title: G-CSF supplementation with chemotherapy can promote revascularization and subsequent tumor regrowth: prevention by a CXCR4 antagonist.
abstract: Recombinant granulocyte colony-stimulating factor (G-CSF) is used to accelerate recovery from chemotherapy-induced myelosuppression. G-CSF has been recently shown to stimulate angiogenesis mediated by several types of bone marrow-derived cell populations. To investigate whether G-CSF may alter tumor response to therapy, we studied Lewis lung and EMT/6 breast carcinomas in mice treated with paclitaxel (PTX) chemotherapy in combination with G-CSF. We compared the results obtained to mice treated with PTX and AMD3100, a small-molecule drug antagonist of CXCR4 which, like G-CSF, can be used to mobilize hematopoietic cells. We show that PTX combined with G-CSF treatment facilitates revascularization, leading to an improvement in blood perfusion in LLC tumors, and a decrease in hypoxia in EMT/6 tumors, thus enhancing tumor growth in comparison to PTX or PTX and AMD3100 therapies. We found that hemangiocytes but not Gr-1(+) CD11b(+) cells colonize EMT/6 tumors after treatment with PTX and G-CSF, but not PTX and AMD3100, and therefore may contribute to angiogenesis. However, increases in hemangiocyte colonization were not observed in LLC PTX and G-CSF-treated tumors, suggesting distinct mechanisms of tumor revascularization after G-CSF. Overall, our observations suggest that despite its known considerable clinical benefits, G-CSF might contribute to tumor revascularization by various mechanisms, and diminish the antitumor activity of chemotherapy, an effect that can be prevented by AMD3100.
authors.affiliation: Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Tali
authors.initials: T
authors.lastname: Voloshin
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gingis-Velitski
authors.forename: Rotem
authors.initials: R
authors.lastname: Bril
authors.forename: Liat
authors.initials: L
authors.lastname: Benayoun
authors.forename: Michal
authors.initials: M
authors.lastname: Munster
authors.forename: Chloe
authors.initials: C
authors.lastname: Milsom
authors.forename: Shan
authors.initials: S
authors.lastname: Man
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
authors.forename: Yuval
authors.initials: Y
authors.lastname: Shaked
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001596:Benzylamines; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000080027:Cyclams; D004338:Drug Combinations; D005260:Female; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D058922:Inflammatory Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D007274:Injections, Intraperitoneal; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000517:prevention & control; D017239:Paclitaxel / Q000008:administration & dosage*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001596:Benzylamines; D000080027:Cyclams; D004338:Drug Combinations; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A; D016179:Granulocyte Colony-Stimulating Factor; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D017239:Paclitaxel; C088327:plerixafor