Paracrine effect of GTP cyclohydrolase and angiopoietin-1 interaction in stromal fibroblasts on tumor Tie2 activation and breast cancer growth
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Liye Chen1,*, Xin Zeng1,6,*, Esther Kleibeuker1, Francesca Buffa1, Alessandro Barberis1, Russell D. Leek1, Ioannis Roxanis2, Wei Zhang3, Andrew Worth4, John S. Beech5, Adrian L. Harris1, Shijie Cai1
1Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK
2Department of Cellular Pathology, Oxford University Hospitals and NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK
3Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Oxford OX3 9DU, UK
4Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK
5Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK
6Current address: Xiamen Institute for Diabetes Research, The First Affiliated Hospital of Xiamen University, Xiamen, China
*These authors have contributed equally to this work
Shijie Cai, e-mail: firstname.lastname@example.org
Keywords: cancer-associated fibroblasts, RTK Tie2, angiopoietin, GTP cyclohydrolase, breast cancer
Received: August 03, 2015 Accepted: December 26, 2015 Published: January 22, 2016
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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