Engineering the perfect (bacterial) cancer therapy

This article has been updated

Abstract

Bacterial therapies possess many unique mechanisms for treating cancer that are unachievable with standard methods. Bacteria can specifically target tumours, actively penetrate tissue, are easily detected and can controllably induce cytotoxicity. Over the past decade, Salmonella, Clostridium and other genera have been shown to control tumour growth and promote survival in animal models. In this Innovation article I propose that synthetic biology techniques can be used to solve many of the key challenges that are associated with bacterial therapies, such as toxicity, stability and efficiency, and can be used to tune their beneficial features, allowing the engineering of 'perfect' cancer therapies.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Bacteria are the optimal robot factory cancer therapies.
Figure 2: The transport properties of bacterial therapies produce preferable drug concentration profiles.
Figure 3: Gene triggering systems.

Change history

  • 16 December 2010

    On page 787 of this article the Salmonella strain VNP20009 was incorrectly referred to as VNP200009.

References

  1. 1

    Minchinton, A. I. & Tannock, I. F. Drug penetration in solid tumours. Nature Rev. Cancer 6, 583–592 (2006).

    CAS  Google Scholar 

  2. 2

    St. Jean, A. T., Zhang, M. M. & Forbes, N. S. Bacterial therapies: completing the cancer treatment toolbox. Curr. Opin. Biotechnol. 19, 511–517 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Jain, R. K. The next frontier of molecular medicine: delivery of therapeutics. Nature Med. 4, 655–657 (1998).

    CAS  PubMed  Google Scholar 

  4. 4

    Pawelek, J. M., Low, K. B. & Bermudes, D. Tumor-targeted Salmonella as a novel anticancer vector. Cancer Res. 57, 4537–4544 (1997).

    CAS  PubMed  Google Scholar 

  5. 5

    Yu, Y. A. et al. Visualization of tumors and metastases in live animals with bacteria and vaccinia virus encoding light-emitting proteins. Nature Biotech. 22, 313–320 (2004).

    CAS  Google Scholar 

  6. 6

    Parker, R. C., Plummer, H. C., Siebenmann, C. O. & Chapman, M. G. Effect of histolyticus infection and toxin on transplantable mouse tumors. Proc. Soc. Exp. Biol. Med. 66, 461–467 (1947).

    CAS  PubMed  Google Scholar 

  7. 7

    Malmgren, R. A. & Flanigan, C. C. Localization of the vegetative form of Clostridium tetani in mouse tumor following intravenous spore administration. Cancer Res. 15, 473–478 (1955).

    CAS  PubMed  Google Scholar 

  8. 8

    Kohwi, Y., Imai, K., Tamura, Z. & Hashimoto, Y. Antitumor effect of Bifidobacterium infantis in mice. Gann 69, 613–618 (1978).

    CAS  PubMed  Google Scholar 

  9. 9

    Bhatnagar, P. K., Awasthi, A., Nomellini, J. F., Smit, J. & Suresh, M. R. Anti-tumor effects of the bacterium caulobacter crescentus in murine tumor models. Cancer Biol. Ther. 5, 485–491 (2006).

    CAS  PubMed  Google Scholar 

  10. 10

    Pan, Z. K., Weiskirch, L. M. & Paterson, Y. Regression of established B16F10 melanoma with a recombinant Listeria monocytogenes vaccine. Cancer Res. 59, 5264–5269 (1999).

    CAS  PubMed  Google Scholar 

  11. 11

    Kim, S. H., Castro, F., Paterson, Y. & Gravekamp, C. High efficacy of a Listeria-based vaccine against metastatic breast cancer reveals a dual mode of action. Cancer Res. 69, 5860–5866 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Arakawa, M., Sugiura, K., Reilly, H. C. & Stock, C. C. Oncolytic effect of Proteus mirabilis upon tumor-bearing animals. II. Effect on transplantable mouse and rat tumors. Gann 59, 117–122 (1968).

    CAS  PubMed  Google Scholar 

  13. 13

    Maletzki, C., Linnebacher, M., Kreikemeyer, B. & Emmrich, J. Pancreatic cancer regression by intratumoural injection of live Streptococcus pyogenes in a syngeneic mouse model. Gut 57, 483–491 (2008).

    CAS  PubMed  Google Scholar 

  14. 14

    Dang, L. H., Bettegowda, C., Huso, D. L., Kinzler, K. W. & Vogelstein, B. Combination bacteriolytic therapy for the treatment of experimental tumors. Proc. Natl Acad. Sci. USA 98, 15155–15160 (2001).

