CXCL12γ 诱导人前列腺和乳腺发育。
CXCL12γ induces human prostate and mammary gland development.
机构信息
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan.
Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan.
出版信息
Prostate. 2020 Sep;80(13):1145-1156. doi: 10.1002/pros.24043. Epub 2020 Jul 13.
BACKGROUND
Epithelial stem cells (ESCs) demonstrate a capacity to maintain normal tissues homeostasis and ESCs with a deregulated behavior can contribute to cancer development. The ability to reprogram normal tissue epithelial cells into prostate or mammary stem-like cells holds great promise to help understand cell of origin and lineage plasticity in prostate and breast cancers in addition to understanding normal gland development. We previously showed that an intracellular chemokine, CXCL12γ induced cancer stem cells and neuroendocrine characteristics in both prostate and breast adenocarcinoma cell lines. However, its role in normal prostate or mammary epithelial cell fate and development remains unknown. Therefore, we sought to elucidate the functional role of CXCL12γ in the regulation of ESCs and tissue development.
METHODS
Prostate epithelial cells (PNT2) or mammary epithelial cells (MCF10A) with overexpressed CXCL12γ was characterized by quantitative real-time polymerase chain reaction, Western blots, and immunofluorescence for lineage marker expression, and fluorescence activated cell sorting analyses and sphere formation assays to examine stem cell surface phenotype and function. Xenotransplantation animal models were used to evaluate gland or acini formation in vivo.
RESULTS
Overexpression of CXCL12γ promotes the reprogramming of cells with a differentiated luminal phenotype to a nonluminal phenotype in both prostate (PNT2) and mammary (MCF10A) epithelial cells. The CXCL12γ-mediated nonluminal type cells results in an increase of epithelial stem-like phenotype including the subpopulation of EPCAM /CD49f /CD24 /CD44 cells capable of sphere formation. Critically, overexpression of CXCL12γ promotes the generation of robust gland-like structures from both prostate and mammary epithelial cells in in vivo xenograft animal models.
CONCLUSIONS
CXCL12γ supports the reprogramming of epithelial cells into nonluminal cell-derived stem cells, which facilitates gland development.
背景
上皮干细胞（ESCs）具有维持正常组织稳态的能力，而行为失调的 ESCs 可能有助于癌症的发展。将正常组织上皮细胞重编程为前列腺或乳腺干细胞样细胞的能力有望帮助我们理解前列腺癌和乳腺癌的起源细胞和谱系可塑性，同时也有助于理解正常腺体的发育。我们之前的研究表明，细胞内趋化因子 CXCL12γ 可诱导前列腺和乳腺癌腺癌细胞系中的癌症干细胞和神经内分泌特征。然而，其在正常前列腺或乳腺上皮细胞命运和发育中的作用尚不清楚。因此，我们试图阐明 CXCL12γ 在调节 ESCs 和组织发育中的功能作用。
方法
通过定量实时聚合酶链反应、Western blot 和免疫荧光分析检测过表达 CXCL12γ 的前列腺上皮细胞（PNT2）或乳腺上皮细胞（MCF10A）的谱系标记表达，并进行荧光激活细胞分选分析和球体形成实验，以研究干细胞表面表型和功能。使用异种移植动物模型评估体内腺体或小泡的形成。
结果
过表达 CXCL12γ 可促进前列腺（PNT2）和乳腺（MCF10A）上皮细胞中具有分化的腔上皮表型的细胞向非腔上皮表型重编程。CXCL12γ 介导的非腔型细胞导致上皮干细胞样表型增加，包括具有球体形成能力的 EPCAM/CD49f/CD24/CD44 细胞亚群。重要的是，过表达 CXCL12γ 可促进前列腺和乳腺上皮细胞在体内异种移植动物模型中产生强大的腺体型结构。
结论
CXCL12γ 支持上皮细胞向非腔细胞衍生的干细胞重编程，从而促进腺体发育。
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