Abstract
ELL-associated factor 2 (EAF2) is an androgen-responsive tumor suppressor frequently deleted in advanced prostate cancer that functions as a transcription elongation factor of RNA Pol II through interaction with the ELL family proteins. EAF2 knockout mice on a 129P2/OLA-C57BL/6J background developed late-onset lung adenocarcinoma, hepatocellular carcinoma, B-cell lymphoma and high-grade prostatic intraepithelial neoplasia. In order to further characterize the role of EAF2 in the development of prostatic defects, the effects of EAF2 loss were compared in different murine strains. In the current study, aged EAF2−/− mice on both the C57BL/6J and FVB/NJ backgrounds exhibited mPIN lesions as previously reported on a 129P2/OLA-C57BL/6J background. In contrast to the 129P2/OLA-C57BL/6J mixed genetic background, the mPIN lesions in C57BL/6J and FVB/NJ EAF2−/− mice were associated with stromal defects characteristic of a reactive stroma and a statistically significant increase in prostate microvessel density. Stromal inflammation and increased microvessel density was evident in EAF2-deficient mice on a pure C57BL/6J background at an early age and preceded the development of the histologic epithelial hyperplasia and neoplasia found in the prostates of older EAF2−/− animals. Mice deficient in EAF2 had an increased recovery rate and a decreased overall response to the effects of androgen deprivation. EAF2 expression in human cancer was significantly down-regulated and microvessel density was significantly increased compared to matched normal prostate tissue; furthermore EAF2 expression was negatively correlated with microvessel density. These results suggest that the EAF2 knockout mouse on the C57BL/6J and FVB/NJ genetic backgrounds provides a model of PIN lesions associated with an altered prostate microvasculature and reactive stromal compartment corresponding to that reported in human prostate tumors.
Highlights
The prostate gland is tightly regulated by androgens and consists of acini lined by secretory luminal cells and an underlying layer of basal cells embedded within a fibromuscular stroma
EAF22/2 mice were generated on a pure C57BL/6J or a pure FVB/NJ background in order to determine the potential effects of different genetic backgrounds on the prostate phenotype
Another difference was in the incidence of prostate stromal abnormalities in aged C57BL/6J and FVB/NJ EAF22/2 animals associated with prostatic intraepithelial neoplasia (PIN) lesions that were characteristic of a reactive stroma (Fig. 1B)
Summary
The prostate gland is tightly regulated by androgens and consists of acini lined by secretory luminal cells and an underlying layer of basal cells embedded within a fibromuscular stroma. The stromal cells immediately adjacent to prostate tumor cells are characterized by a modified extracellular matrix, increased microvessel density and a myofibroblastic phenotype [2]. The evolution of this reactive stroma and its role in prostate disease development is not yet fully understood, evidence of altered stroma has been identified in precancerous prostatic intraepithelial neoplasia (PIN) lesions as well as in prostate tumors [3,4]. EAF2 loss in a murine model was found to increase microvessel density in aged animals and to enhance the angiogenic effects of Von Hippel-Lindau (VHL) heterozygosity in the liver and prostate [9]. PIN and hepatic vascular lesions in EAF22/2 VHL+/2 animals were characterized by decreased expression of pVHL, suggesting that EAF2 enhanced the angiogenic effects of VHL heterozygosity [9]
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