Research ArticleExperimental Studies
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Accurate and Safe Tumor Targeting of Orally-administered Salmonella typhimurium A1-R Leads to Regression of an Aggressive Fibrosarcoma in Nude Mice

SEI MORINAGA, MING ZHAO, KOHEI MIZUTA, BYUNG MO KANG, MOTOKAZU SATO, MICHAEL BOUVET, NORIO YAMAMOTO, KATSUHIRO HAYASHI, HIROAKI KIMURA, SHINJI MIWA, KENTARO IGARASHI, TAKASHI HIGUCHI, HIROYUKI TSUCHIYA, SATORU DEMURA and ROBERT M. HOFFMAN
In Vivo November 2024, 38 (6) 2601-2609; DOI: https://doi.org/10.21873/invivo.13736

Abstract

Background/Aim: Salmonella typhimurium A1-R has been shown to target and inhibit many types of cancers in mouse models without continuous infection of normal tissue. The objective of the present study was to determine the effective dose of orally-administered Salmonella typhimurium A1-R, expressing-green fluorescent protein (GFP), on an HT1080 human-fibrosarcoma nude-mouse model. Materials and Methods: The HT1080-human- fibrosarcoma nude-mouse models were randomized into the following three groups: G1: untreated control; G2: Oral Salmonella typhimurium A1-R (5×107 colony forming units [CFU]/body, twice a week, 2 weeks); G3: Oral Salmonella typhimurium A1-R (3.3×108 CFU/body, twice a week, 2 weeks). Each group comprised five mice. Body weight and tumor volume were measured twice a week. The number of colonies of Salmonella typhimurium A1-R-GFP in excised tumors and excised livers in groups G2 and G3 were determined on day 3, day 7 and 14 by growth on agar plates. Tukey-Kramer analysis was used to examine the relationships between variables. Statistically-significant results are defined as those with p≤0.05. Results: Salmonella typhimurium A1-R was administered orally at a dose of 3.3×108 CFU, which successfully regressed the HT1080 tumor in nude mice. However, this effect was not observed at a lower dose of 5×107 CFU. After administering Salmonella typhimurium A1-R at 3.3×108 CFU, tumors and liver tissues were harvested, homogenized, and cultured on days 3, 7 and 14. Resulting GFP-expressing Salmonella typhimurium A1-R colonies were then counted. The number of GFP-bacterial colonies derived from excised tumors at intervals of 3, 7, and 14 days increased over time post-administration of oral GFP-Salmonella typhimurium. Conversely, the number of GFP-Salmonella typhimurium A1-R colonies that could be grown from excised livers decreased over time, following oral administration of GFP-Salmonella typhimurium. Additionally, the GFP-bacterial colonies grown from the excised tumors were significantly larger than those grown from the excised livers. Conclusion: The present study showed that an aggressive fibrosarcoma could be regressed by orally-administered Salmonella typhimurium A1-R which accurately targeted tumors without continuous growth in normal organs. The present results suggested the potential of orally-administered Salmonella typhimurium A1-R as a probiotic to treat aggressive soft-tissue sarcoma.

Key Words:

It has been reported, over at least two hundred years, that some cancer patients, who survived a bacterial infection, experienced remission of their cancer. At the end of the 19th century and the beginning of the 20th century, William B. Coley first used live bacteria and subsequently killed bacteria (Coley’s toxins) as first-line therapy for sarcoma and other recalcitrant cancers with much success (1-3). Unfortunately, bacterial therapy of cancer was arbitrarily halted in 1930’s. In recent decades, a number of different bacteria types, such as Bifidobactum and Clostridium, which are absolute anaerobes, were tested for cancer therapy with mixed results in mouse models (4-6).

Salmonella is a facultative anaerobe and it was shown to be promising as an anticancer agent, such as Salmonella typhimurium VNP20009, which however, failed in a clinical trial (7).

We have developed tumor-targeting Salmonella typhimurium A1-R labeled with green fluorescent protein (GFP), with auxotrophic mutations for leucine and arginine, which preclude continuous infection in normal organs. Salmonella typhimurium A1-R has a wide range of efficacy against all major tumor types with minimal negative side-effects (8). Salmonella typhimurium A1-R demonstrated significant efficacy in treating primary and metastatic cancer when injected by various routes in mouse models of major cancer types (8-47).

Jia et al. (48, 49) showed that Salmonella typhimurium VNP20009 could be effectively administered orally, and it slowed tumor growth but did not regress the tumor.

The objective of the present study was to determine the effective dose of oral Salmonella typhimurium A1-R on an HT1080-human-fibrosarcoma nude-mouse model.

Materials and Methods

Mice. Nude mice (4-6 weeks, athymic nu/nu; AntiCancer Inc., San Diego, CA, USA) were used. All studies were conducted with an AntiCancer Institutional Animal Care and Use Committee protocol specifically approved for this study and followed the principles and procedures in the National Institutes of Health Guide for the Care and Use of Animals. All experiments were conducted in compliance with Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines 2.0.

