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Open Access 01-12-2015 | Research

Genetically modified "obligate" anaerobic Salmonella typhimurium as a therapeutic strategy for neuroblastoma

Authors: Zhu-Ling Guo, Bin Yu, Bo-Tao Ning, Shing Chan, Qiu-Bin Lin, James Chun-Bong Li, Jian-Dong Huang, Godfrey Chi-Fung Chan

Published in: Journal of Hematology & Oncology | Issue 1/2015

Abstract

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.

Wan TSK, Ma ESK, Chan GCF, Chan LC. Investigation of MYCN status in neuroblastoma by fluorescence in situ hybridization. Int J Mol Med. 2004;14:981–7.PubMed

Pugh TJ, Morozova O, Attiyeh EF, Asgharzadeh S, Wei JS, Auclair D, et al. The genetic landscape of high-risk neuroblastoma. Nat Genet. 2013;45:279–84.PubMedCentralCrossRefPubMed

Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 2003;3:203–16.CrossRefPubMed

Ma M, Ye JY, Deng R, Dee CM, Chan GC-F. Mesenchymal stromal cells may enhance metastasis of neuroblastoma via SDF-1/CXCR4 and SDF-1/CXCR7 signaling. Cancer Lett. 2011;312:1–10.CrossRefPubMed

Jones D, Vichaya EG, Wang XS, Williams LA, Shah ND, Thomas SK, et al. Validation of the M. D. Anderson Symptom Inventory multiple myeloma module. J Hematol Oncol. 2013;6:13.PubMedCentralCrossRefPubMed

Schulenburg A, Blatt K, Cerny-Reiterer S, Sadovnik I, Herrmann H, Marian B, et al. Cancer stem cells in basic science and in translational oncology: can we translate into clinical application? J Hematol Oncol. 2015;8:16.PubMedCentralCrossRefPubMed

Sun Z, Wang S, Zhao RC. The roles of mesenchymal stem cells in tumor inflammatory microenvironment. J Hematol Oncol. 2014;7:14.PubMedCentralCrossRefPubMed

Bell JCPF. Taming measles virus to create an effective cancer therapeutic. Mayo Clin Proc. 2014;89:863–5.CrossRefPubMed

Huebener N, Lange B, Lemmel C, Rammensee HG, Strandsby A, Wenkel J, et al. Vaccination with minigenes encoding for novel ‘self’ antigens are effective in DNA-vaccination against neuroblastoma. Cancer Lett. 2003;197:211–7.CrossRefPubMed

10.

Barnett SJ, Soto LJ, Sorenson BS, Nelson BW, Bulander R, Leonard AS, et al. Attenuated Salmonella typhimurium in the treatment of neuroblastoma. Trends Cancer Res. 2007;3:47–52.

11.

Kumari S, Mg S, Mayor S. Endocytosis unplugged: multiple ways to enter the cell. Cell Res. 2010;20:256–75.CrossRefPubMed

12.

Wirawan E, Berghe TV, Lippens S, Agostinis P, Vandenabeele P. Autophagy: for better or for worse. Cell Res. 2012;22:43–61.PubMedCentralCrossRefPubMed

13.

Yu B, Yang M, Shi L, Yao Y, Jiang Q, Li X, et al. Explicit hypoxia targeting with tumor suppression by creating an “obligate” anaerobic Salmonella typhimurium strain. Sci Rep. 2012;2:436.PubMedCentralPubMed

14.

Tentler JJ, Tan AC, Weekes CD, Jimeno A, Leong S, Pitts TM, et al. Patient-derived tumour xenografts as models for oncology drug development. Nat Rev Clin Oncol. 2012;9:338–50.PubMedCentralCrossRefPubMed

15.

Morton CL, Houghton PJ. Establishment of human tumor xenografts in immunodeficient mice. Nat Protoc. 2007;2:247–50.CrossRefPubMed

16.

Nelson PS, Montgomery B. Unconventional therapy for prostate cancer: good, bad or questionable? Nat Rev Cancer. 2003;3:845–58.CrossRefPubMed

17.

Colquhoun D. Science degrees without the science. Nature. 2007;446:373–4.CrossRefPubMed

18.

Anonymous. Trial watch: immunotherapy shows promise in phase III neuroblastoma trial. Nat Rev Drug Discov. 2009;8:604–4.

19.

Oppenheimer O, Alaminos M, Gerald WL. Genomic medicine and neuroblastoma. Expert Rev Mol Diagn. 2003;3:39–54.CrossRefPubMed

20.

Nakagawara A. Molecular basis of spontaneous regression of neuroblastoma: role of neurotrophic signals and genetic abnormalities. Hum Cell. 1998;11:115–24.PubMed

21.

Arenson EB, Hutter JJ, Restuccia RD, Holton CP. Neuroblastoma in father and son. JAMA. 1976;235:727–9.CrossRefPubMed

22.

Pertl U, Wodrich H, Ruehlmann JM, Gillies SD, Lode HN, Reisfeld RA. Immunotherapy with a posttranscriptionally modified DNA vaccine induces complete protection against metastatic neuroblastoma. Blood. 2003;101:649–54.CrossRefPubMed

23.

Daudel D, Weidinger G, Spreng S. Use of attenuated bacteria as delivery vectors for DNA vaccines. Expert Rev Vaccines. 2007;6:97–110.CrossRefPubMed

24.

