Development of a reactive stroma associated with prostatic intraepithelial neoplasia in EAF2 deficient mice

Laura E. Pascal; Junkui Ai; Khalid Z. Masoodi; Yujuan Wang; Dan Wang; Kurtis Eisermann; Lora H. Rigatti; Katherine J. O'Malley; Hei M. Ma; Xinhui Wang; Javid A. Dar; Anil V. Parwani; Brian W. Simons; Michael M. Ittman; Luyuan Li; Benjamin J. Davies; Zhou Wang

doi:10.1371/journal.pone.0079542

Development of a reactive stroma associated with prostatic intraepithelial neoplasia in EAF2 deficient mice

Laura E. Pascal, Junkui Ai, Khalid Z. Masoodi, Yujuan Wang, Dan Wang, Kurtis Eisermann, Lora H. Rigatti, Katherine J. O'Malley, Hei M. Ma, Xinhui Wang, Javid A. Dar, Anil V. Parwani, Brian W. Simons, Michael M. Ittman, Luyuan Li, Benjamin J. Davies, Zhou Wang

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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.

Original language	English (US)
Article number	e79542
Journal	PloS one
Volume	8
Issue number	11
DOIs	https://doi.org/10.1371/journal.pone.0079542
State	Published - Nov 18 2013
Externally published	Yes

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Pascal, L. E., Ai, J., Masoodi, K. Z., Wang, Y., Wang, D., Eisermann, K., Rigatti, L. H., O'Malley, K. J., Ma, H. M., Wang, X., Dar, J. A., Parwani, A. V., Simons, B. W., Ittman, M. M., Li, L., Davies, B. J., & Wang, Z. (2013). Development of a reactive stroma associated with prostatic intraepithelial neoplasia in EAF2 deficient mice. PloS one, 8(11), Article e79542. https://doi.org/10.1371/journal.pone.0079542

Pascal, LE, Ai, J, Masoodi, KZ, Wang, Y, Wang, D, Eisermann, K, Rigatti, LH, O'Malley, KJ, Ma, HM, Wang, X, Dar, JA, Parwani, AV, Simons, BW, Ittman, MM, Li, L, Davies, BJ & Wang, Z 2013, 'Development of a reactive stroma associated with prostatic intraepithelial neoplasia in EAF2 deficient mice', PloS one, vol. 8, no. 11, e79542. https://doi.org/10.1371/journal.pone.0079542

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title = "Development of a reactive stroma associated with prostatic intraepithelial neoplasia in EAF2 deficient mice",

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.",

author = "Pascal, {Laura E.} and Junkui Ai and Masoodi, {Khalid Z.} and Yujuan Wang and Dan Wang and Kurtis Eisermann and Rigatti, {Lora H.} and O'Malley, {Katherine J.} and Ma, {Hei M.} and Xinhui Wang and Dar, {Javid A.} and Parwani, {Anil V.} and Simons, {Brian W.} and Ittman, {Michael M.} and Luyuan Li and Davies, {Benjamin J.} and Zhou Wang",

year = "2013",

month = nov,

day = "18",

doi = "10.1371/journal.pone.0079542",

language = "English (US)",

volume = "8",

journal = "PloS one",

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T1 - Development of a reactive stroma associated with prostatic intraepithelial neoplasia in EAF2 deficient mice

AU - Pascal, Laura E.

AU - Ai, Junkui

AU - Masoodi, Khalid Z.

AU - Wang, Yujuan

AU - Wang, Dan

AU - Eisermann, Kurtis

AU - Rigatti, Lora H.

AU - O'Malley, Katherine J.

AU - Ma, Hei M.

AU - Wang, Xinhui

AU - Dar, Javid A.

AU - Parwani, Anil V.

AU - Simons, Brian W.

AU - Ittman, Michael M.

AU - Li, Luyuan

AU - Davies, Benjamin J.

AU - Wang, Zhou

PY - 2013/11/18

Y1 - 2013/11/18

N2 - 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.

AB - 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.

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Development of a reactive stroma associated with prostatic intraepithelial neoplasia in EAF2 deficient mice

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