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Androgen signaling is essential for development of prostate cancer initiated from prostatic basal cells.

ABSTRACT: Emerging evidence has shown that both prostatic basal and luminal cells are able to initiate oncogenic transformation. However, despite the diversity of tumor-initiating cells, most prostate cancer cells express the androgen receptor (AR) and depend on androgens for their growth and expansion, implicating an essential role of androgen signaling in prostate tumorigenesis. Prostatic basal cells express p63 and are able to differentiate into luminal, neuroendocrine, and basal cells. Here, we directly assessed the essential role of androgen signaling in prostatic p63-expressing cell initiated oncogenic transformation and tumor formation. Using novel and relevant mouse models, we demonstrated that, with stabilized ?-catenin expression, prostatic p63-expressing cells possess the ability to initiate oncogenic transformation and, in the presence of androgens, they further transdifferentiate into luminal-like tumor cells and develop adenocarcinomas. Castration prior to activating stabilized ?-catenin sensitizes p63-expressing cells and increases their sensitivity to androgens, resulting in aggressive and fast growing tumor phenotypes. These findings are consistent with what have been observed in human prostate cancers, demonstrating an essential role for androgen signaling in prostate cancer initiation and progression. This study also provides fresh insight into developing new therapeutic strategies for better treating prostate cancer patients.

SUBMITTER: He Y

PROVIDER: S-EPMC6440846 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Androgen signaling is essential for development of prostate cancer initiated from prostatic basal cells.

He Yongfeng Y Hooker Erika E Yu Eun-Jeong EJ Cunha Gerald R GR Liao Lan L Xu Jianming J Earl Andrew A Wu Huiqing H Gonzalgo Michael L ML Sun Zijie Z

Oncogene 20181203 13

Emerging evidence has shown that both prostatic basal and luminal cells are able to initiate oncogenic transformation. However, despite the diversity of tumor-initiating cells, most prostate cancer cells express the androgen receptor (AR) and depend on androgens for their growth and expansion, implicating an essential role of androgen signaling in prostate tumorigenesis. Prostatic basal cells express p63 and are able to differentiate into luminal, neuroendocrine, and basal cells. Here, we direct ...[more]

PMID: 30510232

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Project description:Objective and Impact Statement. Identifying benign mimics of prostatic adenocarcinoma remains a significant diagnostic challenge. In this work, we developed an approach based on label-free, high-resolution molecular imaging with multispectral deep ultraviolet (UV) microscopy which identifies important prostate tissue components, including basal cells. This work has significant implications towards improving the pathologic assessment and diagnosis of prostate cancer. Introduction. One of the most important indicators of prostate cancer is the absence of basal cells in glands and ducts. However, identifying basal cells using hematoxylin and eosin (H&E) stains, which is the standard of care, can be difficult in a subset of cases. In such situations, pathologists often resort to immunohistochemical (IHC) stains for a definitive diagnosis. However, IHC is expensive and time-consuming and requires more tissue sections which may not be available. In addition, IHC is subject to false-negative or false-positive stains which can potentially lead to an incorrect diagnosis. Methods. We leverage the rich molecular information of label-free multispectral deep UV microscopy to uniquely identify basal cells, luminal cells, and inflammatory cells. The method applies an unsupervised geometrical representation of principal component analysis to separate the various components of prostate tissue leading to multiple image representations of the molecular information. Results. Our results show that this method accurately and efficiently identifies benign and malignant glands with high fidelity, free of any staining procedures, based on the presence or absence of basal cells. We further use the molecular information to directly generate a high-resolution virtual IHC stain that clearly identifies basal cells, even in cases where IHC stains fail. Conclusion. Our simple, low-cost, and label-free deep UV method has the potential to improve and facilitate prostate cancer diagnosis by enabling robust identification of basal cells and other important prostate tissue components.

Project description:BackgroundCastration resistant prostate cancer (CRPC) develops as a consequence of hormone therapies used to deplete androgens in advanced prostate cancer patients. CRPC cells are able to grow in a low androgen environment and this is associated with anomalous activity of their endogenous androgen receptor (AR) despite the low systemic androgen levels in the patients. Therefore, the reactivated tumor cell androgen signaling pathway is thought to provide a target for control of CRPC. Previously, we reported that Hedgehog (Hh) signaling was conditionally activated by androgen deprivation in androgen sensitive prostate cancer cells and here we studied the potential for cross-talk between Hh and androgen signaling activities in androgen deprived and androgen independent (AI) prostate cancer cells.ResultsTreatment of a variety of androgen-deprived or AI prostate cancer cells with the Hh inhibitor, cyclopamine, resulted in dose-dependent modulation of the expression of genes that are regulated by androgen. The effect of cyclopamine on endogenous androgen-regulated gene expression in androgen deprived and AI prostate cancer cells was consistent with the suppressive effects of cyclopamine on the expression of a reporter gene (luciferase) from two different androgen-dependent promoters. Similarly, reduction of smoothened (Smo) expression with siRNA co-suppressed expression of androgen-inducible KLK2 and KLK3 in androgen deprived cells without affecting the expression of androgen receptor (AR) mRNA or protein. Cyclopamine also prevented the outgrowth of AI cells from androgen growth-dependent parental LNCaP cells and suppressed the growth of an overt AI-LNCaP variant whereas supplemental androgen (R1881) restored growth to the AI cells in the presence of cyclopamine. Conversely, overexpression of Gli1 or Gli2 in LNCaP cells enhanced AR-specific gene expression in the absence of androgen. Overexpressed Gli1/Gli2 also enabled parental LNCaP cells to grow in androgen depleted medium. AR protein co-immunoprecipitates with Gli2 protein from transfected 293T cell lysates.ConclusionsCollectively, our results indicate that Hh/Gli signaling supports androgen signaling and AI growth in prostate cancer cells in a low androgen environment. The finding that Gli2 co-immunoprecipitates with AR protein suggests that an interaction between these proteins might be the basis for Hedgehog/Gli support of androgen signaling under this condition.

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Androgen signaling is essential for development of prostate cancer initiated from prostatic basal cells.

Publications

Androgen signaling is essential for development of prostate cancer initiated from prostatic basal cells.

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