Interferon-γ targets cancer cells and osteoclasts to prevent tumor-associated bone loss and bone metastases

Zhiqiang Xu, Michelle A. Hurchla, Hongju Deng, Özge Uluçkan, Fang Bu, Andrew Berdy, Mark C. Eagleton, Emanuela A. Heller, Desiree H. Floyd, Wessel P. Dirksen, Sherry Shu, Yuetsu Tanaka, Soledad A. Fernandez, Thomas J. Rosol, Katherine N. Weilbaecher

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29 Scopus citations

Abstract

Interferon-γ (IFN-γ) has been shown to enhance anti-tumor immunity and inhibit the formation of bone-resorbing osteoclasts. We evaluated the role of IFN-γ in bone metastases, tumor-associated bone destruction,and hypercalcemia in human T cell lymphotrophic virus type 1-Tax transgenic mice. Compared with Tax+IFN-γ +/+ mice, Tax+IFN-γ +-/- mice developed increased osteolytic bone lesions and soft tissue tumors, as well as increased osteoclast formation and activity. In vivo administration of IFN-γ to tumor-bearing Tax+IFN-γ-/- mice prevented new tumor development and resulted in decreased bromodeoxyuridine uptake by established tumors. In vitro, IFN-γ directly decreased the viability of Tax+ tumor cells through inhibition of proliferation, suppression of ERK phosphorylation, and induction of apoptosis and caspase 3 cleavage. IFN-γ also inhibited macrophage colony-stimulating factor-mediated proliferation and survival of osteoclast progenitors in vitro. Administration of IFN-γ to C57BL/6 mice decreased Tax+ tumor growth and prevented tumor-associated bone loss and hypercalcemia. In contrast, IFN-γ treatment failed to protect IFN-γR1-/-mice from Tax+tumor-induced skeletal complications, despite decreasing tumor growth. These data demonstrate that IFN-γ suppressed tumor-induced bone loss and hypercalcemia in Tax+ mice by inhibiting both Tax+ tumor cell growth and host-induced osteolysis. These data suggest a protective role for IFN-γ in patients with bone metastases and hypercalcemia of malignancy.

Original languageEnglish
Pages (from-to)4658-4666
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number7
DOIs
StatePublished - Feb 13 2009

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    Xu, Z., Hurchla, M. A., Deng, H., Uluçkan, Ö., Bu, F., Berdy, A., Eagleton, M. C., Heller, E. A., Floyd, D. H., Dirksen, W. P., Shu, S., Tanaka, Y., Fernandez, S. A., Rosol, T. J., & Weilbaecher, K. N. (2009). Interferon-γ targets cancer cells and osteoclasts to prevent tumor-associated bone loss and bone metastases. Journal of Biological Chemistry, 284(7), 4658-4666. https://doi.org/10.1074/jbc.M804812200