title: Paracrine effect of GTP cyclohydrolase and angiopoietin-1 interaction in stromal fibroblasts on tumor Tie2 activation and breast cancer growth.
abstract: 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.
authors.affiliation: Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Liye
authors.initials: L
authors.lastname: Chen
authors.affiliation: Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.|Current address: Xiamen Institute for Diabetes Research, The First Affiliated Hospital of Xiamen University, Xiamen, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Esther
authors.initials: E
authors.lastname: Kleibeuker
authors.affiliation: Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Buffa
authors.affiliation: Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Barberis
authors.affiliation: Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Russell D
authors.initials: RD
authors.lastname: Leek
authors.affiliation: Department of Cellular Pathology, Oxford University Hospitals and NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Roxanis
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Worth
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: John S
authors.initials: JS
authors.lastname: Beech
authors.affiliation: Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.affiliation: Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Shijie
authors.initials: S
authors.lastname: Cai
mesh_terms: D016475:3T3 Cells; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D042787:Receptor, TIE-2 / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism; D046888:Tissue Array Analysis; D014183:Transplantation, Heterologous
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D012333:RNA, Messenger; D001708:Biopterins; D042787:Receptor, TIE-2; D006136:GTP Cyclohydrolase; C003402:sapropterin
keywords: GTP cyclohydrolase; RTK Tie2; angiopoietin; breast cancer; cancer-associated fibroblasts
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