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Inhibition of GTP cyclohydrolase attenuates tumor growth by reducing angiogenesis and M2‐like polarization of tumor associated macrophages
Author(s) -
Pickert Geethanjali,
Lim HeeYoung,
Weigert Andreas,
Häussler Annett,
Myrczek Thekla,
Waldner Maximilian,
Labocha Sandra,
Ferreirós Nerea,
Geisslinger Gerd,
Lötsch Jörn,
Becker Christoph,
Brüne Bernhard,
Tegeder Irmgard
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27706
Subject(s) - angiogenesis , cancer research , tetrahydrobiopterin , neovascularization , biopterin , colorectal cancer , gtp cyclohydrolase i , cancer cell , biology , chemistry , medicine , cancer , endocrinology , nitric oxide synthase , nitric oxide
GTP cyclohydrolase (GCH1) is the key‐enzyme to produce the essential enzyme cofactor, tetrahydrobiopterin. The byproduct, neopterin is increased in advanced human cancer and used as cancer‐biomarker, suggesting that pathologically increased GCH1 activity may promote tumor growth. We found that inhibition or silencing of GCH1 reduced tumor cell proliferation and survival and the tube formation of human umbilical vein endothelial cells, which upon hypoxia increased GCH1 and endothelial NOS expression, the latter prevented by inhibition of GCH1. In nude mice xenografted with HT29‐Luc colon cancer cells GCH1 inhibition reduced tumor growth and angiogenesis, determined by in vivo luciferase and near‐infrared imaging of newly formed blood vessels. The treatment with the GCH1 inhibitor shifted the phenotype of tumor associated macrophages from the proangiogenic M2 towards M1, accompanied with a shift of plasma chemokine profiles towards tumor‐attacking chemokines including CXCL10 and RANTES. GCH1 expression was increased in mouse AOM/DSS‐induced colon tumors and in high grade human colon and skin cancer and oppositely, the growth of GCH1‐deficient HT29‐Luc tumor cells in mice was strongly reduced. The data suggest that GCH1 inhibition reduces tumor growth by ( i ) direct killing of tumor cells, ( ii ) by inhibiting angiogenesis, and ( iii ) by enhancing the antitumoral immune response.