Dataset Information

The Sca-1⁺ and Sca-1^- mouse prostatic luminal cell lineages are independently sustained.

ABSTRACT: The phenotypic and functional heterogeneity of the mouse prostate epithelial cell lineages remains incompletely characterized. We show that the Sca-1⁺ luminal cells at the mouse proximal prostate express Sox2. These cells are replicative quiescent, castration resistant, and do not possess secretory function. We use the Probasin-CreER^T2 and Sox2-CreER^T2 models in concert with a fluorescent reporter line to label the Sca-1^- and Sca-1⁺ luminal cells, respectively. By a lineage tracing approach, we show that the two luminal cell populations are independently sustained. Sox2 is dispensable for the maintenance of the Sca-1⁺ luminal cells but is essential for their facultative bipotent differentiation capacity. The Sca-1⁺ luminal cells share molecular features with the human TACSTD2⁺ luminal cells. This study corroborates the heterogeneity of the mouse prostate luminal cell lineage and shows that the adult mouse prostate luminal cell lineage is maintained by distinct cellular entities rather than a single progenitor population.

SUBMITTER: Kwon OJ

PROVIDER: S-EPMC7606766 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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The Sca-1+ and Sca-1- mouse prostatic luminal cell lineages are independently sustained.

Kwon Oh-Joon OJ Choi Jong Min JM Zhang Li L Jia Deyong D Li Zhouyihan Z Zhang Yiqun Y Jung Sung Yun SY Creighton Chad J CJ Xin Li L

Stem cells (Dayton, Ohio) 20200808 11

The phenotypic and functional heterogeneity of the mouse prostate epithelial cell lineages remains incompletely characterized. We show that the Sca-1+ luminal cells at the mouse proximal prostate express Sox2. These cells are replicative quiescent, castration resistant, and do not possess secretory function. We use the Probasin-CreERT2 and Sox2-CreERT2 models in concert with a fluorescent reporter line to label the Sca-1- and Sca-1+ luminal ...[more]

PMID: 32627901

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Project description:Lo-MYC and Hi-MYC mice develop prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma as a result of MYC overexpression in the mouse prostate. However, prior studies have not determined precisely when, and in which cell types, MYC is induced. Using immunohistochemistry (IHC) to localize MYC expression in Lo-MYC transgenic mice, we show that morphological and molecular alterations characteristic of high grade PIN arise in luminal epithelial cells as soon as MYC overexpression is detected. These changes include increased nuclear and nucleolar size and large scale chromatin remodeling. Mouse PIN cells retained a columnar architecture and abundant cytoplasm and appeared as either a single layer of neoplastic cells or as pseudo-stratified/multilayered structures with open glandular lumina-features highly analogous to human high grade PIN. Also using IHC, we show that the onset of MYC overexpression and PIN development coincided precisely with decreased expression of the homeodomain transcription factor and tumor suppressor, Nkx3.1. Virtually all normal appearing prostate luminal cells expressed high levels of Nkx3.1, but all cells expressing MYC in PIN lesions showed marked reductions in Nkx3.1, implicating MYC as a key factor that represses Nkx3.1 in PIN lesions. To determine the effects of less pronounced overexpression of MYC we generated a new line of mice expressing MYC in the prostate under the transcriptional control of the mouse Nkx3.1 control region. These "Super-Lo-MYC" mice also developed PIN, albeit a less aggressive form. We also identified a histologically defined intermediate step in the progression of mouse PIN into invasive adenocarcinoma. These lesions are characterized by a loss of cell polarity, multi-layering, and cribriform formation, and by a "paradoxical" increase in Nkx3.1 protein. Similar histopathological changes occurred in Hi-MYC mice, albeit with accelerated kinetics. Our results using IHC provide novel insights that support the contention that MYC overexpression is sufficient to transform prostate luminal epithelial cells into PIN cells in vivo. We also identified a novel histopathologically identifiable intermediate step prior to invasion that should facilitate studies of molecular pathway alterations occurring during early progression of prostatic adenocarcinomas.

Dataset Information

The Sca-1⁺ and Sca-1^- mouse prostatic luminal cell lineages are independently sustained.

Publications

The Sca-1<sup>+</sup> and Sca-1<sup>-</sup> mouse prostatic luminal cell lineages are independently sustained.

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