Toussaint B, Chauchet X, Wang Y, Polack B, Gouëllec AL. Live-attenuated bacteria as a cancer vaccine vector. Expert Rev Vaccines. 2013;12:1139–54.CrossRefPubMed

25.

M-F R, Larivière L, Wilkinson R, Tam M, Stevenson MM, Malo D. Incremental expression of TLR4 correlates with mouse resistance to Salmonella infection and fine regulation of relevant immune genes. Genes Immun. 2006;7:372–83.CrossRef

26.

Andonegui G, Zhou H, Bullard D, Kelly MM, Mullaly SC, McDonald B, et al. Mice that exclusively express TLR4 on endothelial cells can efficiently clear a lethal systemic Gram-negative bacterial infection. J Clin Investig. 2009;119:1921–30.PubMedCentralPubMed

27.

Wilson RP, Raffatellu M, Chessa D, Winter SE, Tükel C, Bäumler AJ. The Vi-capsule prevents Toll-like receptor 4 recognition of Salmonella. Cell Microbiol. 2008;10:876–90.CrossRefPubMed

28.

Beutler B, Milsark IW, Cerami AC. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science (New York, NY). 1985;229:869–71.CrossRef

29.

Dziarski R, Gupta D. Role of MD-2 in TLR2- and TLR4-mediated recognition of Gram-negative and Gram-positive bacteria and activation of chemokine genes. J Endotoxin Res. 2000;6:401–5.CrossRefPubMed

30.

Zheng Z, Cheng S, Wu W, Wang L, Zhao Y, Shen Y, et al. c-FLIP is involved in tumor progression of peripheral T-cell lymphoma and targeted by histone deacetylase inhibitors. J Hematol Oncol. 2014;7:88.PubMedCentralCrossRefPubMed

31.

Chan GC-F, Chan WK, Sze DM-Y. The effects of beta-glucan on human immune and cancer cells. J Hematol Oncol. 2009;2:25.PubMedCentralCrossRefPubMed

32.

Xiao G, Wang X, Sheng J, Lu S, Yu X, Wu JD. Soluble NKG2D ligand promotes MDSC expansion and skews macrophage to the alternatively activated phenotype. J Hematol Oncol. 2015;8:13.PubMedCentralCrossRefPubMed

33.

Roy R, Kumar D, Sharma A, Gupta P, Chaudhari BP, Tripathi A, et al. ZnO nanoparticles induced adjuvant effect via toll-like receptors and Src signaling in Balb/c mice. Toxicol Lett. 2014;230:421–33.CrossRefPubMed

34.

Li J-F, Huang R-Z, Yao G-Y, Ye M-Y, Wang H-S, Pan Y-M, et al. Synthesis and biological evaluation of novel aniline-derived asiatic acid derivatives as potential anticancer agents. Eur J Med Chem. 2014;86:175–88.CrossRefPubMed

35.

Banjerdpongchai R, Kongtawelert P, Khantamat O, Srisomsap C, Chokchaichamnankit D, Subhasitanont P, et al. Mitochondrial and endoplasmic reticulum stress pathways cooperate in zearalenone-induced apoptosis of human leukemic cells. J Hematol Oncol. 2010;3:50.PubMedCentralCrossRefPubMed

36.

Usmani SZ, Bona RD, Chiosis G, Li Z. The anti-myeloma activity of a novel purine scaffold HSP90 inhibitor PU-H71 is via inhibition of both HSP90A and HSP90B1. J Hematol Oncol. 2010;3:40.PubMedCentralCrossRefPubMed

37.

Wang H, Yang S, Zhou H, Sun M, Du L, Wei M, et al. Aloperine executes antitumor effects against multiple myeloma through dual apoptotic mechanisms. J Hematol Oncol. 2015;8:26.PubMedCentralCrossRefPubMed

38.

Wudtiwai B, Sripanidkulchai B, Kongtawelert P, Banjerdpongchai R. Methoxyflavone derivatives modulate the effect of TRAIL-induced apoptosis in human leukemic cell lines. J Hematol Oncol. 2011;4:52.PubMedCentralCrossRefPubMed

39.

Kvezereli M, Michie SA, Yu T, Creusot RJ, Fontaine MJ. TSG-6 protein expression in the pancreatic islets of NOD mice. J Mol Histol. 2008;39:585–93.CrossRefPubMed

40.

Cao TV, La M, Getting SJ, Day AJ, Perretti M. Inhibitory effects of TSG-6 Link module on leukocyte-endothelial cell interactions in vitro and in vivo. Microcirculation. 2004;11:615–24.CrossRefPubMed

41.

Weiss WA, Aldape K, Mohapatra G, Feuerstein BG, Bishop JM. Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO J. 1997;16(11):2985–95.PubMedCentralCrossRefPubMed

42.

Heukamp LC, Thor T, Schramm A, De Preter K, Kumps C, De Wilde B, et al. Targeted expression of mutated ALK induces neuroblastoma in transgenic mice. Sci Translat Med. 2012;4(141):141ra91.

Title: Genetically modified "obligate" anaerobic Salmonella typhimurium as a therapeutic strategy for neuroblastoma
Authors: Zhu-Ling Guo
Bin Yu
Bo-Tao Ning
Shing Chan
Qiu-Bin Lin
James Chun-Bong Li
Jian-Dong Huang
Godfrey Chi-Fung Chan
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2015
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-015-0196-3

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