Dataset Information

Intratumoural production of TNF? by bacteria mediates cancer therapy.

ABSTRACT: Systemic administration of the highly potent anticancer therapeutic, tumour necrosis factor alpha (TNF?) induces high levels of toxicity and is responsible for serious side effects. Consequently, tumour targeting is required in order to confine this toxicity within the locality of the tumour. Bacteria have a natural capacity to grow within tumours and deliver therapeutic molecules in a controlled fashion. The non-pathogenic E. coli strain MG1655 was investigated as a tumour targeting system in order to produce TNF? specifically within murine tumours. In vivo bioluminescence imaging studies and ex vivo immunofluorescence analysis demonstrated rapid targeting dynamics and prolonged survival, replication and spread of this bacterial platform within tumours. An engineered TNF? producing construct deployed in mouse models via either intra-tumoural (i.t.) or intravenous (i.v.) administration facilitated robust TNF? production, as evidenced by ELISA of tumour extracts. Tumour growth was impeded in three subcutaneous murine tumour models (CT26 colon, RENCA renal, and TRAMP prostate) as evidenced by tumour volume and survival analyses. A pattern of pro-inflammatory cytokine induction was observed in tumours of treated mice vs.

Controls

Mice remained healthy throughout experiments. This study indicates the therapeutic efficacy and safety of TNF? expressing bacteria in vivo, highlighting the potential of non-pathogenic bacteria as a platform for restricting the activity of highly potent cancer agents to tumours.

SUBMITTER: Murphy C

PROVIDER: S-EPMC5491124 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Intratumoural production of TNFα by bacteria mediates cancer therapy.

Murphy Carola C Rettedal Elizabeth E Lehouritis Panos P Devoy Ciarán C Tangney Mark M

PloS one 20170629 6

Systemic administration of the highly potent anticancer therapeutic, tumour necrosis factor alpha (TNFα) induces high levels of toxicity and is responsible for serious side effects. Consequently, tumour targeting is required in order to confine this toxicity within the locality of the tumour. Bacteria have a natural capacity to grow within tumours and deliver therapeutic molecules in a controlled fashion. The non-pathogenic E. coli strain MG1655 was investigated as a tumour targeting system in o ...[more]

PMID: 28662099

Similar Datasets

Project description:Smac mimetics antagonize IAP proteins, which are highly expressed in several cancers. Recent reports indicate that Smac mimetics trigger a broad cytokine response and synergize with immune modulators to induce cell death. Here, we identify a differential requirement of TRAIL or TNF? as mediators of IFN?/Smac mimetic-induced cell death depending on the cellular context. Subtoxic concentrations of Smac mimetics cooperate with IFN? to induce cell death in various solid tumor cell lines in a highly synergistic manner as determined by combination index. Mechanistic studies show that IFN?/BV6 cotreatment promotes the formation of a caspase-8-activating complex together with the adaptor protein FADD and RIP1. Assembly of this RIP1/FADD/caspase-8 complex represents a critical event, since RIP1 silencing inhibits IFN?/BV6-induced cell death. Strikingly, pharmacological inhibition of paracrine/autocrine TNF? signaling by the TNF? scavenger Enbrel rescues HT-29 colon carcinoma cells, but not A172 glioblastoma cells from IFN?/BV6-induced cell death. By comparison, A172 cells are significantly protected against IFN?/BV6 treatment by blockage of TRAIL signaling through genetic silencing of TRAIL or its cognate receptor TRAIL receptor 2 (DR5). Despite this differential requirement of TNF? and TRAIL signaling, mRNA and protein expression is increased by IFN?/BV6 cotreatment in both cell lines. Interestingly, A172 cells turn out to be resistant to exogenously added recombinant TNF? even in the presence of BV6, whereas they display a high sensitivity towards TRAIL/BV6. In contrast, BV6 efficiently sensitizes HT-29 cells to TNF? while TRAIL only had limited efficacy. This demonstrates that a differential sensitivity towards TRAIL or TNF? determines the dependency on either death receptor ligand for IFN?/Smac mimetic-induced cell death. Thus, by concomitant stimulation of both death receptor systems IFN?/Smac mimetic combination treatment is an effective strategy to induce cell death in TNF?- or TRAIL-responsive cancers.