Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor regression in vivo.
The identification of novel tumor-interactive chemokines and the associated insights into the molecular and cellular basis of tumor-microenvironment interactions have continued to stimulate the development of targeted cancer therapeutics. Recently, we have identified monocyte chemoattractant protein 1 (MCP-1; CCL2) as a prominent regulator of prostate cancer growth and metastasis. Using neutralizing antibodies to human CCL2 (CNTO888) and the mouse homologue CCL2/JE (C1142), we show that treatment with anti-CCL2/JE antibody (2 mg/kg, twice weekly i.p.) attenuated PC-3Luc-mediated overall tumor burden in our in vivo model of prostate cancer metastasis by 96% at 5 weeks postintracardiac injection. Anti-CCL2 inhibition was not as effective as docetaxel (40 mg/kg, every week for 3 weeks) as a single agent, but inhibition of CCL2 in combination with docetaxel significantly reduced overall tumor burden compared with docetaxel alone, and induced tumor regression relative to initial tumor burden. These data suggest an interaction between tumor-derived chemokines and host-derived chemokines acting in cooperation to promote tumor cell survival, proliferation, and metastasis.
Loberg
Robert D
RD
Department of Urology, University of Michigan Urology Center, Ann Arbor, Michigan 48109-0946, USA. rloberg@umich.edu
Ying
Chi
C
Craig
Matt
M
Day
Lashon L
LL
Sargent
Erin
E
Neeley
Chris
C
Wojno
Kirk
K
Snyder
Linda A
LA
Yan
Li
L
Pienta
Kenneth J
KJ
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology*; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000276:immunology; D000077143:Docetaxel; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000096:biosynthesis; D043823:Taxoids / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000906:Antibodies; C111835:CCL2 protein, human; C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D007074:Immunoglobulin G; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D043823:Taxoids; D000077143:Docetaxel