Paracrine effect of GTP cyclohydrolase and angiopoietin-1 interaction in stromal fibroblasts on tumor Tie2 activation and breast cancer growth

Oncotarget
Liye ChenShijie Cai

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 acti...Continue Reading

References

Jul 1, 1997·British Journal of Haematology·E KukkR Alitalo
Oct 17, 1998·Science·C SuriG D Yancopoulos
Mar 3, 1999·Proceedings of the National Academy of Sciences of the United States of America·D M ValenzuelaG D Yancopoulos
Oct 12, 2000·British Journal of Cancer·A J HayesL Y Li
Mar 20, 2002·Nature Reviews. Cancer·M J Bissell, D Radisky
Mar 28, 2002·Thyroid : Official Journal of the American Thyroid Association·N MitsutakeS Yamashita
May 11, 2002·Current Drug Metabolism·C MurrD Fuchs
Jul 25, 2003·Cancer Chemotherapy and Pharmacology·Jennifer Walter-YohrlingBeverly A Teicher
Nov 28, 2007·Annual Review of Pathology·Thea D Tlsty, Lisa M Coussens
Feb 17, 2009·Proceedings of the National Academy of Sciences of the United States of America·Martin AugstenArne Ostman
Feb 21, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Iris HelfrichHellmut G Augustin
Feb 24, 2009·Nature Reviews. Molecular Cell Biology·Hellmut G AugustinKari Alitalo
Oct 6, 2009·Journal of Biomechanics·Boris Hinz
Jul 24, 2010·Nature Reviews. Cancer·Hanhua HuangRodney Lappe
Aug 12, 2010·Oncotarget·Geoff S HigginsFrancesca M Buffa
Sep 18, 2010·The American Journal of Pathology·Liye ChenShijie Cai
Oct 28, 2010·Breast Cancer : the Journal of the Japanese Breast Cancer Society·Masako YamashitaTaizo Shiraishi
Aug 27, 2011·The Biochemical Journal·Ernst R WernerBeat Thöny
Dec 7, 2011·Proceedings of the National Academy of Sciences of the United States of America·Debanjan ChakrobortySujit Basu
May 16, 2012·The Journal of Clinical Investigation·Moritz FelchtHellmut G Augustin
Sep 12, 2012·Journal of Physics. Condensed Matter : an Institute of Physics Journal·Petra Tegeder
Jul 22, 2014·The American Journal of Pathology·Melissa K BrunckhorstQin Yu

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Citations

Jan 29, 2020·ACS Central Science·Vanessa A N KraftJoel A Schick

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Datasets Mentioned

BETA
GSE9195
GSE9014

Methods Mentioned

BETA
xenograft
ELISA
xenografts
transfection
confocal microscopy

Software Mentioned

R
Image J
ImageJ
Incucyte

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