Contribution of granulocyte colony-stimulating factor to the acute mobilization of endothelial precursor cells by vascular disrupting agents.
Vascular disrupting agents (VDA) cause acute shutdown of abnormal established tumor vasculature, followed by massive intratumoral hypoxia and necrosis. However, a viable rim of tumor tissue invariably remains from which tumor regrowth rapidly resumes. We have recently shown that an acute systemic mobilization and homing of bone marrow-derived circulating endothelial precursor (CEP) cells could promote tumor regrowth following treatment with either a VDA or certain chemotherapy drugs. The molecular mediators of this systemic reactive host process are unknown. Here, we show that following treatment of mice with OXi-4503, a second-generation potent prodrug derivative of combretastatin-A4 phosphate, rapid increases in circulating plasma vascular endothelial growth factor, stromal derived factor-1 (SDF-1), and granulocyte colony-stimulating factor (G-CSF) levels are detected. With the aim of determining whether G-CSF is involved in VDA-induced CEP mobilization, mutant G-CSF-R(-/-) mice were treated with OXi-4503. We found that as opposed to wild-type controls, G-CSF-R(-/-) mice failed to mobilize CEPs or show induction of SDF-1 plasma levels. Furthermore, Lewis lung carcinomas grown in such mice treated with OXi-4503 showed greater levels of necrosis compared with tumors treated in wild-type mice. Evidence for rapid elevations in circulating plasma G-CSF, vascular endothelial growth factor, and SDF-1 were also observed in patients with VDA (combretastatin-A4 phosphate)-treated cancer. These results highlight the possible effect of drug-induced G-CSF on tumor regrowth following certain cytotoxic drug therapies, in this case using a VDA, and hence G-CSF as a possible therapeutic target.
Shaked
Yuval
Y
Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. yshaked@tx.technion.ac.il
Tang
Terence
T
Woloszynek
Jill
J
Daenen
Laura G
LG
Man
Shan
S
Xu
Ping
P
Cai
Shi-Rong
SR
Arbeit
Jeffrey M
JM
Voest
Emile E
EE
Chaplin
David J
DJ
Smythe
Jon
J
Harris
Adrian
A
Nathan
Paul
P
Judson
Ian
I
Rustin
Gordon
G
Bertolini
Francesco
F
Link
Daniel C
DC
Kerbel
Robert S
RS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab; D054377:Chemokine CXCL12 / Q000097:blood; D011756:Diphosphates / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood* / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods; D006801:Humans; D008545:Melanoma / Q000097:blood / Q000098:blood supply / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D009369:Neoplasms / Q000097:blood* / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D011355:Prodrugs / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D054377:Chemokine CXCL12; D011756:Diphosphates; C465018:Oxi 4503; D011355:Prodrugs; D013267:Stilbenes; D042461:Vascular Endothelial Growth Factor A; D016179:Granulocyte Colony-Stimulating Factor; D000068258:Bevacizumab; C058728:fosbretabulin