TY - JOUR
T1 - Lipid osteoclastokines regulate breast cancer bone metastasis
AU - Krzeszinski, Jing Y.
AU - Schwaid, Adam G.
AU - Cheng, Wing Yin
AU - Jin, Zixue
AU - Gallegos, Zachary R.
AU - Saghatelian, Alan
AU - Wan, Yihong
N1 - Publisher Copyright:
© 2017 by the Endocrine Society.
PY - 2017/3/1
Y1 - 2017/3/1
N2 - 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 b-catenin constitutive activation or peroxisome proliferator-activated receptor g 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.
AB - 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 b-catenin constitutive activation or peroxisome proliferator-activated receptor g 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.
UR - http://www.scopus.com/inward/record.url?scp=85014431047&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85014431047&partnerID=8YFLogxK
U2 - 10.1210/en.2016-1570
DO - 10.1210/en.2016-1570
M3 - Article
C2 - 27967239
AN - SCOPUS:85014431047
SN - 0013-7227
VL - 158
SP - 477
EP - 489
JO - Endocrinology
JF - Endocrinology
IS - 3
ER -