Granulocyte colony-stimulating factor enhances bone tumor growth in mice in an osteoclast-dependent manner

Abstract

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 bisphosphonatetreated 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.

Lipopolysaccharide-Induced Osteoclastogenesis from Mononuclear Precursors: A Mechanism for Osteolysis in Chronic Otitis

“…In addition to TNF-α (Azuma et al 2000), IL-1α (Jimi et al 1999), IL-6 (Kudo et al 2003), monocyte chemoattractant protein-1 (MCP-1; Lu et al 2007), macrophage inflammatory protein-1 alpha (MIP-1α; Lee et al 2007), and granulocyte colony-stimulating factor (G-CSF; Hirbe et al 2007), which have all recently been shown to promote Oc formation, we have also identified IL-10, IL-12p70, IL-9, leptin, and Regulated upon Activation, Normal T cell expressed, and secreted (RANTES) as highly expressed cytokines in pOcs undergoing P. aeruginosa LPS-mediated Oc formation.…”

Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow

“…Conversely, AMD3100 -which does not mobilize HSCs by activating osteoclastogenesis, but rather by interfering directly with CXCR4/CXCL12 bindingdid not active osteoclasts to mobilize PCa cells, as predicted (Supplemental Figure 6, J and K; and ref. 27). Together, these data suggest that disseminated PCa cells compete with HSCs for the niche using the same molecular mechanisms as do HSCs to gain access and egress of the niche (e.g., CXCR4/CXCL12).…”

Monocytic cell differentiation from band-stage neutrophils under inflammatory conditions via MKK6 activation

“…Several studies previously showed that G-CSF promotes osteopenia, 51,52 and transgenic mice encoding human G-CSF developed osteoporosis with increased osteoclast activity. 53 Consistently, mononuclear cells from G-CSF-mobilized blood showed higher osteoclast differentiation potential than those isolated from healthy controls, 54 and G-CSF augments osteoclast formation in vitro.…”

“…53 Consistently, mononuclear cells from G-CSF-mobilized blood showed higher osteoclast differentiation potential than those isolated from healthy controls, 54 and G-CSF augments osteoclast formation in vitro. 51 Moreover, G-CSF treatment can exacerbate arthritis, and rheumatoid arthritis is associated with elevated serum G-CSF levels, 55 whereas G-CSF receptor-deficient mice are refractory to collagen-induced arthritis. 56 Of note, arthritis patients contain increased percentages of activated neutrophils, and these cells may represent a major reservoir of osteoclasts in psoriatic arthritis patients.…”