The dramatic responses tumors display to targeted therapies are limited by acquired or pre-existing mechanisms of therapy resistance. We recently discovered that androgen receptor blockade by the anti-androgen enzalutamide paradoxically enhanced metastasis and that these pro-metastatic effects were mediated by the chemoattractant CCL2.
CCL2 is regulated by TNF, which is negatively regulated by androgen signaling. Thus, we asked if TNF mediates the pro-metastatic effects of enzalutamide. We found that androgen withdrawal or enzalutamide induced TNF mRNA and protein secretion in castration resistant prostate cancer (C4-2) cells, but not in macrophage-like (THP1) or myofibroblast-like (WPMY1) cells. Androgen deprivation therapy (ADT) induced autocrine CCL2 expression in C4-2 (as well as a murine CRPC cell line), while exogenous TNF induced CCL2 in THP1 and WPMY1. TNF was most potent in myofibroblast cultures, suggesting ADT induces CCL2 via paracrine interactions within the tumor microenvironment. A soluble TNF receptor (etanercept) blocked enzalutamide-induced CCL2 protein secretion and mRNA, implying dependence on secreted TNF. A small molecule inhibitor of CCR2 (the CCL2 receptor) significantly reduced TNF induced migration, while etanercept inhibited enzalutamide-induced migration and invasion of C4-2. Analysis of human prostate cancers suggests that a TNF-CCL2 paracrine loop is induced in response to ADT and might account for some forms of prostate cancer therapy resistance.
Oncotarget. 2015 Jul 30 [Epub ahead of print]
Kai Sha, Shuyuan Yeh, Chawnshang Chang, Kent L Nastiuk, John J Krolewski
Department of Pathology and Laboratory Medicine, University of Rochester, School of Medicine and Dentistry; Rochester, NY 14642, USA. , Department of Pathology and Laboratory Medicine, University of Rochester, School of Medicine and Dentistry; Rochester, NY 14642, USA. , Department of Pathology and Laboratory Medicine, University of Rochester, School of Medicine and Dentistry; Rochester, NY 14642, USA. , Department of Pathology and Laboratory Medicine, University of Rochester, School of Medicine and Dentistry; Rochester, NY 14642, USA. , Department of Pathology and Laboratory Medicine, University of Rochester, School of Medicine and Dentistry; Rochester, NY 14642, USA.