    CAS  PubMed  Google Scholar 

  15. 15

    Kasinskas, R. W. & Forbes, N. S. Salmonella typhimurium specifically chemotax and proliferate in heterogeneous tumor tissue in vitro. Biotechnol. Bioeng. 94, 710–721 (2006).

    CAS  PubMed  Google Scholar 

  16. 16

    Kasinskas, R. W. & Forbes, N. S. Salmonella typhimurium lacking ribose chemoreceptors localize in tumor quiescence and induce apoptosis. Cancer Res. 67, 3201–3209 (2007).

    CAS  PubMed  Google Scholar 

  17. 17

    Nguyen, V. H. et al. Genetically engineered Salmonella typhimurium as an imageable therapeutic probe for cancer. Cancer Res. 70, 18–23 (2010).

    CAS  PubMed  Google Scholar 

  18. 18

    Jiang, S. N. et al. Inhibition of tumor growth and metastasis by a combination of Escherichia coli-mediated cytolytic therapy and radiotherapy. Mol. Ther. 18, 635–642 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Ryan, R. M. et al. Bacterial delivery of a novel cytolysin to hypoxic areas of solid tumors. Gene Ther. 16, 329–339 (2009).

    CAS  PubMed  Google Scholar 

  20. 20

    Loeffler, M., Le'Negrate, G., Krajewska, M. & Reed, J. C. Attenuated Salmonella engineered to produce human cytokine LIGHT inhibit tumor growth. Proc. Natl Acad. Sci. USA 104, 12879–12883 (2007).

    CAS  PubMed  Google Scholar 

  21. 21

    Loeffler, M., Le'Negrate, G., Krajewska, M. & Reed, J. C. Salmonella typhimurium engineered to produce CCL21 inhibit tumor growth. Cancer Immunol. Immunother. 58, 769–775 (2009).

    CAS  PubMed  Google Scholar 

  22. 22

    Gentschev, I. et al. Use of a recombinant Salmonella enterica serovar Typhimurium strain expressing C-Raf for protection against C-Raf induced lung adenoma in mice. BMC Cancer 5, 15 (2005).

    PubMed  PubMed Central  Google Scholar 

  23. 23

    Ganai, S., Arenas, R. B. & Forbes, N. S. Tumour-targeted delivery of TRAIL using Salmonella typhimurium enhances breast cancer survival in mice. Br. J. Cancer 101, 1683–1691 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Loeffler, M., Le'Negrate, G., Krajewska, M. & Reed, J. C. Inhibition of tumor growth using Salmonella expressing Fas ligand. J. Natl Cancer Inst. 100, 1113–1116 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Theys, J. et al. Stable Escherichia coliClostridium acetobutylicum shuttle vector for secretion of murine tumor necrosis factor α. Appl. Environ. Microbiol. 65, 4295–4300 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Nuyts, S. et al. Increasing specificity of anti-tumor therapy: cytotoxic protein delivery by non-pathogenic clostridia under regulation of radio-induced promoters. Anticancer Res. 21, 857–861 (2001).

    CAS  PubMed  Google Scholar 

  27. 27

    Nuyts, S. et al. Radio-responsive recA promoter significantly increases TNFα production in recombinant clostridia after 2 Gy irradiation. Gene Ther. 8, 1197–1201 (2001).

    CAS  PubMed  Google Scholar 

  28. 28

    Loessner, H. et al. Remote control of tumour-targeted Salmonella enterica serovar Typhimurium by the use of L-arabinose as inducer of bacterial gene expression in vivo. Cell. Microbiol. 9, 1529–1537 (2007).

    CAS  PubMed  Google Scholar 

  29. 29

    Stritzker, J. et al. Tumor-specific colonization, tissue distribution, and gene induction by probiotic Escherichia coli Nissle 1917 in live mice. Int. J. Med. Microbiol. 297, 151–162 (2007).

    CAS  PubMed  Google Scholar 

  30. 30

    Nuyts, S. et al. The use of radiation-induced bacterial promoters in anaerobic conditions: a means to control gene expression in clostridium-mediated therapy for cancer. Radiat. Res. 155, 716–723 (2001).

    CAS  PubMed  Google Scholar 

  31. 31

    Zhao, M. et al. Tumor-targeting bacterial therapy with amino acid auxotrophs of GFP-expressing Salmonella typhimurium. Proc. Natl Acad. Sci. USA 102, 755–760 (2005).

    CAS  PubMed  Google Scholar 

  32. 32

    Hoffman, R. M. & Zhao, M. Whole-body imaging of bacterial infection and antibiotic response. Nature Protoc. 1, 2988–2994 (2006).