Cells. The HT1080 human fibrosarcoma cells were acquired from the American Type Culture Collection (Manassas, VA, USA). The cells were cultivated in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1 IU/ml penicillin/streptomycin.

Preparation of Salmonella typhimurium A1-R. GFP-expressing Salmonella typhimurium A1-R (AntiCancer Inc.,) were grown overnight in Luria-Bertani (LB) medium (Fisher Sci., Hanover Park, IL, USA) containing ampicillin and then diluted 1:10 in LB medium for further growth. Bacteria were harvested at late-log phase, washed with phosphate buffered sodium (PBS), and then diluted in PBS (50).

Establishment of HT-1080 subcutaneous tumors for experiments. Nude mice were injected subcutaneously with HT1080 cells (106) in the right flank. One month after injection, subcutaneous tumors were established. The subcutaneously-grown tumors were harvested and minced into 3-4 mm3 fragments and implanted into the right flank of nude mice. Two weeks later, subcutaneous tumors for experiments were established.

Quantification of Salmonella typhimurium A1-R in tumors and organs over time after oral administration. Mice bearing HT1080 tumors (n=3 for each group) were given 5×107 or 3.3×108 colony forming units (CFU) of Salmonella typhimurium A1-R, in 100 μl by oral gavage twice a week after the subcutaneous HT1080 tumors had grown. The subcutaneous tumors and livers were removed after 72 h, one week, and two weeks. Tumors and livers were harvested and homogenized, and supernatants were plated on LB agar with ampicillin. The number of CFU of Salmonella typhimurium A1-R-GFP per gram of tumor or organ was calculated.

Treatment study protocol. The HT1080 nude mouse models were randomized into three groups when the tumor volume was over 100 mm3: Group 1: untreated control mice; Group 2: Salmonella typhimurium A1-R-treated mice [oral administration (PO), 5×107 CFU Salmonella typhimurium A1-R-in 100 μl PBS (twice a week, for two weeks)]; Group 3: Salmonella typhimurium A1-R treated mice [PO, 3.3×108 CFU Salmonella typhimurium A1-R in 100 μl PBS (twice a week, for two weeks)]. Each group comprised five mice, respectively. Tumor size and body weight were measured twice a week. Tumor volume was calculated using the following formula: tumor volume (mm3)=length (mm)×width (mm)×width (mm)×1/2.

Statistical analysis. Statistical analysis was performed using EZR software, developed by the Saitama Medical Center and Jichi Medical University in Saitama, Japan (51). Tukey-Kramer analysis was employed to examine the relationships between variables. Statistically-significant results were defined as those with p-values ≤ 0.05.

Results

Quantification of GFP-Salmonella typhimurium A1-R in the tumor and the liver. Tumors and livers were harvested on days 3, 7 and 14 from nude mice treated with an oral dose of 3.3×108 CFU Salmonella typhimurium A1-R. GFP-Salmonella typhimurium A1-R colonies in agar culturre, grown from tumors excised over time, increased after oral administration of Salmonella typhimurium A1-R. In contrast, the number of GFP-Salmonella typhimurium A1-R colonies that could be grown from livers excised over time, decreased after oral administration of Salmonella typhimurium A1-R (Figure 1).

Figure 1.
Figure 1.

Quantification of Salmonella typhimurium A1-R cultured from excised tumors and livers over time after oral administration to nude mice with HT-1080 tumors. The tumors and livers were removed from mice at 3 days, 7 days, and 14 days after oral administration of Salmonella typhimurium A1-R. CFU: Colony forming units.

The GFP-Salmonella typhimurium A1-R colonies from the tumors were much larger than colonies from the liver (Figure 2). Tumor regression by Salmonella typhimurium A1-R. The HT1080 tumor volume regressed in nude mice treated orally with 3.3×108 CFU Salmonella typhimurium A1-R. In contrast oral Salmonella typhimurium A1-R did not regress the HT-1080 tumors in nude mice after treatment with 5×107 CFU (Figure 3). There was no body weight loss in any group (Figure 4).

Figure 2.
Figure 2.

Representative images of GFP-labeled Salmonella typhimurium A1-R isolated and cultured from the liver and HT-1080 fibrosarcoma tumor of nude mice on day 7 after oral administration of tthe bacteria (A) Bright field image of Salmonella typhimurium A1-R colonies from the liver of mice administered 3.3×108 Salmonella typhimurium A1-R twice a week PO for two weeks; (B) Fluorescence image of A; (C) Bright field image of Salmonella typhimurium A1-R colonies from the HT-1080 tumor in mice-orally administered 3.3×108 Salmonella typhimurium A1-R twice a week PO for two weeks; (D) Fluorescence image of C. PO: Oral administration.

Figure 3.
Figure 3.

(A) Time course efficacy of orally-administered Salmonella typhimurium A1-R on HT1080 tumors in nude mice. (B) HT1080 tumor volume on day 14. Data are shown as the mean±standard deviation. A1-R: Salmonella typhimurium A1-R.

