Abstract
We have recently described antitumor properties of Lactobacillus casei BL23 strain in both a mouse allograft model of human papilloma virus (HPV)-induced cancer and dimethylhydrazine-associated colorectal cancer. However, the mechanisms underlying these beneficial effects are still unknown. Interestingly, in vitro cellular models show that this bacterium is able to stimulate the production of high levels of IL-2. Because this cytokine has well-known antitumor properties, we decided to explore its role in the anti-cancer effects of BL23 using the HPV-induced cancer model. We found a negative correlation between IL-2 and tumor size confirming the necessity of IL-2 to protect from tumor development. Then, we blocked IL-2 synthesis using neutralizing monoclonal antibodies in mice that were challenged with lethal levels of tumor cells; this led to a significant reduction in the protective abilities of BL23. Next, we used a genetically modified strain of Lactococcus lactis to deliver exogenous IL-2 to the system, and in doing so, we were able to partially mimic the antitumor properties of BL23. Additionally, we showed the systemic role of T-cells in tumor protection through a negative correlation between tumor size and T-cells subpopulations and an increasement of BL23-specific local Foxp3 levels in tumor-bearing mice. Finally, we observed a negative correlation between tumor size and NK+ cells, but local recruitment of NK cells and cytotoxic activity appeared specific to BL23 treatment. Taken together, our data suggest that IL-2 signaling pathway plays an important role in the anti-tumoral effects of probiotic strain L. casei BL23. These results encourage further investigation in the use of probiotic strains for potential therapeutic applications to clinical practice, in particular for the treatment of colorectal cancer. Furthermore, our approach could be extended and applied to other potential beneficial microorganisms, such as gut microbiota, in order to better understand the crosstalk between microbes and the host.
Highlights
The Food and Agriculture Organization of the United Nations World Health Organization has defined probiotics as “live microorganisms which, when administered in adequate amounts, confer health benefits on the host” (FAO/WHO, 2002)
In the model of DMH-associated colorectal cancer (CRC) we showed that the defense against cancer demonstrated by L. casei BL23 was associated with the modulation of T-cells toward a Th17-biased immune response, accompanied by the expression of regulatory cytokines (e.g., IL-6, IL-17, IL-10, and TGF-β)
Lactobacillus casei BL23 Has a Protective Effect Against Tumors in the TC-1 Allograft Model of human papilloma virus (HPV)-Induced Cancer
Summary
The Food and Agriculture Organization of the United Nations World Health Organization has defined probiotics as “live microorganisms which, when administered in adequate amounts, confer health benefits on the host” (FAO/WHO, 2002). Some strains of Lactobacillus have been used for centuries in the preservation and production of fermented foods (e.g., yogurt and cheese; (Bernardeau et al, 2008)) and are “Generally Recognized As Safe” by the U.S Food and Drug Administration. These microorganisms exert beneficial health effects on the host, mainly by modulating immune response (Martin et al, 2013). Despite the number of studies that have shown anti-cancer effects of different strains of Lactobacillus (Khazaie et al, 2012; Konishi et al, 2016; Lenoir et al, 2016), the precise host molecular mechanisms of these antitumor properties remain unclear
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