PDF file - 524KB, Supplementary Figure 1. Endothelial cell-secreted EGF induces phenotypic changes consistent with EMT in head and neck squamous cell carcinoma cells. Supplementary Figure 2. Endothelial cell-secreted factors enhance the motility of HNSCC. Supplementary Figure 3. Endothelial cell-secreted factors activate STAT3, Akt and ERK signaling. Supplementary Figure 4. Endothelial cell-secreted EGF induces Snail expression via PI3K/Akt signaling. Supplementary Figure 5. EGF enhances the fraction of cancer stem-like cells. Supplementary Figure 6. Endothelial cell-secreted EGF dose not increase blood vessel density in tumors in vivo.
ARTICLE ABSTRACTEmerging evidence suggests that endothelial cell-secreted factors contribute to the pathobiology of squamous cell carcinoma (SCC) by enhancing invasive migration and resistance to anoikis. Here, we report that SCC cells within the perivascular niche have undergone epithelial to mesenchymal transition (EMT) in a primary human SCC of a patient that developed distant metastases. Endothelial cell–secreted EGF induced EMT of human SCC cells in vitro and also induced acquisition of a stem-like phenotype. In vivo, tumor xenografts vascularized with EGF-silenced endothelial cells exhibited a smaller fraction of cancer stem-like cells (ALDH+CD44+) and were less invasive than tumors vascularized with control endothelial cells. Collectively, these results demonstrated that endothelial cell-EGF induces EMT and acquisition of stem-like properties by head and neck tumor cells. On this basis, we suggest that vascular endothelial cells contribute to tumor dissemination by secreting factors that endow carcinoma cells with enhanced motility and stemness. Cancer Res; 74(10); 2869–81. ©2014 AACR.