Beneficial effect of probiotic fermented milk is mediated by modulation of host immune response in mice bearing breast cancer or metastasis

G. PERDIGON; E. MENDEZ UTZ; A. DE MORENO DE LEBLANC

San Miguel de Tucuman

Simposio; SIBAL 2016 - V Simposio Internacional de Bacterias Lácticas; 2016

SIBAL 2016

Metastasis from breast cancer are associated to high mortality rate worldwide. The host immune system plays an important role against cancer and metastasis. Immune cells produce cytokines to inhibit or to decrease tumor growth. However, tumor cells also stimulate the production of cytokines and growth factors which favour their growth and metastasis. It was reported that administration of milk fermented by Lactobacillus casei CRL431 (probiotic fermented milk, PFM) to mice bearing breast cancer diminished tumor growth and lung metastasis. The aim of this study was to evaluate the effect of PFM administration on certain cytokines modulated by 4T1 breast cancer cells in a mouse model. Mice were injected subcutaneously with 4T1 cells to induce mammary tumors, and mice without tumor induction were healthy controls. Ten mice that developed tumor (1cm3 of volume) were randomly divided into two groups: PFM group and milk group, according they received PFM or milk during 21 days. To evaluate metastasis, ten other tumors (1cm3 of volume) were surgically removed; mice were separated into two groups (PFM group and milk group) and euthanized after 70-80 days. Host immune response was evaluated through the cytokines produced by splenocytes and their concentrations in serum. Splenocytes from tumor bearing and healthy mice were incubated with or without 4T1 cells and 4T1 conditioned medium (CM). In the model of mice bearing tumor, PFM decreased tumor volume compared to milk group. Splenocytes from milk group did not modify significantly the release of IFNγ when they were cultured with different stimuli and at different time points (24 and 48h). At difference, splenocytes from PFM group increased significantly the concentrations of IFNγ, in all culture conditions, compared to milk group. The highest IFNγ levels were obtained after 24h with 4T1 stimulation (without CM), showing the presence of regulatory factors in the CM, as was reported previously. Healthy mice given PFM increased also significantly the production of IFNγ by splenocytes (in co-cultures with 4T1 cells), compared to milk group. Similar results between groups were obtained for TNFα production, especially in 24h cultures. In metastasis model; milk group showed an inflammatory systemic response (associated to metastasis) with increased serum concentrations of IL17, TNFα, IFNγ and IL-6. Mice from PFM group decreased these pro-inflammatory cytokines; only IFNγ was maintained significantly increased compared to milk group. In conclusion, our results show that beneficial effects of PFM in mice bearing breast tumor and metastasis was associated to changes on the host immune response, which was modified by tumor cells to favour tumor growth and metastasis.