Scutellarin suppresses the metastasis of triple-negative breast cancer via targeting TNFα/TNFR2-RUNX1-triggered G-CSF expression in endothelial cells

by Selleckchem | Nov 13 2023

Triple-negative breast cancer (TNBC) is heterogeneous and aggressive, with high vascularity and frequent metastasis. We have already found natural flavonoid scutellarin (SC) suppressed spontaneous TNBC metastasis via normalizing tumor vasculature in vivo. In this study, supernatant from tumor necrosis factorα (TNFα)-treated human mammary microvascular endothelial cell (HMMEC) promoted cell migration and pseudopod formation in TNBC cells, but these phenomena were disappeared in SC-co-treated HMMEC. TNFα enhanced the expression of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in both HMMEC and human umbilical vein endothelial cell (HUVEC). G-CSF promoted TNBC migration and invasion in vitro, while G-CSF neutralization antibody and SC both inhibited TNBC metastasis in Balb/c mice. SC had no inhibition on the G-CSF-induced TNBC cell migration, but reduced G-CSF content in TNBC tumor tissues and TNFα-stimulated endothelial cells (ECs). SC restricted the nuclear translocation of runt-related transcription factor 1 (RUNX1) in TNBC tumor vessels and TNFα-treated ECs. RUNX1 was found to directly bind to the promoter of G-CSF in TNBC tumor vessels and regulated G-CSF expression. TNF receptor 2 (TNFR2) was crucial for regulating the TNFα-induced RUNX1 activation and G-CSF expression. Notably, SC hindered the interaction between TNFα and TNFR2 via binding to TNFR2. This work demonstrated that SC reduced TNBC metastasis by targeting TNFα/TNFR2-initiated RUNX1 activation and subsequent G-CSF production in TNBC-associated ECs.

Comments:

The study you've described investigates the role of the natural flavonoid scutellarin (SC) in suppressing metastasis in triple-negative breast cancer (TNBC) by targeting the TNFα/TNFR2-initiated RUNX1 activation and subsequent G-CSF production in TNBC-associated endothelial cells (ECs). Here's a breakdown of the key findings and the mechanisms involved:

1. **Background**: TNBC is known for its aggressiveness, heterogeneity, high vascularity, and frequent metastasis. The study aims to understand how SC can inhibit TNBC metastasis by normalizing tumor vasculature and targeting the TNFα/TNFR2 pathway.

2. **Effect of TNFα on TNBC cells and ECs**: The study observed that supernatant from TNFα-treated human mammary microvascular endothelial cells (HMMEC) promoted cell migration and pseudopod formation in TNBC cells. However, when SC was co-treated with HMMEC, these effects were abolished.

3. **Role of G-CSF and GM-CSF**: TNFα was found to enhance the expression of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in both HMMEC and human umbilical vein endothelial cell (HUVEC). G-CSF was shown to promote TNBC migration and invasion in vitro.

4. **Inhibition of TNBC metastasis**: Both G-CSF neutralization antibody and SC were effective in inhibiting TNBC metastasis in Balb/c mice. SC reduced G-CSF content in TNBC tumor tissues and TNFα-stimulated ECs.

5. **Role of RUNX1**: Scutellarin (SC) restricted the nuclear translocation of runt-related transcription factor 1 (RUNX1) in TNBC tumor vessels and TNFα-treated ECs. RUNX1 was found to directly bind to the promoter of G-CSF in TNBC tumor vessels, regulating G-CSF expression.

6. **Role of TNFR2**: TNF receptor 2 (TNFR2) was identified as crucial for regulating TNFα-induced RUNX1 activation and G-CSF expression.

7. **SC's mechanism of action**: SC hindered the interaction between TNFα and TNFR2 by binding to TNFR2. This disruption of the TNFα/TNFR2 interaction played a key role in reducing TNBC metastasis.

In summary, the study provides insights into the mechanisms by which scutellarin (SC) can suppress TNBC metastasis. It does so by targeting the TNFα/TNFR2-initiated RUNX1 activation and subsequent G-CSF production in TNBC-associated endothelial cells (ECs). This research sheds light on potential therapeutic strategies for treating TNBC by modulating the tumor microenvironment and vasculature.