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Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer.

Publication ,  Journal Article
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 ...
Published in: Sci Transl Med
December 4, 2019

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.

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Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

December 4, 2019

Volume

11

Issue

521

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • Signal Transduction
  • Receptors, Interleukin-8B
  • Prostatic Neoplasms
  • Phenotype
  • Neurosecretory Systems
  • Neuroendocrine Tumors
  • Neovascularization, Pathologic
  • Neoplastic Stem Cells
  • Neoplasm Grading
 

Citation

APA
Chicago
ICMJE
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Li, Y., He, Y., Butler, W., Xu, L., Chang, Y., Lei, K., … Huang, J. (2019). Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer. Sci Transl Med, 11(521). https://doi.org/10.1126/scitranslmed.aax0428
Li, Yanjing, Yiping He, William Butler, Lingfan Xu, Yan Chang, Kefeng Lei, Hong Zhang, et al. “Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer.Sci Transl Med 11, no. 521 (December 4, 2019). https://doi.org/10.1126/scitranslmed.aax0428.
Li Y, He Y, Butler W, Xu L, Chang Y, Lei K, et al. Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer. Sci Transl Med. 2019 Dec 4;11(521).
Li, Yanjing, et al. “Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer.Sci Transl Med, vol. 11, no. 521, Dec. 2019. Pubmed, doi:10.1126/scitranslmed.aax0428.
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, Huang J. Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer. Sci Transl Med. 2019 Dec 4;11(521).

Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

December 4, 2019

Volume

11

Issue

521

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • Signal Transduction
  • Receptors, Interleukin-8B
  • Prostatic Neoplasms
  • Phenotype
  • Neurosecretory Systems
  • Neuroendocrine Tumors
  • Neovascularization, Pathologic
  • Neoplastic Stem Cells
  • Neoplasm Grading