    CAS  Google Scholar 

  33. 33

    Benoit, M. R. et al. Visualizing implanted tumors in mice with magnetic resonance imaging using magnetotactic bacteria. Clin. Cancer Res. 15, 5170–5177 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Tjuvajev, J. et al. Salmonella-based tumor-targeted cancer therapy: tumor amplified protein expression therapy (TAPET) for diagnostic imaging. J. Control. Release 74, 313–315 (2001).

    CAS  PubMed  Google Scholar 

  35. 35

    Soghomonyan, S. A. et al. Positron emission tomography (PET) imaging of tumor-localized Salmonella expressing HSV1-TK. Cancer Gene Ther. 12, 101–108 (2005).

    CAS  PubMed  Google Scholar 

  36. 36

    Brader, P. et al. Escherichia coli Nissle 1917 facilitates tumor detection by positron emission tomography and optical imaging. Clin. Cancer Res. 14, 2295–2302 (2008).

    CAS  Google Scholar 

  37. 37

    Nagakura, C. et al. Efficacy of a genetically-modified Salmonella typhimurium in an orthotopic human pancreatic cancer in nude mice. Anticancer Res. 29, 1873–1878 (2009).

    PubMed  Google Scholar 

  38. 38

    Lambin, P. et al. Colonisation of Clostridium in the body is restricted to hypoxic and necrotic areas of tumours. Anaerobe 4, 183–188 (1998).

    CAS  PubMed  Google Scholar 

  39. 39

    Minton, N. P. Clostridia in cancer therapy. Nature Rev. Microbiol. 1, 237–242 (2003).

    CAS  Google Scholar 

  40. 40

    Forbes, N. S., Munn, L. L., Fukumura, D. & Jain, R. K. Sparse initial entrapment of systemically injected Salmonella typhimurium leads to heterogeneous accumulation within tumors. Cancer Res. 63, 5188–5193 (2003).

    CAS  PubMed  Google Scholar 

  41. 41

    Leschner, S. et al. Tumor invasion of Salmonella enterica serovar Typhimurium is accompanied by strong hemorrhage promoted by TNF-α. PLoS ONE 4, e6692 (2009).

    PubMed  PubMed Central  Google Scholar 

  42. 42

    Sznol, M., Lin, S. L., Bermudes, D., Zheng, L. M. & King, I. Use of preferentially replicating bacteria for the treatment of cancer. J. Clin. Invest. 105, 1027–1030 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Clairmont, C. et al. Biodistribution and genetic stability of the novel antitumor agent VNP20009, a genetically modified strain of Salmonella typhimurium. J. Infect. Dis. 181, 1996–2002 (2000).

    CAS  PubMed  Google Scholar 

  44. 44

    Lee, C. H., Wu, C. L. & Shiau, A. L. Endostatin gene therapy delivered by Salmonella choleraesuis in murine tumor models. J. Gene Med. 6, 1382–1393 (2004).

    CAS  PubMed  Google Scholar 

  45. 45

    Zheng, L. M. et al. Tumor amplified protein expression therapy: Salmonella as a tumor-selective protein delivery vector. Oncol. Res. 12, 127–135 (2000).

    CAS  PubMed  Google Scholar 

  46. 46

    Low, K. B. et al. Lipid A mutant Salmonella with suppressed virulence and TNFα induction retain tumor-targeting in vivo. Nature Biotech. 17, 37–41 (1999).

    CAS  Google Scholar 

  47. 47

    Theys, J. et al. Repeated cycles of Clostridium-directed enzyme prodrug therapy result in sustained antitumour effects in vivo. Br. J. Cancer 95, 1212–1219 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Zhao, M. et al. Targeted therapy with a Salmonella typhimurium leucine–arginine auxotroph cures orthotopic human breast tumors in nude mice. Cancer Res. 66, 7647–7652 (2006).

    CAS  PubMed  Google Scholar 

  49. 49

    Streilein, J. W. Unraveling immune privilege. Science 270, 1158–1159 (1995).

    CAS  PubMed  Google Scholar 

  50. 50

    Westphal, K., Leschner, S., Jablonska, J., Loessner, H. & Weiss, S. Containment of tumor-colonizing bacteria by host neutrophils. Cancer Res. 68, 2952–2960 (2008).

