Editors' ChoiceSYNTHETIC BIOLOGY

A probiotic for treating cancer

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Science Translational Medicine  17 Jul 2019:
Vol. 11, Issue 501, eaay3576
DOI: 10.1126/scitranslmed.aay3576

Abstract

A probiotic engineered to express a fusion of two tumor-inhibiting proteins shows targeted anticancer activity in mice.

The futurist Ray Kurzweil famously predicted that autonomous nanobots, swimming in their millions in our bodies and keeping disease at bay, will be staples of medicine by 2030. Replace “autonomous nanobots” with “engineered bacteria” and Kurzweil’s prediction might be nearer than you think. Earlier this year, a probiotic E. coli strain that had been engineered to treat hyperammonemia successfully completed phase I clinical testing. Now, He and colleagues from the Hunan Normal University report remarkable growth inhibition and reduction in the volume of solid tumors of human hepatocellular carcinoma cells in mice using a strain of the probiotic E. coli Nissle 1917 (EcN).

EcN was engineered to express and secrete a fusion protein of two tumor inhibiting proteins—the active fragment of the antiangiogenic protein tumstatin (Tum-5) and the tumor suppressor protein p53—directly into the tumor microenvironment. The authors tagged Tum-5 to the small ubiquitin-like modifier (SUMO) chaperonin at its N terminus to facilitate folding and improve solubilization, and p53 was tagged with the transduction domain of azurin (p18) at its N terminus to promote its penetration into the tumor cells. The authors expressed the fusion protein downstream of the signaling domain of pectate lyase B (pelB) of E. carotovora to ensure that it localized to and was eventually secreted from the bacterial periplasm. The coding sequence of the fusion protein was introduced into EcN on a plasmid under the control of the hypoxia-responsive transcriptional promoter of the Vitreoscilla hemoglobin gene, Pvhb. The authors also introduced a matrix metalloproteinase (MMP) cleavage site between SUMO–Tum-5 and p18-p53 for effective detachment within the tumor and subsequent translocation to their intended sites of action.

The authors observed that the fusion protein was only soluble when p18-p53 was located at the C terminus of the complex. Nevertheless, when tumor-bearing mice were injected with EcN cells expressing the engineered fusion, the tumor volume reduction and inhibition rate were as high as 69.5% and 62.5%, respectively, over three weeks. Moreover, the bacteria only accumulated within the hepatocellular tumors in the mice (not in healthy tissue) after intravenous injection. Tumor inhibition was achieved through upregulation of caspase-3 and down-regulation of antigen Ki-67. Still, some questions remain—notably, whether fusing the tumor-inhibiting proteins together is necessary and whether the strategy could be used to target other solid tumors. Nevertheless, this work has laid a strong foundation for the heterologous expression of human therapeutic proteins by probiotic strains and high precision gene therapy for targeted cancer treatment.

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