title: Contribution of granulocyte colony-stimulating factor to the acute mobilization of endothelial precursor cells by vascular disrupting agents.
abstract: 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.
authors.affiliation: Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. yshaked@tx.technion.ac.il
authors.forename: Yuval
authors.initials: Y
authors.lastname: Shaked
authors.forename: Terence
authors.initials: T
authors.lastname: Tang
authors.forename: Jill
authors.initials: J
authors.lastname: Woloszynek
authors.forename: Laura G
authors.initials: LG
authors.lastname: Daenen
authors.forename: Shan
authors.initials: S
authors.lastname: Man
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.forename: Shi-Rong
authors.initials: SR
authors.lastname: Cai
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Arbeit
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
authors.forename: David J
authors.initials: DJ
authors.lastname: Chaplin
authors.forename: Jon
authors.initials: J
authors.lastname: Smythe
authors.forename: Adrian
authors.initials: A
authors.lastname: Harris
authors.forename: Paul
authors.initials: P
authors.lastname: Nathan
authors.forename: Ian
authors.initials: I
authors.lastname: Judson
authors.forename: Gordon
authors.initials: G
authors.lastname: Rustin
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertolini
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
mesh_terms: 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
chemical_list: 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