    CAS  PubMed  Google Scholar 

  51. 51

    Lee, C. H., Wu, C. L. & Shiau, A. L. Systemic administration of attenuated Salmonella choleraesuis carrying thrombospondin-1 gene leads to tumor-specific transgene expression, delayed tumor growth and prolonged survival in the murine melanoma model. Cancer Gene Ther. 12, 175–184 (2005).

    CAS  PubMed  Google Scholar 

  52. 52

    Lee, C. H., Wu, C. L., Tai, Y. S. & Shiau, A. L. Systemic administration of attenuated Salmonella choleraesuis in combination with cisplatin for cancer therapy. Mol. Ther. 11, 707–716 (2005).

    CAS  PubMed  Google Scholar 

  53. 53

    Vaupel, P., Kallinowski, F. & Okunieff, P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 49, 6449–6465 (1989).

    CAS  PubMed  Google Scholar 

  54. 54

    Heimann, D. M. & Rosenberg, S. A. Continuous intravenous administration of live genetically modified Salmonella typhimurium in patients with metastatic melanoma. J. Immunother. 26, 179–180 (2003).

    PubMed  PubMed Central  Google Scholar 

  55. 55

    Toso, J. F. et al. Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. J. Clin. Oncol. 20, 142–152 (2002).

    PubMed  PubMed Central  Google Scholar 

  56. 56

    Nemunaitis, J. et al. Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients. Cancer Gene Ther. 10, 737–744 (2003).

    CAS  PubMed  Google Scholar 

  57. 57

    Hall, S. S. A Commotion in the Blood: Life, Death, and the Immune System (Henry Holt, New York, 1997).

    Google Scholar 

  58. 58

    Coley, W. B. Contribution to the knowledge of sarcoma. Ann. Surg. 14, 199–220 (1891).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Nauts, H. C., Swift, W. E. & Coley, B. L. The treatment of malignant tumors by bacterial toxins as developed by the late William B. Coley, MD, reviewed in the light of modern research. Cancer Res. 6, 205–216 (1946).

    CAS  Google Scholar 

  60. 60

    Fensterle, J. et al. Cancer immunotherapy based on recombinant Salmonella enterica serovar Typhimurium aroA strains secreting prostate-specific antigen and cholera toxin subunitB. Cancer Gene Ther. 15, 85–93 (2008).

    CAS  PubMed  Google Scholar 

  61. 61

    Mottram, J. C. Factors of importance in radiosensitivity of tumors. Br. J. Radiol. 9, 606–614 (1936).

    Google Scholar 

  62. 62

    Möse, J. R. & Möse, G. Oncogenesis by clostridia. I. Activity of Clostridium butyricum (M-55) and other nonpathogenic clostridia against the Ehrlich carcinoma. Cancer Res. 24, 212–216 (1964).

    Google Scholar 

  63. 63

    Carey, R. W., Holland, J. F., Whang, H. Y., Neter, E. & Bryant, B. Clostridial oncolysis in man. Eur. J. Cancer 3, 37–46 (1967).

    Google Scholar 

  64. 64

    Lee, C. H., Wu, C. L. & Shiau, A. L. Salmonella choleraesuis as an anticancer agent in a syngeneic model of orthotopic hepatocellular carcinoma. Int. J. Cancer 122, 930–935 (2008).

    CAS  PubMed  Google Scholar 

  65. 65

    Thamm, D. H. et al. Systemic administration of an attenuated, tumor-targeting Salmonella typhimurium to dogs with spontaneous neoplasia: Phase I evaluation. Clin. Cancer Res. 11, 4827–4834 (2005).

    CAS  PubMed  Google Scholar 

  66. 66

    Jia, L. J. et al. Oral delivery of tumor-targeting Salmonella for cancer therapy in murine tumor models. Cancer Sci. 98, 1107–1112 (2007).

    CAS  PubMed  Google Scholar 

  67. 67

    Chen, G. et al. Oral delivery of tumor-targeting Salmonella exhibits promising therapeutic efficacy and low toxicity. Cancer Sci. 100, 2437–2443 (2009).

    CAS  PubMed  Google Scholar 

  68. 68

    Bermudes, D., Low, B. & Pawelek, J. Tumor-targeted Salmonella. Highly selective delivery vectors. Adv. Exp. Med. Biol. 465, 57–63 (2000).

    CAS  PubMed  Google Scholar 

  69. 69

    Hedley, D., Ogilvie, L. & Springer, C. Carboxypeptidase-G2-based gene-directed enzyme-prodrug therapy: a new weapon in the GDEPT armoury. Nature Rev. Cancer 7, 870–879 (2007).

