Keratinocyte‐derived chemokine induces prostate epithelial hyperplasia and reactive stroma in a novel transgenic mouse model

Abstract

BACKGROUND Interleukin‐8 (IL‐8) is upregulated in fibrotic and malignant diseases and is a key mediator of proliferative responses. Elevated IL‐8 was recently correlated with benign prostatic hyperplasia epithelium and a myofibroblast reactive stroma. Thus, we sought to determine whether overexpressed IL‐8 and keratinocyte‐derived chemokine (KC), the functional murine homolog of IL‐8, induce prostate epithelial hyperplasia and a reactive phenotype. METHODS Transgenic mice that overexpress KC within prostate epithelia and xenograft models with engineered human cells that overexpress IL‐8 were developed. RESULTS Overexpression of KC in transgenic mice produced hyperplastic prostate epithelial acini associated with a periacinar reactive stroma. KC induced an altered epithelial/stroma proliferation index ratio, increased acini diameter, epithelial infolding, and expression of prototypical reactive stroma markers. Overexpression of IL‐8 in normal human prostate epithelial xenografts correlated with elevated epithelial proliferation index and altered morphology. Elevated human prostate stromal and epithelial cell proliferation, nodule‐like morphology and increased xenograft survival were observed in IL‐8‐overexpressing orthotopic xenografts. CONCLUSIONS Together, these data demonstrate that overexpression of IL‐8/KC results in a prostate epithelial hyperplasia with an associated reactive stroma phenotype. The novel transgenic mouse and human xenograft models described here may be useful in dissecting key mechanisms of IL‐8 induced prostate hyperplasia and reactive stroma. Prostate 69:373–384, 2009.