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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.

Original publication

DOI

10.18632/oncotarget.6981

Type

Journal article

Journal

Oncotarget

Publication Date

02/2016

Volume

7

Pages

9353 - 9367

Addresses

Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.

Keywords

Cell Line, Tumor, 3T3 Cells, Stromal Cells, Epithelial Cells, Animals, Mice, Inbred BALB C, Humans, Mice, Mice, SCID, Breast Neoplasms, Neovascularization, Pathologic, Biopterin, GTP Cyclohydrolase, Receptor, TIE-2, Angiopoietin-1, RNA, Messenger, Transplantation, Heterologous, Tissue Array Analysis, Neoplasm Transplantation, Cell Proliferation, Cell Movement, Enzyme Activation, Phosphorylation, Female, Human Umbilical Vein Endothelial Cells