    CAS  Google Scholar 

  70. 70

    Brown, J. M. & Wilson, W. R. Exploiting tumour hypoxia in cancer treatment. Nature Rev. Cancer 4, 437–447 (2004).

    CAS  Google Scholar 

  71. 71

    Walczak, H. et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nature Med. 5, 157–163 (1999).

    CAS  PubMed  Google Scholar 

  72. 72

    Barbe, S. et al. Secretory production of biologically active rat interleukin-2 by Clostridium acetobutylicum DSM792 as a tool for anti-tumor treatment. FEMS Microbiol. Lett. 246, 67–73 (2005).

    CAS  PubMed  Google Scholar 

  73. 73

    Saltzman, D. A. et al. Attenuated Salmonella typhimurium containing interleukin-2 decreases MC-38 hepatic metastases: a novel anti-tumor agent. Cancer Biother. Radiopharm. 11, 145–153 (1996).

    CAS  PubMed  Google Scholar 

  74. 74

    Loeffler, M., Le'Negrate, G., Krajewska, M. & Reed, J. C. IL-18-producing Salmonella inhibit tumor growth. Cancer Gene Ther. 15, 787–794 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Sorenson, B. S., Banton, K. L., Frykman, N. L., Leonard, A. S. & Saltzman, D. A. Attenuated Salmonella typhimurium with interleukin 2 gene prevents the establishment of pulmonary metastases in a model of osteosarcoma. J. Pediatr. Surg. 43, 1153–1158 (2008).

    PubMed  Google Scholar 

  76. 76

    Sorenson, B. S., Banton, K. L., Frykman, N. L., Leonard, A. S. & Saltzman, D. A. Attenuated Salmonella typhimurium with IL-2 gene reduces pulmonary metastases in murine osteosarcoma. Clin. Orthop. Relat. Res. 466, 1285–1291 (2008).

    PubMed  PubMed Central  Google Scholar 

  77. 77

    Al-Ramadi, B. K. et al. Potent anti-tumor activity of systemically-administered IL-2-expressing Salmonella correlates with decreased angiogenesis and enhanced tumor apoptosis. Clin. Immunol. 130, 89–97 (2009).

    CAS  PubMed  Google Scholar 

  78. 78

    Barnett, S. J. et al. Attenuated Salmonella typhimurium invades and decreases tumor burden in neuroblastoma. J. Pediatr. Surg. 40, 993–997 (2005).

    PubMed  Google Scholar 

  79. 79

    Feltis, B. A. et al. Liver and circulating NK1.1+CD3- cells are increased in infection with attenuated Salmonella typhimurium and are associated with reduced tumor in murine liver cancer. J. Surg. Res. 107, 101–107 (2002).

    CAS  PubMed  Google Scholar 

  80. 80

    Saltzman, D. A. et al. Antitumor mechanisms of attenuated Salmonella typhimurium containing the gene for human interleukin-2: a novel antitumor agent? J. Pediatr. Surg. 32, 301–306 (1997).

    CAS  PubMed  Google Scholar 

  81. 81

    Lee, S. R. et al. Multi-immunogenic outer membrane vesicles derived from a MsbB-deficient Salmonella enterica serovar typhimurium mutant. J. Microbiol. Biotechnol. 19, 1271–1279 (2009).

    CAS  PubMed  Google Scholar 

  82. 82

    Nishikawa, H. et al. In vivo antigen delivery by a Salmonella typhimurium type III secretion system for therapeutic cancer vaccines. J. Clin. Invest. 116, 1946–1954 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Groot, A. J. et al. Functional antibodies produced by oncolytic clostridia. Biochem. Biophys. Res. Commun. 364, 985–989 (2007).

    CAS  PubMed  Google Scholar 

  84. 84

    Sizemore, D. R., Branstrom, A. A. & Sadoff, J. C. Attenuated Shigella as a DNA delivery vehicle for DNA-mediated immunization. Science 270, 299–302 (1995).

    CAS  PubMed  Google Scholar 

  85. 85

    Darji, A. et al. Oral somatic transgene vaccination using attenuated S. typhimurium. Cell 91, 765–775 (1997).

    CAS  PubMed  Google Scholar 

  86. 86

    Weiss, S. & Chakraborty, T. Transfer of eukaryotic expression plasmids to mammalian host cells by bacterial carriers. Curr. Opin. Biotechnol. 12, 467–472 (2001).

    CAS  PubMed  Google Scholar 

  87. 87

    Palffy, R. et al. Bacteria in gene therapy: bactofection versus alternative gene therapy. Gene Ther. 13, 101–105 (2006).

