Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin

Oh-Joon Kwon, Li Zhang, Michael M. Ittmann, and Li Xin
PNAS first published December 23, 2013 https://doi.org/10.1073/pnas.1318157111

  1. Edited by Owen N. Witte, Howard Hughes Medical Institute, University of California, Los Angeles, CA, and approved December 4, 2013 (received for review October 15, 2013)

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Significance

Inflammation promotes the initiation of various malignancies by inducing genetic and epigenetic changes. Here we show that bacterial infection-induced prostatitis results in microenvironmental changes that enhance the differentiation of prostate basal cells into luminal cells, a cellular process that rarely occurs under normal physiological conditions. Previously, we showed in a mouse model that disease initiation for prostate cancer with a basal cell origin requires and is limited by basal-to-luminal differentiation and that prostatic inflammation induced by bacterial infection accelerates disease initiation by enhancing basal-to-luminal differentiation. Collectively, our results show that inflammation-induced microenvironmental changes alter the prostate epithelial lineage differentiation program, and we propose this alteration as a distinct and complementary process through which inflammation promotes tumor initiation.

Abstract

Chronic inflammation has been shown to promote the initiation and progression of diverse malignancies by inducing genetic and epigenetic alterations. In this study, we investigate an alternative mechanism through which inflammation promotes the initiation of prostate cancer. Adult murine prostate epithelia are composed predominantly of basal and luminal cells. Previous studies revealed that the two lineages are largely self-sustained when residing in their native microenvironment. To interrogate whether tissue inflammation alters the differentiation program of basal cells, we conducted lineage tracing of basal cells using a K14-CreER;mTmG model in concert with a murine model of prostatitis induced by infection from the uropathogenic bacteria CP9. We show that acute prostatitis causes tissue damage and creates a tissue microenvironment that induces the differentiation of basal cells into luminal cells, an alteration that rarely occurs under normal physiological conditions. Previously we showed that a mouse model with prostate basal cell-specific deletion of Phosphatase and tensin homolog (K14-CreER;Ptenfl/fl) develops prostate cancer with a long latency, because disease initiation in this model requires and is limited by the differentiation of transformation-resistant basal cells into transformation-competent luminal cells. Here, we show that CP9-induced prostatitis significantly accelerates the initiation of prostatic intraepithelial neoplasia in this model. Our results demonstrate that inflammation results in a tissue microenvironment that alters the normal prostate epithelial cell differentiation program and that through this cellular process inflammation accelerates the initiation of prostate cancer with a basal cell origin.

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: xin{at}bcm.edu.

  • Author contributions: L.X. designed research; O.-J.K. and L.Z. performed research; O.-J.K., M.M.I., and L.X. analyzed data; and L.X. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1318157111/-/DCSupplemental.

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Inflammation and prostate lineage hierarchy
Oh-Joon Kwon, Li Zhang, Michael M. Ittmann, Li Xin
Proceedings of the National Academy of Sciences Dec 2013, 201318157; DOI: 10.1073/pnas.1318157111
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