Figure 4.
Figure 4.

Effect of oral administration of Salmonella typhimurium A1-R on body weight of nude mice with HT1080 tumors. Data are shown as the mean±standard deviation. G1: untreated control; G2: Oral Salmonella typhimurium A1-R (5×107 CFU/body, twice a week, 2 weeks); G3: Oral Salmonella typhimurium A1-R (3.3×108 CFU/body, twice a week, 2 weeks).

Discussion

Salmonella typhimurium A1-R is an autotrophic strain of Salmonella typhimurium established by our laboratory that requires leucine and arginine to grow. It can survive with or without oxygen and has the ability to selectively grow in all types of tumors tested (8-47).

Many types of bacterial species have demonstrated the ability to specifically target and eliminate cancers. Salmonella typhimurium A1-R can can target and grow in tumors and stimulate T-cell infiltration into the tumor (47).

Our prior experiments have demonstrated that Salmonella typhimurium A1-R has the ability to directly kill cancer cells in vitro (8, 15). Salmonella typhimurium A1-R also eradicates tumor blood vessels (14). Salmonella typhimurium A1-R can decoy quiescent cancer cells to transition from G0/G1 phase to S/G2/M phase and therefore enhances the susceptibility of cancer cells to chemotherapy (20, 33).

Oral administration of another strain of Salmonella typhimurium, VNP20009 was described as safe and effective on a syngeneic mouse model of cancer (48, 49). Zhang et al. investigated the optimal route of administration of Salmonella typhimurium A1-R to target breast cancer in nude mice (11). However, the dose of oral Salmonella typhimurium A1-R of 2×108 CFU did not significantly decrease the tumor volume more than the untreated control, although the number of colonies in liver and spleen was lower compared to intravenous injection and intraperitoneal injection.

In the present study, the effective dose of oral Salmonella typhimurium A1-R was 3.3×108 CFU for an HT1080 nude-mouse model. The number of Salmonella typhimurium A1-R colonies that could be cultured from excised tumors increased over time and decreased in the excised livers with eventual elimination.

The present study used athymic (nu/nu) nude mice as host for HT1080 fibrosarcoma cells. Salmonella typhimurium A1-R directly targets cancer cells (8-10). Tumor targeting by Salmonella typhimurium A1-R is poorly understood. In part, the targeting mechanism may be due to the leucine-arginine auxotrophy of Salmonella typhimurium A1-R (8-10), whereby, the tumor provides a nutrition-rich environment with the presence of sufficient amounts of these two amino acids, in contrast to normal tissue (8-10). Tumor necrosis factor-α (TNF-α) in tumor vessels may play a role in tumor targeting by Salmonella typhimurium (52). Chemotaxis of Salmonella toward tumors has been observed (53, 54). Further research is necessary to learn more about the mechanism of tumor targeting by Salmonella typhimurium A1-R.

The present study showed that an aggressive fibrosarcoma could be regressed by orally-administered Salmonella typhimurium A1-R which accurately targeted the tumors. The present results suggest the potential of orally-administered Salmonella typhimurium A1-R as a probiotic to treat aggressive soft-tissue sarcoma.

Acknowledgements

This paper is dedicatd to the memory of A.R. Moossa, MD, Sun Lee, MD, Professor Gordon H. Sato, Professor Li Jiaxi, Masaki Kitajima, MD, Shigeo Yagi, Ph.D., Jack Geller, MD, Joseph R Bertino, MD, J.A.R. Mead, PhD, Eugene P. Frenkel, MD, Professor Lev Bergelson, Professor Sheldon Penman, Professor John R. Raper, John Mendelsohn, MD and Joseph Leighton, MD.

Footnotes

  • Authors’ Contributions

    SM and RMH designed the study. SM performed experiments. SM was a major contributor to writing the manuscript and RMH revised the paper. MZ, KM, BMK, MS, MB, NY, KH, HK, SM, KI, TH, HT and SD critically read and approved the final manuscript.

  • Conflicts of Interest

    The Authors declare no competing interests.

  • Received June 14, 2024.
  • Revision received July 16, 2024.
  • Accepted July 30, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Accurate and Safe Tumor Targeting of Orally-administered Salmonella typhimurium A1-R Leads to Regression of an Aggressive Fibrosarcoma in Nude Mice
SEI MORINAGA, MING ZHAO, KOHEI MIZUTA, BYUNG MO KANG, MOTOKAZU SATO, MICHAEL BOUVET, NORIO YAMAMOTO, KATSUHIRO HAYASHI, HIROAKI KIMURA, SHINJI MIWA, KENTARO IGARASHI, TAKASHI HIGUCHI, HIROYUKI TSUCHIYA, SATORU DEMURA, ROBERT M. HOFFMAN
In Vivo Nov 2024, 38 (6) 2601-2609; DOI: 10.21873/invivo.13736
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