Breast Cancer: Co-Inflammatory Roles of TGFβ are Revealed in the Presence of TNFα and Amplify Pro-Tumoral Traits of Mesenchymal Stem/Stromal Cells

Accumulating evidence substantiates potent pro-malignancy roles for bone marrow-derived mesenchymal stem/stromal cells (MSC) in breast cancer. In parallel, the breast tumor microenvironment (TME) is enriched with inflammatory cytokines such as TNFα, having causative roles in promoting disease course. The breast TME also possesses many immune-suppressive properties that promote tumor growth and progression, including the cytokine TGFβ.

In this study, we investigated the impact of the inflammatory balance between TNFα and TGFβ on pro-malignancy traits of MSC and their functional implications in dictating breast cancer progression. Based on microarray analysis, that was validated at the protein level, we have identified genes that are significantly and prominently up-regulated by both TNFα and TGFβ. Focusing on those genes known as having tumor-promoting activities, we found that TGFβ amplified the ability of TNFα to induce the expression of tumor-promoting mediators in MSC. Our findings propose that TAK1 is an up-stream master-regulator involved in the activation of NF-κB, p38, JNK and SMAD-3, and that the joint activities of TNFα+TGFβ are channeled to activation of p65, then inducing the up-regulation of the tumor-promoting genes.

By applying the conditioned-media of stimulated-MSC to breast cancer cells, we examined the effects of MSC-derived secreted factors on cancer cell-remodeling and motility. Our results indicate that following combined stimulation of MSC by TNFα+TGFβ, the MSC-secreted factors amplify migratory and invasive properties of breast tumor cells.

Our findings indicate that cytokines with seemingly opposing roles, TNFα and TGFβ, act together to promote inflammatory and pro-malignancy traits in MSC and breast tumor cells, and reveal inflammation-supporting activities for TGFβ. In future studies, we will investigate inflammation-MSC interactions, determining their functional implications on disease course.