Granulocyte colony-stimulating factor enhances bone tumor growth in mice in an osteoclast-dependent manner.
Inhibition of osteoclast (OC) activity has been associated with decreased tumor growth in bone in animal models. Increased recognition of factors that promote osteoclastic bone resorption in cancer patients led us to investigate whether increased OC activation could enhance tumor growth in bone. Granulocyte colony-stimulating factor (G-CSF) is used to treat chemotherapy-induced neutropenia, but is also associated with increased markers of OC activity and decreased bone mineral density (BMD). We used G-CSF as a tool to investigate the impact of increased OC activity on tumor growth in 2 murine osteolytic tumor models. An 8-day course of G-CSF alone (without chemotherapy) significantly decreased BMD and increased OC perimeter along bone in mice. Mice administered G-CSF alone demonstrated significantly increased tumor growth in bone as quantitated by in vivo bioluminescence imaging and histologic bone marrow tumor analysis. Short-term administration of AMD3100, a CXCR4 inhibitor that mobilizes neutrophils with little effect on bone resorption, did not lead to increased tumor burden. However, OC-defective osteoprotegerin transgenic (OPG(Tg)) mice and bisphosphonate-treated mice were resistant to the effects of G-CSF administration upon bone tumor growth. These data demonstrate a G-CSF-induced stimulation of tumor growth in bone that is OC dependent.
Hirbe
Angela C
AC
Department of Medicine and Division of Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Uluçkan
Ozge
O
Morgan
Elizabeth A
EA
Eagleton
Mark C
MC
Prior
Julie L
JL
Piwnica-Worms
David
D
Trinkaus
Kathryn
K
Apicelli
Anthony
A
Weilbaecher
Katherine
K
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D001596:Benzylamines; D015519:Bone Density / Q000187:drug effects*; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001862:Bone Resorption / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects; D000080027:Cyclams; D016179:Granulocyte Colony-Stimulating Factor / Q000009:adverse effects* / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental; D009503:Neutropenia / Q000188:drug therapy; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D047368:Tumor Burden / Q000187:drug effects*
D019380:Anti-HIV Agents; D001596:Benzylamines; C514936:CXCR4 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D016179:Granulocyte Colony-Stimulating Factor; C088327:plerixafor