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Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):14776-81. doi: 10.1073/pnas.1416498111. Epub 2014 Sep 29.

Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts.

Author information

1
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology, and Moores Cancer Center, School of Medicine, University of California, San Diego, La Jolla, CA, 92093.
2
Moores Cancer Center, School of Medicine, University of California, San Diego, La Jolla, CA, 92093.
3
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology, and Moores Cancer Center, School of Medicine, University of California, San Diego, La Jolla, CA, 92093 karinoffice@ucsd.edu.

Abstract

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-β signaling that promotes myofibroblast activation and CXCL13 induction. In addition to TGF-β 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.

KEYWORDS:

cancer; cancer-associated fibroblasts; inflammation; tumor microenvironment

PMID:
25267627
PMCID:
PMC4205637
DOI:
10.1073/pnas.1416498111
[Indexed for MEDLINE]
Free PMC Article

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