    CAS  PubMed  Google Scholar 

  88. 88

    Fu, W., Chu, L., Han, X. W., Liu, X. Y. & Ren, D. M. Synergistic antitumoral effects of human telomerase reverse transcriptase-mediated dual-apoptosis-related gene vector delivered by orally attenuated Salmonella enterica serovar Typhimurium in murine tumor models. J. Gene Med. 10, 690–701 (2008).

    CAS  PubMed  Google Scholar 

  89. 89

    Li, Y. H. et al. Prophylaxis of tumor through oral administration of IL-12 GM-CSF gene carried by live attenuated Salmonella. Chin. Sci. Bull. 46, 1107–1112 (2001).

    CAS  Google Scholar 

  90. 90

    Li, Y. H. et al. Oral cytokine gene therapy against murine tumor using attenuated Salmonella typhimurium. Int. J. Cancer 94, 438–443 (2001).

    CAS  Google Scholar 

  91. 91

    Qi, H., Li, Y. H. & Zheng, S. B. Oral gene therapy via live attenuated Salmonella leads to tumor regression and survival prolongation in mice. Nan Fang Yi Ke Da Xue Xue Bao 26, 1738–1741 (2006).

    CAS  PubMed  Google Scholar 

  92. 92

    Yoon, W. S., Choi, W. C., Sin, J. I. & Park, Y. K. Antitumor therapeutic effects of Salmonella typhimurium containing Flt3 ligand expression plasmids in melanoma-bearing mouse. Biotechnol. Lett. 29, 511–516 (2007).

    CAS  PubMed  Google Scholar 

  93. 93

    Zuo, S. G. et al. Orally administered DNA vaccine delivery by attenuated Salmonella typhimurium targeting fetal liver kinase 1 inhibits murine Lewis lung carcinoma growth and metastasis. Biol. Pharm. Bull. 33, 174–182 (2010).

    CAS  PubMed  Google Scholar 

  94. 94

    Feng, K. et al. Anti-angiogenesis effect on glioma of attenuated Salmonella typhimurium vaccine strain with flk-1 gene. J. Huazhong Univ. Sci. Technol. Med. Sci. 24, 389–391 (2004).

    CAS  PubMed  Google Scholar 

  95. 95

    Chou, C. K., Hung., J. Y., Liu, J. C., Chen, C. T. & Hung., M. C. An attenuated Salmonella oral DNA vaccine prevents the growth of hepatocellular carcinoma and colon cancer that express α-fetoprotein. Cancer Gene Ther. 13, 746–752 (2006).

    CAS  PubMed  Google Scholar 

  96. 96

    Zhang, L. et al. Intratumoral delivery and suppression of prostate tumor growth by attenuated Salmonella enterica serovar typhimurium carrying plasmid-based small interfering RNAs. Cancer Res. 67, 5859–5864 (2007).

    CAS  PubMed  Google Scholar 

  97. 97

    Yang, N., Zhu, X., Chen, L., Li, S. & Ren, D. Oral administration of attenuated S. typhimurium carrying shRNA-expressing vectors as a cancer therapeutic. Cancer Biol. Ther. 7, 145–151 (2008).

    CAS  PubMed  Google Scholar 

  98. 98

    Guzman, L. M., Belin, D., Carson, M. J. & Beckwith, J. Tight regulation, modulation, and high-level expression by vectors containing the arabinose PBAD promoter. J. Bacteriol. 177, 4121–4130 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Royo, J. L. et al. In vivo gene regulation in Salmonella spp. by a salicylate-dependent control circuit. Nature Methods 4, 937–942 (2007).

    CAS  PubMed  Google Scholar 

  100. 100

    Nuyts, S. et al. Insertion or deletion of the Cheo box modifies radiation inducibility of Clostridium promoters. Appl. Environ. Microbiol. 67, 4464–4470 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Mengesha, A. et al. Development of a flexible and potent hypoxia-inducible promoter for tumor-targeted gene expression in attenuated Salmonella. Cancer Biol. Ther. 5, 1120–1128 (2006).

    CAS  PubMed  Google Scholar 

  102. 102

    Strauch, K. L., Lenk, J. B., Gamble, B. L. & Miller, C. G. Oxygen regulation in Salmonella typhimurium. J. Bacteriol. 161, 673–680 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Arrach, N., Zhao, M., Porwollik, S., Hoffman, R. M. & McClelland, M. Salmonella promoters preferentially activated inside tumors. Cancer Res. 68, 4827–4832 (2008).

