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Development of a reactive stroma associated with prostatic intraepithelial neoplasia in EAF2 deficient mice
Laura E Pascal1, Junkui Ai, Khalid Z Masoodi
1Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
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.
Insights
Loss of ELL-associated factor 2 (EAF2) in mice causes prostate lesions with reactive stroma and increased blood vessels, mirroring human prostate cancer. EAF2 deficiency impacts androgen deprivation response and is linked to tumor progression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- ELL-associated factor 2 (EAF2) is an androgen-responsive tumor suppressor crucial for RNA Pol II transcription elongation.
- EAF2 deletions are common in advanced prostate cancer.
- Previous studies showed EAF2 knockout mice develop various cancers, including prostatic intraepithelial neoplasia (PIN).
Purpose of the Study:
- To investigate the role of EAF2 in prostate defect development across different mouse genetic backgrounds.
- To characterize the stromal and microvascular changes associated with EAF2 loss in the prostate.
- To compare EAF2's role in mouse models with its expression and microvessel density in human prostate cancer.
Main Methods:
- Comparison of EAF2 knockout (EAF2(-/-)) mice on C57BL/6J, FVB/NJ, and 129P2/OLA-C57BL/6J backgrounds.
- Histological analysis of prostate tissues to identify lesions, stromal defects, and microvessel density.
- Assessment of EAF2-deficient mice's response to androgen deprivation.
- Analysis of EAF2 expression and microvessel density in human prostate cancer tissues.
Main Results:
- Aged EAF2(-/-) mice on C57BL/6J and FVB/NJ backgrounds developed mPIN lesions, similar to those on a mixed background.
- Prostatic lesions in C57BL/6J and FVB/NJ EAF2(-/-) mice showed reactive stromal defects and significantly increased prostate microvessel density.
- Stromal inflammation and increased microvessel density preceded epithelial hyperplasia and neoplasia in EAF2-deficient mice.
- EAF2 deficiency led to increased recovery and decreased response to androgen deprivation.
- Human prostate cancer tissues exhibited down-regulated EAF2 expression and increased microvessel density compared to normal tissues, with a negative correlation between EAF2 expression and microvessel density.
Conclusions:
- EAF2 knockout mice on C57BL/6J and FVB/NJ backgrounds serve as a valuable model for studying PIN lesions associated with altered prostate microvasculature and reactive stroma.
- These findings highlight EAF2's role in maintaining prostate homeostasis and its potential as a therapeutic target in prostate cancer.
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