care Unit, Shanghai Children's medical Center affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, PR China;
2. Department of Peadiatrics & Adolescent, Queen Mary Hospital, LKS Faculty of Medicine, the University of Hong Kong, Pokfulam, Hong Kong SAR, PR China;
3. Department of Biochemistry, LKS Faculty of Medicine, the University of Hong Kong, Pokfulam, Hong Kong SAR, PR China;
4. Center of Cancer Research, LKS Faculty of Medicine, the University of Hong Kong, Pokfulam, Hong Kong SAR, PR China.
* Equal contribution
Purpose Neuroblastoma is an embryonic solid tumor derived from the progenitors of the sympathetic nervous system. More than half of the patients developed metastatic disease at the time of initial diagnosis and had poor outcome with current therapeutic approaches. In recent years, some obligate and facultative anaerobic bacteria were reported to target the hypoxic and necrotic region of solid tumor models and caused tumor regression. We recently successfully constructed an “obligate” anaerobic Salmonella strain YB1 that was applied in breast cancer nude mice model by us. Here, we report the application of YB1 in neuroblastoma treatment.
Methods The anti-cancer effect and side-effects of YB1 was examined in both in vitro and in vivo experiment. Previous established orthotopic neuroblastoma SCID/beige murine model using SK-NLP/luciferase cell line was adopted.
Results In vitro, YB1 induced apoptosis for up to 31.4% of the neuroblastoma cells under anaerobic condition, three times more than that under aerobic condition (10.9%). The expression of both Toll like Receptor 4 and 5 (TLR4 and TLR5) in cancer cells were significantly up-regulated (p<0.05, p<0.01 respectively) after the treatment of YB1 under anaerobic condition. In mouse model, YB1 preferentially accumulated inside the core of the tumors, rather than in normal tissues as our previous reported. This is suggestive of the hypoxic nature of tumor core. Tumor growth was significantly retarded in YB1 treatment group (n=6, P<0.01). Furthermore, there was no long-term organ damage noted in all the organs examined including heart, lung, liver, spleen and brain in the YB1 treated mice.
Conclusion The genetic modified Salmonella strain YB1 is a promising anti-tumor strategy against the tumor bulk for neuroblastoma. Future study can be extended to other common cancer types to verify the relative efficacy on different neoplastic cells.
Keywords: neuroblastoma, xenograft, Salmonella, hypoxia, target-killing.
Ning BT, Yu B, Chan S, Chan Jl, Huang JD, Chan GCF. Treatment of Neuroblastoma with an Engineered “Obligate” Anaerobic Salmonella typhimurium Strain YB1. J Cancer 2017; 8(9):1609-1618. doi:10.7150/jca.18776. Available from http://www.jcancer.org/v08p1609.htm