title: Inhibition of CCL2 signaling in combination with docetaxel treatment has profound inhibitory effects on prostate cancer growth in bone.
abstract: The C-C chemokine ligand 2 (CCL2) stimulates migration, proliferation, and invasion of prostate cancer (PCa) cells, and its signaling also plays a role in the activation of osteoclasts. Therefore targeting CCL2 signaling in regulation of tumor progression in bone metastases is an area of intense research. The objective of our study was to investigate the efficacy of CCL2 blockade by neutralizing antibodies to inhibit the growth of PCa in bone. We used a preclinical model of cancer growth in the bone in which PCa C4-2B cells were injected directly into murine tibiae. Animals were treated for ten weeks with neutralizing anti-CCL2 antibodies, docetaxel, or a combination of both, and then followed an additional nine weeks. CCL2 blockade inhibited the growth of PCa in bone, with even more pronounced inhibition in combination with docetaxel. CCL2 blockade also resulted in increases in bone mineral density. Furthermore, our results showed that the tumor inhibition lasted even after discontinuation of the treatment. Our data provide compelling evidence that CCL2 blockade slows PCa growth in bone, both alone and in combination with docetaxel. These results support the continued investigations of CCL2 blockade as a treatment for advanced metastatic PCa.
authors.affiliation: Department of Urology, University of Washington, Seattle, WA 98195, USA. ecorey@uw.edu.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Kirk
authors.forename: Theodore
authors.initials: T
authors.lastname: Koreckij
authors.forename: Holly M
authors.initials: HM
authors.lastname: Nguyen
authors.forename: Lisha G
authors.initials: LG
authors.lastname: Brown
authors.forename: Linda A
authors.initials: LA
authors.lastname: Snyder
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.forename: Eva
authors.initials: E
authors.lastname: Corey
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001859:Bone Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D000077143:Docetaxel; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D016513:Mice, SCID; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects*; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage; D013997:Time Factors; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D057134:Antibodies, Neutralizing; D018932:Chemokine CCL2; D043823:Taxoids; D000077143:Docetaxel; D017430:Prostate-Specific Antigen