Abstract
Bacterial cancer therapy relies on the properties of certain bacterial species capable of targeting and proliferating within solid malignancies. If these bacteria could be loaded with antitumor proteins, the efficacy of this approach could be greatly increased. However, because most antitumor proteins are also toxic to normal tissue, they must be expressed by bacteria that specifically target and exclusively localize to tumor tissue. As a strategy for treating solid malignancies, we recently evaluated L-asparaginase (L-ASNase) delivered by tumor-targeted Salmonella. In this system, L-ASNase was expressed under the control of the araBAD promoter (PBAD) of the E. coli arabinose operon, which is induced by injection of L-arabinose. Here, we further improved the performance of recombinant Salmonella in cancer therapy by exploiting the quorum-sensing (QS) system, which uses cell mass-dependent auto-induction logic. This approach obviates the necessity of monitoring intratumoral bacterial status and inducing cargo protein expression by administration of an exogenous compound. Recombinant Salmonella in tumors expressed and secreted active L-ASNase in a cell mass-dependent manner, yielding significant anticancer effects. These results suggest that expression of a therapeutic protein under the control of the QS system represents a promising engineering platform for the production of recombinant proteins in vivo.
Highlights
Bacterial cancer therapy relies on the natural propensity of certain bacteria, including Escherichia coli [1], Salmonella [2], Clostridium [3], and Listeria [4], to accumulate and replicate in various types of tumors [5]
For efficient co-expression of transcriptionally coupled proteins with LuxI, a wellknown ribosome-binding sequence (RBS) from pQE30 was included (Figure 1A). mCherry was deployed as a reporter to test the QS elements
The glmS gene was incorporated into these recombinant plasmids to generate a balanced-lethal host vector system [57] that complemented the phenotype of the GlmS- mutant, which undergoes lysis unless its catalytic product N-acetyl-D-glucosamine is provided or complemented by a GlmS+-containing plasmid. These plasmids were transformed into an avirulent ΔppGpp Salmonella typhimurium, 14028s
Summary
Bacterial cancer therapy relies on the natural propensity of certain bacteria, including Escherichia coli [1], Salmonella [2], Clostridium [3], and Listeria [4], to accumulate and replicate in various types of tumors [5]. In the case of Salmonella typhimurium, the first such strain (VNP20009) used for cancer therapy carried a mutation in msbB, which altered lipid A structure, and purI, to confer purine auxotrophy [6,7,8] Another strain used in this context is the A1-R mutant, a leucine–arginine auxotroph with elevated antitumor activity that arose during selection by tumor passage [9,10,11,12,13,14]. This strain exerts extraordinary antitumor www.impactjournals.com/oncotarget effects in patient-derived orthotopic xenograft mouse models, especially in combination with chemotherapy [15,16,17,18,19,20,21,22,23,24]. This feature is ascribed to the ability of this strain to induce quiescent cancer cells to cycle, rendering them chemosensitive [25, 26]
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