Interferon-gamma targets cancer cells and osteoclasts to prevent tumor-associated bone loss and bone metastases.
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(+)IFN-gamma(+/+) mice, Tax(+)IFN-gamma(-/-) 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(+)IFN-gamma(-/-) mice prevented new tumor development and resulted in decreased bromodeoxyuridine uptake by established tumors. In vitro, IFN-gamma 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-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(+) tumor growth and prevented tumor-associated bone loss and hypercalcemia. In contrast, IFN-gamma treatment failed to protect IFN-gammaR1(-/-) mice from Tax(+) tumor-induced skeletal complications, despite decreasing tumor growth. These data demonstrate that IFN-gamma 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-gamma in patients with bone metastases and hypercalcemia of malignancy.
Xu
Zhiqiang
Z
Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri 63110.
Hurchla
Michelle A
MA
Deng
Hongju
H
Uluçkan
Ozge
O
Bu
Fang
F
Berdy
Andrew
A
Eagleton
Mark C
MC
Heller
Emanuela A
EA
Floyd
Desiree H
DH
Dirksen
Wessel P
WP
Shu
Sherry
S
Tanaka
Yuetsu
Y
Fernandez
Soledad A
SA
Rosol
Thomas J
TJ
Weilbaecher
Katherine N
KN
D000818:Animals; D001859:Bone Neoplasms / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D001862:Bone Resorption / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism; D015368:Human T-lymphotropic virus 1; D006801:Humans; D006934:Hypercalcemia / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
D016356:Gene Products, tax; D007371:Interferon-gamma