The type 1 lysophosphatidic acid receptor is a target for therapy in bone metastases.
Platelet-derived lysophosphatidic acid (LPA) supports the progression of breast and ovarian cancer metastasis to bone. The mechanisms through which LPA promotes bone metastasis formation are, however, unknown. Here we report that silencing of the type 1 LPA receptor (LPA(1)) in cancer cells blocks the production of tumor-derived cytokines that are potent activators of osteoclast-mediated bone destruction and significantly reduces the progression of osteolytic bone metastases. Moreover, functional blockade of LPA action on its cognate receptor LPA(1) using a pharmacological antagonist mimics the effects of silencing LPA(1) in tumor cells in vitro and substantially reduces bone metastasis progression in animals. Overall, these results suggest that inhibition of platelet-derived LPA action on LPA(1) expressed by tumor cells may be a promising therapeutic target for patients with bone metastases.
Boucharaba
Ahmed
A
Institut National de la Santé et de la Recherche Médicale (INSERM) U664, 69372 Lyon, France.
Serre
Claire-Marie
CM
Guglielmi
Julien
J
Bordet
Jean-Claude
JC
Clézardin
Philippe
P
Peyruchaud
Olivier
O
D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007555:Isoxazoles / Q000627:therapeutic use; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism; D011422:Propionates / Q000627:therapeutic use; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors* / Q000145:classification* / Q000378:metabolism
C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D016207:Cytokines; D007555:Isoxazoles; D008246:Lysophospholipids; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid