title: Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin.
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;Pten(fl/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.
authors.affiliation: Departments of Molecular and Cellular Biology and Pathology and Immunology and the Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Oh-Joon
authors.initials: OJ
authors.lastname: Kwon
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ittmann
authors.forename: Li
authors.initials: L
authors.lastname: Xin
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000150:complications / Q000473:pathology; D063646:Carcinogenesis / Q000473:pathology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D060833:Cellular Microenvironment; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D006965:Hyperplasia; D007249:Inflammation / Q000150:complications / Q000473:pathology*; D053547:Keratin-14 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018295:Neoplasms, Basal Cell / Q000209:etiology* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011467:Prostate / Q000382:microbiology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000209:etiology* / Q000473:pathology; D011472:Prostatitis / Q000150:complications* / Q000382:microbiology / Q000473:pathology*; D017154:Stromal Cells / Q000473:pathology
chemical_list: D053547:Keratin-14; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: cells-of-origin for cancer; prostate stem cells