期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 41, 页码 14776-14781出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1416498111
关键词
tumor microenvironment; inflammation; cancer; cancer-associated fibroblasts
资金
- National Institutes of Health [R01 CA127923]
- Congressionally Directed Medical Research Programs
- German Research Foundation [SH721/1-1]
Prostate cancer (PC) is a slowly progressing malignancy that often responds to androgen ablation or chemotherapy by becoming more aggressive, acquiring a neuroendocrine phenotype, and undergoing metastatic spread. We found that B lymphocytes recruited into regressing androgen-deprived tumors by C-X-C motif chemokine 13 (CXCL13), a chemokine whose expression correlates with clinical severity, play an important role in malignant progression and metastatic dissemination of PC. We now describe how androgen ablation induces CXCL13 expression. In both allografted and spontaneous mouse PC, CXCL13 is expressed by tumor-associated myofibroblasts that are activated on androgen ablation through a hypoxia-dependent mechanism. The same cells produce CXCL13 after chemotherapy. Myofibroblast activation and CXCL13 expression also occur in the normal prostate after androgen deprivation, and CXCL13 is expressed by myofibroblasts in human PC. Hypoxia activates hypoxia-inducible factor 1 (HIF-1) and induces autocrine TGF-beta signaling that promotes myofibroblast activation and CXCL13 induction. In addition to TGF-beta receptor kinase inhibitors, myofibroblast activation and CXCL13 induction are blocked by phosphodiesterase 5 (PDE5) inhibitors. Both inhibitor types and myofibroblast immunodepletion block the emergence of castration-resistant PC in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of spontaneous metastatic PC with neuroendocrine differentiation.
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