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2017 ; 158
(3
): 477-489
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Lipid Osteoclastokines Regulate Breast Cancer Bone Metastasis
#MMPMID27967239
Krzeszinski JY
; Schwaid AG
; Cheng WY
; Jin Z
; Gallegos ZR
; Saghatelian A
; Wan Y
Endocrinology
2017[Mar]; 158
(3
): 477-489
PMID27967239
show ga
Bone metastasis is a deadly consequence of cancers, in which osteoclast forms a
vicious cycle with tumor cells. Bone metastasis attenuation by clinical usage of
osteoclast inhibitors and in our osteopetrotic mouse genetic models with
?-catenin constitutive activation or peroxisome proliferator-activated receptor ?
deficiency fully support the important role of osteoclast in driving the bone
metastatic niche. However, the mechanisms for this "partnership in crime" are
underexplored. Here we show that osteoclasts reprogram their lipid secretion to
support cancer cells. Metabolomic profiling reveals elevated prometastatic
arachidonic acid (AA) but reduced antimetastatic lysophosphatidylcholines (LPCs).
This shift in lipid osteoclastokines synergistically stimulates tumor cell
proliferation, migration, survival, and expression of prometastatic genes.
Pharmacologically, combined treatment with LPCs and BW-755C, an inhibitor of AA
signaling via blocking lipoxygenase and cyclooxygenase, impedes breast cancer
bone metastasis. Our findings elucidate key paracrine mechanisms for the
osteoclast-cancer vicious cycle and uncover important therapeutic targets for
bone metastasis.
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