1. Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer.
- Author
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Li Y, He Y, Butler W, Xu L, Chang Y, Lei K, Zhang H, Zhou Y, Gao AC, Zhang Q, Taylor DG, Cheng D, Farber-Katz S, Karam R, Landrith T, Li B, Wu S, Hsuan V, Yang Q, Hu H, Chen X, Flowers M, McCall SJ, Lee JK, Smith BA, Park JW, Goldstein AS, Witte ON, Wang Q, Rettig MB, Armstrong AJ, Cheng Q, and Huang J
- Subjects
- Animals, Biomarkers, Tumor metabolism, Cell Line, Tumor, Cell Membrane metabolism, Disease Progression, Humans, Male, Mice, Nude, Neoplasm Grading, Neoplastic Stem Cells pathology, Neovascularization, Pathologic metabolism, Neovascularization, Pathologic pathology, Neuroendocrine Tumors blood supply, Neuroendocrine Tumors drug therapy, Neuroendocrine Tumors pathology, Neurosecretory Systems pathology, Phenotype, Prostatic Neoplasms blood supply, Prostatic Neoplasms pathology, Receptors, Interleukin-8B metabolism, Signal Transduction, Tumor Microenvironment, Drug Resistance, Neoplasm, Molecular Targeted Therapy, Prostatic Neoplasms drug therapy, Receptors, Interleukin-8B antagonists & inhibitors
- Abstract
Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR
+ luminal tumor cells and AR- neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2019
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