| Literature DB >> 31801883 |
Yanjing Li1, Yiping He1, William Butler1, Lingfan Xu1,2, Yan Chang1,3, Kefeng Lei1,4, Hong Zhang1, Yinglu Zhou1, Allen C Gao5, Qingfu Zhang1,6, Daniel G Taylor7, Donghui Cheng8, Suzette Farber-Katz9, Rachid Karam9, Tyler Landrith9, Bing Li9, Sitao Wu9, Vickie Hsuan9, Qing Yang10, Hailiang Hu1, Xufeng Chen1, Melissa Flowers1, Shannon J McCall1, John K Lee11,12, Bryan A Smith8, Jung Wook Park8, Andrew S Goldstein7,13,14, Owen N Witte8,13,15, Qianben Wang1, Matthew B Rettig11,14,16, Andrew J Armstrong17, Qing Cheng18, Jiaoti Huang19.
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.Entities:
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Year: 2019 PMID： 31801883 PMCID： PMC7238624 DOI： 10.1126/scitranslmed.aax0428
Source DB: PubMed Journal: Sci Transl Med ISSN： 1946-6234 Impact factor: 17.956