Targeted therapy via oral administration of attenuated Salmonella expression plasmid-vectored Stat3-shRNA cures orthotopically transplanted mouse HCC

Abstract

The development of RNA interference-based cancer gene therapies has been delayed due to the lack of effective tumor-targeting delivery systems. Attenuated Salmonella enterica serovar Typhimurium (S. Typhimurium) has a natural tropism for solid tumors. We report here the use of attenuated S. Typhimurium as a vector to deliver shRNA directly into tumor cells. Constitutively activated signal transducer and activator of transcription 3 (Stat3) is a key transcription factor involved in both hepatocellular carcinoma (HCC) growth and metastasis. In this study, attenuated S. Typhimurium was capable of delivering shRNA-expressing vectors to the targeted cancer cells and inducing RNA interference in vivo. More importantly, a single oral dose of attenuated S. Typhimurium carrying shRNA-expressing vectors targeting Stat3 induced remarkably delayed and reduced HCC (in 70% of mice). Cancer in these cured mice did not recur over 2 years following treatment. These data demonstrated that RNA interference combined with Salmonella as a delivery system may offer a novel clinical approach for cancer gene therapy.

Delivery of the co-expression plasmid pEndo-Si-Stat3 by attenuated Salmonella serovar typhimurium for prostate cancer treatment

“…Regardless of the route of administration (i.e., oral, intravenous, intratumoral or intraperitoneal inoculation), Salmonella -delivered therapy resulted in significant anti-tumor effects with no evident toxicity in the mouse models (Kimura et al 2010; Liu et al 2010; Momiyama et al 2012; Zhao et al 2001, 2006, 2007). Our previous experimental findings and those of other reports (Tian et al 2012; Pawelek et al 1997; Low et al 1999) show that attenuated S. typhimurium can specifically home to tumor cells, possibly via tumor-associated macrophages. The Endostatin and Si-Stat3 combination therapy also activates anti-tumor immune responses (Jia et al 2012).…”

Use of Bacteria in Cancer Therapy (Review)

“…Второй методический подход предполагает использование бактерий, которые в процессе колонизации опухолей способны сами продуцировать и секретировать терапевтически активные субстанции, например бактериальные токсины (α-гемолизин [21,56]), рекомбинантные эффекторные белки (mTNF-α, rIL-2 [57]), малые шпилечные молекулы РНК (shRNA [58,59]).…”

Shaping cancerous landscapes with microbial communities

“…The second approach concerns production and subsequent secretion of therapeutically active compounds by the bacteria themselves during tumor colonization. Therapeutic molecules include bacterial toxins like α-Hemolysin or Azurin [36,37], recombinant effector proteins such as TNF-α and IL-2 [38], or small hairpin RNAs [39] (shRNAs) targeting, for instance, STAT3 (in case of Hepatocellular Carcinoma) [40] or IDO (in case of melanoma) [41]. The transport of these molecules across bacterial membranes to the extracellular environment around or within the tumor is critical.…”