Interferon-γ Targets Cancer Cells and Osteoclasts to Prevent Tumor-associated Bone Loss and Bone Metastases

Abstract

Interferon-␥ (IFN-␥ IFN-␥3 is a multifunctional cytokine produced mainly by NK cells and activated T cells that plays a critical role in host immune responses against pathogens and cancer (1). Mice deficient in IFN-␥, the R1 subunit of the IFN-␥ receptor, or the transcription factor STAT1 are more susceptible to spontaneous tumor development (1-3). IFN-␥ has also been found to have direct anti-proliferative and pro-apoptotic effects on tumor cells in animal models (4, 5); however, administration of high dose IFN-␥ to patients with advanced renal and ovarian cancer has had only limited success and failed to improve overall survival (1, 6).IFN-␥ has been shown to regulate bone cell differentiation and function with complex effects on skeletal health. However, the role of IFN-␥ in pathological bone disease is largely controversial. Previously, it has been reported that IFN-␥ can inhibit the critical osteoclast regulator, receptor activator of NFB ligand (RANKL), by activating ubiquitin-mediated degradation of its signaling pathway adaptor protein 8). Mice deficient for IFN-␥ or its receptor develop enhanced bone loss associated with collagen-induced arthritis (9 -11). In contrast, Gao et al. (12) recently found that IFN-␥ indirectly stimulates osteoclast formation and bone loss after ovariectomy via antigen-driven T cell activation, resulting in the production of osteoclast-activating factors. Interestingly, IFN-␥ has been used to treat infantile osteopetrosis in which patients suffered from high bone mass secondary to osteoclast dysfunction or osteoblast hyperactivity, but the mechanism of action may be through modulation of the host immune system rather than direct effects on bone cells (13-15). However, the role of IFN-␥ in the treatment of osteolytic bone metastases has not been elucidated.We evaluated the effects of IFN-␥ in HTLV-1-Tax transgenic mice that develop osteolytic bone tumors and hypercalcemia (16,17). Previously, it was shown that HTLV-1-Taxmice develop increased numbers of soft tissue tumors with enhanced tumor-associated angiogenesis and up-regulation of vascular endothelial growth factor expression; however, the impact on bone metastases and hypercalcemia in these mice * This work was supported, in whole or in part, by National Institutes of Health Grants PPG CA100730 and R01 CA 097250 (to Z. X., M. H., H. D., M. C. E., D. H. F., E. A. H., and K. N. W.), Grant T32 CA09547 (cancer biology training grant to O. U. and M. H.), and Grant RO1 CA100730 (to T. J. R. and W. P. D. and NCRR to S. S.), as well as by the St. Louis Men's Club Against Cancer (to K. N. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The Two Faces of Galectin-3: Roles in Various Pathological Conditions

“…It has been reported that IFN-γ has direct antiproliferative and proapoptotic effects on tumour cells in animal models (104,105) and that these effects prevent B16 experimental metastasis by directly inhibiting cell growth (106). We observed higher serum levels of IFN-γ and IL-17 in tumour-bearing hosts in Galectin-3 deficiency, which was not accompanied by differences in the number of CD4 + and CD8 + T cells in the spleen.…”

The role of cytokines in inflammatory bone loss

“…IFN-g induced suppression of osteoclastogenesis is associated with down-regulation of cathepsin K (Kamolmatyakul et al, 2001). The antiresorptive properties of IFN-g may be of importance for prevention of tumorassociated bone loss and bone metastases (Xu et al, 2009).…”

Changes of serum cytokines-related Th1/Th2/Th17 concentration in patients with postmenopausal osteoporosis

“…Despite its undoubted regulatory roles in osteoclast formation [10], IFN-g exhibited different functions in the in vitro and in vivo experiments. IFN-g was found to strongly inhibit osteoclast formation under in vitro condition, but IFN-g inhibited osteoclast formation directly [11] and promoted osteoclast formation indirectly [12] under in vivo condition.…”