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.
Highlights
The development of carcinoma requires a complex surrounding microenvironment, which is composed of extracellular matrix (ECM), soluble growth factors, stromal cells and blood vessels [1]
We show that high GTP cyclohydrolase (GTPCH) expression in stromal fibroblasts supports breast cancer growth in vitro and in vivo
The underpinning mechanism involves Receptor tyrosine kinases (RTKs) Tie2 signal transduction on tumor cells mediated by Ang-1 secreted as a result of a GTPCH/Ang-1 interaction in stromal fibroblasts - a previously unrecognized mechanism involved in tumor growth
Summary
The development of carcinoma requires a complex surrounding microenvironment, which is composed of extracellular matrix (ECM), soluble growth factors, stromal cells and blood vessels [1]. The activated cancer-associated fibroblasts (CAFs) are presented in the vicinity of the malignant lesion expressing myofibroblastic www.impactjournals.com/oncotarget markers, often with alpha-smooth muscle actin (α-SMA). They exhibit enhanced proliferation and migratory phenotypes, supporting epithelial proliferation, malignant transformation, tumor vascularization and metastasis in prostate cancer [2], ovarian cancer [3] and breast cancer [4]. This is partly ascribing to dysregulation of their cellular signaling and their abnormal expression of angiogenic factors [5]. Clinical significance of CAFs has been established; they are correlated with poor prognosis in breast carcinoma [6, 7]
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