    CAS  PubMed  Google Scholar 

  104. 104

    Min., J. J. et al. Noninvasive real-time imaging of tumors and metastases using tumor-targeting light-emitting Escherichia coli. Mol. Imaging Biol. 10, 54–61 (2008).

    PubMed  Google Scholar 

  105. 105

    Min., J. J., Nguyen, V. H., Kim, H. J., Hong, Y. J. & Choy, H. E. Quantitative bioluminescence imaging of tumor-targeting bacteria in living animals. Nature Protoc. 3, 629–636 (2008).

    CAS  Google Scholar 

  106. 106

    Cheng, C. M. et al. Tumor-targeting prodrug-activating bacteria for cancer therapy. Cancer Gene Ther. 15, 393–401 (2008).

    CAS  PubMed  Google Scholar 

  107. 107

    Gericke, D. & Engelbart, K. Oncolysis by Clostridia.II. Experiments on tumor spectrum with variety of Clostridia in combination with heavy metal. Cancer Res. 24, 217–221 (1964).

    CAS  PubMed  Google Scholar 

  108. 108

    Dang, L. H. et al. Targeting vascular and avascular compartments of tumors with C. novyi-NT and anti-microtubule agents. Cancer Biol. Ther. 3, 326–337 (2004).

    CAS  PubMed  Google Scholar 

  109. 109

    Bettegowda, C. et al. Overcoming the hypoxic barrier to radiation therapy with anaerobic bacteria. Proc. Natl Acad. Sci. USA 100, 15083–15088 (2003).

    CAS  PubMed  Google Scholar 

  110. 110

    Cheong, I. et al. A bacterial protein enhances the release and efficacy of liposomal cancer drugs. Science 314, 1308–1311 (2006).

    CAS  PubMed  Google Scholar 

  111. 111

    Voigt, C. A. Genetic parts to program bacteria. Curr. Opin. Biotechnol. 17, 548–557 (2006).

    CAS  PubMed  Google Scholar 

  112. 112

    Pfleger, B. F., Pitera, D. J., Smolke, C. D. & Keasling, J. D. Combinatorial engineering of intergenic regions in operons tunes expression of multiple genes. Nature Biotech. 24, 1027–1032 (2006).

    CAS  Google Scholar 

  113. 113

    Salis, H. M., Mirsky, E. A. & Voigt, C. A. Automated design of synthetic ribosome binding sites to control protein expression. Nature Biotech. 27, 946–950 (2009).

    CAS  Google Scholar 

  114. 114

    Ohl, M. E. & Miller, S. I. Salmonella: a model for bacterial pathogenesis. Annu. Rev. Med. 52, 259–274 (2001).

    CAS  PubMed  Google Scholar 

  115. 115

    Engelbart, K. & Gericke, D. Oncolysis by Clostridia.V. Transplanted tumors of the hamster. Cancer Res. 24, 239–243 (1964).

    CAS  PubMed  Google Scholar 

  116. 116

    Thiele, E. H., Boxer, G. E. & Arison, R. N. Oncolysis by Clostridia.III. Effects of Clostridia and chemotherapeutic agents on rodent tumors. Cancer Res. 24, 222–233 (1964).

    CAS  PubMed  Google Scholar 

  117. 117

    Mohr, U., Boldingh, W. H., Behagel, H. A. & Emminger, A. Oncolysis by a new strain of Clostridium. Cancer Res. 32, 1122–1128 (1972).

    CAS  PubMed  Google Scholar 

  118. 118

    Weibel, S., Stritzker, J., Eck, M., Goebel, W. & Szalay, A. A. Colonization of experimental murine breast tumours by Escherichia coli K-12 significantly alters the tumour microenvironment. Cell. Microbiol. 10, 1235–1248 (2008).

    CAS  PubMed  Google Scholar 

  119. 119

    Luo, X. et al. Antitumor effect of VNP20009, an attenuated Salmonella, in murine tumor models. Oncol. Res. 12, 501–508 (2001).

    CAS  PubMed  Google Scholar 

  120. 120

    Rosenberg, S. A., Spiess, P. J. & Kleiner, D. E. Antitumor effects in mice of the intravenous injection of attenuated Salmonella typhimurium. J. Immunother. 25, 218–225 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Zhao, M. et al. Monotherapy with a tumor-targeting mutant of Salmonella typhimurium cures orthotopic metastatic mouse models of human prostate cancer. Proc. Natl Acad. Sci. USA 104, 10170–10174 (2007).

    CAS  PubMed  Google Scholar 

  122. 122

    Kimura, H. et al. Targeted therapy of spinal cord glioma with a genetically modified Salmonella typhimurium. Cell Prolif. 43, 41–48 (2010).

