The Transcription Factor SOX18 Inhibitor Small Molecule 4 Is a Potential Treatment of Cancer-Induced Lymphatic Metastasis and Lymphangiosarcoma.

BACKGROUND: Malignant tumors release growth factors, promoting lymphangiogenesis in primary tumors and draining sentinel lymph nodes, ultimately facilitating lymph node metastasis. As a malignant lymphatic tumor entity, lymphangiosarcomas are characterized by low survival rates and limited treatment options. The transcription factor SOX18 plays a crucial role in both lymphatic endothelial cell differentiation and cancer-induced lymphangiogenesis. AIMS: In this in vitro study, we investigated the potential therapeutic effect of a small molecule called Sm4, which inhibits SOX18, on lymphatic endothelial and lymphangiosarcoma cells in vitro. METHODS AND RESULTS: Human dermal lymphatic endothelial cells (HDLECs), lymphangiosarcoma cells (MO-LAS), and other endothelial cell lines were cultured. We found that Sox18 exhibited high mRNA expression levels in both HDLEC and MO-LAS. Sm4 treatment decreased the Sox18 expression level at the mRNA and protein levels in both HDLEC and MO-LAS significantly, a phenomenon confirmed through immunofluorescence images. Additionally, Sm4 treatment suppressed the expression of key lymphatic phenotype markers (Prox1, Flt4, and Lyve1) and hindered migration in both HDLEC and MO-LAS, all while maintaining cell viability. CONCLUSION: These findings suggest that targeting SOX18 with Sm4 may hold potential as a therapeutic strategy for lymphangiosarcoma and cancer-induced lymphatic metastasis. Further in vitro studies are warranted to investigate the mechanisms and conduct dose-response analyses to evaluate Sm4's potential as a targeted therapy for lymphangiosarcoma and cancer-induced lymphangiogenesis in the future.