| Tumor angiogenesis is necessary for cancer progression and requires active interaction between endothelial cells and tumor cells. It is well established that cancer cells secrete angiogenic factors to recruit and sustain tumor vascular networks. However, little is known about the effect of endothelial cell-secreted factors on the phenotype and behavior of tumor cells. The identification and characterization of signaling events initiated by tumor-associated endothelial cells may have important implications in cancer therapy. The hypothesis underlying this dissertation is that factors secreted by endothelial cells initiate signaling pathways in head and neck squamous cell carcinoma (HNSCC) cells that enhance tumor growth.;Here, we observed that soluble mediators from primary human dermal microvascular endothelial cells activate STAT3, Akt, and ERK signaling in HNSCC cells. HNSCC cells adjacent to blood vessels showed increased phosphorylation of STAT3, Akt, and ERK in xenograft human tumors. IL-6, CXCL8, and EGF are upregulated in endothelial cells co-cultured with HNSCC, and blockade of endothelial cell-derived IL-6, CXCL8, or EGF inhibited the activation of STAT3, Akt, or ERK in tumor cells, respectively. Notably, activation of these pathways by endothelial cells enhanced migration and inhibited anoikis of tumor cells. It is known that Bc1-2 is upregulated in tumor microvessels of patients with HNSCC. Here, we observed that Bcl-2 signaling induces expression of IL-6, CXCL8, and EGF, providing a mechanism for the upregulation of these cytokines in tumor-associated endothelial cells.;We also observed that endothelial cell-induced Akt or ERK signaling in HNSCC has a compensatory effect whereas STAT3 pathway is activated independent of Akt or ERK. Among these three pathways, STAT3 presented the higher phosphorylation levels, and was mainly induced by endothelial cell-secreted IL-6. Interestingly, downregulation of IL-6 in tumor-associated endothelial cells inhibited tumor growth in xenograft human tumors. These results suggest that patients with HNSCC might benefit from targeted inhibition of signaling events initiated by tumor associated-endothelial cells.;Collectively, this work expands the contribution of vascular endothelial cells to the pathobiology of cancer. It shows that endothelial cells function as the initiators of molecular signaling events that enhance head and neck tumor growth. |
