Angiogenic inhibitors delivered by the type III secretion system of tumor-targeting Salmonella typhimurium safely shrink tumors in mice

Abstract

Despite of a growing number of bacterial species that apparently exhibit intrinsic tumor-targeting properties, no bacterium is able to inhibit tumor growth completely in the immunocompetent hosts, due to its poor dissemination inside the tumors. Oxygen and inflammatory reaction form two barriers and restrain the spread of the bacteria inside the tumors. Here, we engineered a Salmonella typhimurium strain named ST8 which is safe and has limited ability to spread beyond the anaerobic regions of tumors. When injected systemically to tumor-bearing immunocompetent mice, ST8 accumulated in tumors at levels at least 100-fold greater than parental obligate anaerobic strain ST4. ST8/pSEndo harboring therapeutic plasmids encoding Endostatin fused with a secreted protein SopA could target vasculature at the tumor periphery, can stably maintain and safely deliver a therapeutic vector, release angiogenic inhibitors through a type III secretion system (T3SS) to interfere with the pro-angiogenic action of growth factors in tumors. Mice with murine CT26 colon cancer that had been injected with ST8/pSEndo showed efficient tumor suppression by inducing more severe necrosis and inhibiting blooding vessel density within tumors. Our findings provide a therapeutic platform for indirectly acting therapeutic strategies such as anti-angiogenesis and immune therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13568-016-0226-8) contains supplementary material, which is available to authorized users.

Salmonella Typhimurium Treated by Gamma Radiation as an Approach for Cancer Management

“…The treatment with S. typhimurium.WT. exposed to 1kGy improved the outcome in solid tumor regression, and induces apoptotic process through caspase-3 activation [30] . This is consistent with our previous results which reveals that S. typhimurium may activate specific apoptotic enzymes including caspase-3 through S. typhimurium effector SipA.…”

“…The Hematoxylin and Eosin (H & E) staining of tumor tissues showed that the Salmonella typhimurium colonization in mice solid tumor resulted in a sharper increase in the number of necrotic solid tumor cells [30,32] .…”

Manipulating the type VI secretion system spike to shuttle passenger proteins

“…In particular, it was previously attempted to use the type III secretion system to deliver specific molecules into an appropriate environment. One example is the T3SS-dependent delivery of angiogenesis inhibitors by Salmonella, which proved significant anti-tumoral activity on mice colon carcinoma [57]. As such, bacterial secretion devices able to deliver proteins directly into the cytosol of human cells are considered the shuttles of choice when developing targeted medicine strategies [58].…”

Rationale redesign of type III secretion systems: toward the development of non-pathogenic E. coli for in vivo delivery of therapeutic payloads

“…In the case of Salmonella T3SS heterologous antigen delivery strains, attenuation has primarily been achieved through the use of strains either that are defective in the biosynthesis of essential nutrients [3,4,10,13,15,16,19] or that lack a major virulence regulatory factor [5,6]. While in the case of the similarly repurposed Pseudomonas strains, one that no longer secretes any effectors has been used [12].…”