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.