Interferon-{gamma} Targets Cancer Cells and Osteoclasts to Prevent Tumor-associated Bone Loss and Bone Metastases

• Published in: The Journal of biological chemistry 2009-02, Vol.284 (7), p.4658-4666
• Main Authors: Xu, Zhiqiang, Hurchla, Michelle A, Deng, Hongju, Uluckan, Ozge, Bu, Fang, Berdy, Andrew, Eagleton, Mark C, Heller, Emanuela A, Floyd, Desiree H, Dirksen, Wessel P, Shu, Sherry, Tanaka, Yuetsu, Fernandez, Soledad A, Rosol, Thomas J, Weilbaecher, Katherine N
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M804812200

Interferon-{gamma} (IFN-{gamma}) has been shown to enhance anti-tumor immunity and inhibit the formation of bone-resorbing osteoclasts. We evaluated the role of IFN-{gamma} in bone metastases, tumor-associated bone destruction, and hypercalcemia in human T cell lymphotrophic virus type 1-Tax transgenic mice. Compared with Tax super(+)IFN-{gamma} super(+/+) mice, Tax super(+)IFN-{gamma} super(-/-) mice developed increased osteolytic bone lesions and soft tissue tumors, as well as increased osteoclast formation and activity. In vivo administration of IFN-{gamma} to tumor-bearing Tax super(+)IFN-{gamma} super(-/-) mice prevented new tumor development and resulted in decreased bromodeoxyuridine uptake by established tumors. In vitro, IFN- {gamma} directly decreased the viability of Tax super(+) tumor cells through inhibition of proliferation, suppression of ERK phosphorylation, and induction of apoptosis and caspase 3 cleavage. IFN-{gamma} also inhibited macrophage colonystimulating factor-mediated proliferation and survival of osteoclast progenitors in vitro. Administration of IFN-{gamma} to C57BL/6 mice decreased Tax super(+) tumor growth and prevented tumor-associated bone loss and hypercalcemia. In contrast, IFN-{gamma} treatment failed to protect IFN- {gamma}R1 super(-/-) mice from Tax super(+) tumor-induced skeletal complications, despite decreasing tumor growth. These data demonstrate that IFN-{gamma} suppressed tumor-induced bone loss and hypercalcemia in Tax super(+) mice by inhibiting both Tax super(+) tumor cell growth and host-induced osteolysis. These data suggest a protective role for IFN-{gamma} in patients with bone metastases and hypercalcemia of malignancy.