    CAS  PubMed  Google Scholar 

  123. 123

    Jia, L. J. et al. Enhanced therapeutic effect by combination of tumor-targeting Salmonella and endostatin in murine melanoma model. Cancer Biol. Ther. 4, 840–845 (2005).

    CAS  PubMed  Google Scholar 

  124. 124

    Platt, J. et al. Antitumour effects of genetically engineered Salmonella in combination with radiation. Eur. J. Cancer 36, 2397–2402 (2000).

    CAS  PubMed  Google Scholar 

  125. 125

    Shilling, D. A. et al. Salmonella typhimurium stimulation combined with tumour-derived heat shock proteins induces potent dendritic cell anti-tumour responses in a murine model. Clin. Exp. Immunol. 149, 109–116 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Al-Ramadi, B. K. et al. Attenuated bacteria as effectors in cancer immunotherapy. Ann. N. Y. Acad. Sci. 1138, 351–357 (2008).

    CAS  PubMed  Google Scholar 

  127. 127

    Liu, S. C., Minton, N. P., Giaccia, A. J. & Brown, J. M. Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis. Gene Ther. 9, 291–296 (2002).

    CAS  PubMed  Google Scholar 

  128. 128

    Liu, S. C. et al. Optimized Clostridium-directed enzyme prodrug therapy improves the antitumor activity of the novel DNA cross-linking agent PR-104. Cancer Res. 68, 7995–8003 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Dubois, L. et al. Efficacy of gene therapy-delivered cytosine deaminase is determined by enzymatic activity but not expression. Br. J. Cancer 96, 758–761 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Jazowiecka-Rakus, J. & Szala, S. Antitumour activity of Salmonella typhimurium VNP20047 in B16(F10) murine melanoma model. Acta Biochim. Pol. 51, 851–856 (2004).

    CAS  PubMed  Google Scholar 

  131. 131

    Friedlos, F. et al. Attenuated Salmonella targets prodrug activating enzyme carboxypeptidase G2 to mouse melanoma and human breast and colon carcinomas for effective suicide gene therapy. Clin. Cancer Res. 14, 4259–4266 (2008).

    CAS  PubMed  Google Scholar 

  132. 132

    Fu, W. et al. Synergistic antitumor efficacy of suicide/ePNP gene and 6-methylpurine 2′-deoxyriboside via Salmonella against murine tumors. Cancer Gene Ther. 15, 474–484 (2008).

    CAS  PubMed  Google Scholar 

  133. 133

    Fu, W., Lan, H. K., Liang, S. H., Gao, T. & Ren, D. M. Suicide gene/prodrug therapy using Salmonella-mediated delivery of Escherichia coli purine nucleoside phosphorylase gene and 6-methoxypurine 2′-deoxyriboside in murine mammary carcinoma 4T1 model. Cancer Sci. 99, 1172–1179 (2008).

    CAS  PubMed  Google Scholar 

  134. 134

    Mei, S., Theys, J., Landuyt, W., Anne, J. & Lambin, P. Optimization of tumor-targeted gene delivery by engineered attenuated Salmonella typhimurium. Anticancer Res. 22, 3261–3266 (2002).

    CAS  PubMed  Google Scholar 

  135. 135

    Hayashi, K. et al. Cancer metastasis directly eradicated by targeted therapy with a modified Salmonella typhimurium. J. Cell. Biochem. 106, 992–998 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Hayashi, K. et al. Systemic targeting of primary bone tumor and lung metastasis of high-grade osteosarcoma in nude mice with a tumor-selective strain of Salmonella typhimurium. Cell Cycle 8, 870–875 (2009).

    CAS  PubMed  Google Scholar 

  137. 137

    Dresselaers, T. et al. Non-invasive 19F MR spectroscopy of 5-fluorocytosine to 5-fluorouracil conversion by recombinant Salmonella in tumours. Br. J. Cancer 89, 1796–1801 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Heppner, F. & Mose, J. R. The liquefaction (oncolysis) of malignant gliomas by a non pathogenic Clostridium. Acta Neurochir. (Wien) 42, 123–125 (1978).

    CAS  Google Scholar 

Download references

Acknowledgements

This work was partly supported by the US National Institutes of Health, National Cancer Institute grant CA120825.

Author information

Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Neil S. Forbes's homepage

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Forbes, N. Engineering the perfect (bacterial) cancer therapy. Nat Rev Cancer 10, 785–794 (2010). https://doi.org/10.1038/nrc2934

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing