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Endocrinology. 2017 Mar 1;158(3):477-489. doi: 10.1210/en.2016-1570.

Lipid Osteoclastokines Regulate Breast Cancer Bone Metastasis.

Author information

1
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, USA.
2
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts.
3
Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.
4
Clayton Foundation Laboratories of Peptide Biology and Helmsley Center for Genomic Medicine, Salk Institute for Biological Studies, La Jolla, California.

Abstract

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 β-catenin constitutive activation or peroxisome proliferator-activated receptor γ 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.

PMID:
27967239
PMCID:
PMC5460780
DOI:
10.1210/en.2016-1570
[Indexed for MEDLINE]
Free PMC Article

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