1. Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer
- Author
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Li, Yanjing, He, Yiping, Butler, William, Xu, Lingfan, Chang, Yan, Lei, Kefeng, Zhang, Hong, Zhou, Yinglu, Gao, Allen C, Zhang, Qingfu, Taylor, Daniel G, Cheng, Donghui, Farber-Katz, Suzette, Karam, Rachid, Landrith, Tyler, Li, Bing, Wu, Sitao, Hsuan, Vickie, Yang, Qing, Hu, Hailiang, Chen, Xufeng, Flowers, Melissa, McCall, Shannon J, Lee, John K, Smith, Bryan A, Park, Jung Wook, Goldstein, Andrew S, Witte, Owen N, Wang, Qianben, Rettig, Matthew B, Armstrong, Andrew J, Cheng, Qing, and Huang, Jiaoti
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Prostate Cancer ,Urologic Diseases ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Animals ,Biomarkers ,Tumor ,Cell Line ,Tumor ,Cell Membrane ,Disease Progression ,Drug Resistance ,Neoplasm ,Humans ,Male ,Mice ,Nude ,Molecular Targeted Therapy ,Neoplasm Grading ,Neoplastic Stem Cells ,Neovascularization ,Pathologic ,Neuroendocrine Tumors ,Neurosecretory Systems ,Phenotype ,Prostatic Neoplasms ,Receptors ,Interleukin-8B ,Signal Transduction ,Tumor Microenvironment ,Biological Sciences ,Medical and Health Sciences ,Medical biotechnology ,Biomedical engineering - 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.
- Published
- 2019