Cancer-associated fibroblasts (CAFs) play a key role in promoting tumor growth, acting through complex paracrine regulation. GTP cyclohydrolase (GTPCH) expression for tetrahydrobiopterin synthesis in tumor stroma is implicated in angiogenesis and tumor development. However, the clinical significance of GTPCH expression in breast cancer is still elusive and how GTPCH regulates stromal fibroblast and tumor cell communication remains unknown. We found that GTPCH was upregulated in breast CAFs and epithelia, and high GTPCH RNA was significantly correlated with larger high grade tumors and worse prognosis. In cocultures, GTPCH expressing fibroblasts stimulated breast cancer cell proliferation and motility, cancer cell Tie2 phosphorylation and consequent downstream pathway activation. GTPCH interacted with Ang-1 in stromal fibroblasts and enhanced Ang-1 expression and function, which in turn phosphorylated tumor Tie2 and induced cell proliferation. In coimplantation xenografts, GTPCH in fibroblasts enhanced tumor growth, upregulating Ang-1 and alpha-smooth muscle actin mainly in fibroblast-like cells. GTPCH inhibition resulted in the attenuation of tumor growth and angiogenesis. GTPCH/Ang-1 interaction in stromal fibroblasts and activation of Tie2 on breast tumor cells could play an important role in supporting breast cancer growth. GTPCH may be an important mechanism of paracrine tumor growth and hence a target for therapy in breast cancer.
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GTP cyclohydrolase, RTK Tie2, angiopoietin, breast cancer, cancer-associated fibroblasts, 3T3 Cells, Angiopoietin-1, Animals, Biopterin, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Cell Proliferation, Enzyme Activation, Epithelial Cells, Female, GTP Cyclohydrolase, Human Umbilical Vein Endothelial Cells, Humans, Mice, Mice, Inbred BALB C, Mice, SCID, Neoplasm Transplantation, Neovascularization, Pathologic, Phosphorylation, RNA, Messenger, Receptor, TIE-2, Stromal Cells, Tissue Array Analysis, Transplantation, Heterologous