Salmonella-Mediated Cancer Therapy: An Innovative Therapeutic Strategy

Abstract

Bacterial-mediated cancer therapy (BMCT) has become a hot topic in the area of antitumor treatment. Salmonella has been recommended to specifically colonize and proliferate inside tumors and even inhibit tumor growth. Salmonella typhimurium (S. typhimurium) is one of the most promising mediators, which can be easily manipulated. S. typhimurium has been engineered and designed as cancer-targeting therapeutics, and can be improved by combining with other therapeutic methods, e.g. chemotherapy and radiotherapy, which regulate the tumor microenvironment synergistically. In view of all these strengths, the engineered attenuated strains have significant advantages for tumor diagnosis and treatment. This treatment has also been approved by the FDA for clinical trial. In this review, we summarized the recent progress and research in the field of Salmonella -mediated cancer therapy.

Keywords: Salmonella; bacterial-mediated cancer therapy; combination therapy; tumor microenvironment.

Figure 1

Schematic depiction of Salmonella-mediated cancer therapy. When administered to tumor-bearing animals, the bacteria will preferentially accumulate within tumors, especially in the nonhypoxic and hypoxic regions. Then, this treatment could obviously shrink the tumors and prolong life survival in animal models.

Figure 2

Schematic depiction of combination therapy for Salmonella. Salmonella could affect P-glycoprotein (P-gp) by the caspase-3 (casp-3) pathway or gap junctions, connexin 43 (Cx43), of cancer cells to enhance chemosensitivity. The underlying mechanisms of Salmonella overcome radioresistance in cancers. Salmonella changed the tumor microenvironment by hypoxia, stroma, and immune modulation to enhance radiotherapy-induced cancer cell damage.

Figure 3

Combination of Salmonella and photothermal therapy in vivo. (A) Tumor volume after the indicated treatments. (B) Survival of mice after the indicated treatments. (C) Infrared thermal images of mice after the intravenous injection of pDA-VNP, followed by irradiation with a near-infrared laser (*P < 0.05; **P < 0.01; ***P < 0.001; ****P<0.0001; #P < 0.05; ##P < 0.01; ###P < 0.001; ####P < 0.0001). Reproduced with permission from , copyright 2018 American Chemical Society.

Figure 4

(A-C) Systemic injection of Salmonella (ΔppGpp) into tumor-bearing mice induces significant growth suppression compared with the effects of Escherichia coli (E. coli) (MG1655) injection . (D) Systemic injection of Salmonella (VNP) into tumor-bearing mice induces significant growth suppression in histological examination . (A) Distribution of bacteria visualized by in vivo bioluminescence imaging after the injection of bacteria expressing bacterial luciferase (lux). (B) The tumor volume was obviously decreased in the ΔppGpp group compared with that in the other groups. (C) The shape of the tumor was noted before (0 days) and after treatment with PBS or bacteria (2 and 5 days). (D) Histologically, the tumors treated with VNP therapy showed extensive necrosis compared with the untreated control. N: necrotic areas, V: viable tumor cells. Reproduced with permission from , , copyright 2015, 2016 Ivyspring International Publisher.

Figure 5

Diagram showing the main antitumor mechanisms induced by Salmonella. (A) Salmonella infection within the tumor microenvironment results in tumor growth inhibition and cell death. (B) Salmonella significantly upregulates IFN-γ and IFN-inducible chemokines to recruit NK cells and T cells to inhibit tumors. (C) Salmonella activates macrophages or dendritic cells by bacterial components. Then, these cells stimulate T cell activities and cytokine expression. (D) Salmonella can lead to the death of tumor cells by inducing apoptosis and autophagy to activate caspase or downregulating the AKT/mTOR signaling pathway. Then, it will generate IL-1β and IL-18 to antitumors.

Figure 6

Immune cell activation of melanoma tumors following intraperitoneal treatment with a S. typhimurium strain. (A) Decreased tumor weights (B-G) Salmonella-treated mice obviously showed the increased percentage and absolute counts of tumor-infiltrating leukocytes (TIL), CD8+ T cells and CD4+ T cells. Reproduced with permission from , copyright 2018 Kaimala, Al-Sbiei, Cabral-Marques, Fernandez-Cabezudo and Al-Ramadi.

Figure 7

Transmission electron microscopy (TEM) of tumor cells infected with S. typhimurium at 1 h (A-D), 4 h (E-G), and 8 h (H, I) displaying various degrees of mitochondria destruction as a result of Salmonella infection. Mitochondria are shown in which cristae are destroyed gradually, leaving a large empty space and vacuole. Tumor cells eventually become apoptotic over time. Reproduced with permission from , copyright 2007 Cambridge University Press