Differential requirements of androgen receptor in luminal progenitors during prostate regeneration and tumor initiation.
Differential requirements of androgen receptor in luminal progenitors during prostate regeneration and tumor initiation.
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DOI：
10.7554/elife.28768
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发表时间：
2018-01-15
期刊：
影响因子：
7.7
通讯作者：
Shen MM
中科院分区：
文献类型：
--
作者：
Chua CW;Epsi NJ;Leung EY;Xuan S;Lei M;Li BI;Bergren SK;Hibshoosh H;Mitrofanova A;Shen MM
组织特化的主调节基因在干/祖细胞中起关键作用，并且通常在癌症中是重要的。在前列腺中，雄激素受体（AR）是发育和肿瘤发生所必需的主要调节因子，但其在前列腺干/祖细胞中的具体功能尚未阐明。我们研究了CARN（去势抵抗性Nkx3.1表达细胞）中的AR功能，CARN是一种在前列腺再生中发挥作用的管腔干/祖细胞。使用基因工程小鼠模型和新型前列腺上皮细胞系，我们发现CARN的祖细胞特性在很大程度上不受AR缺失的影响，除了体内增殖减少。此外，AR缺失抑制了CARN中Pten肿瘤抑制因子缺失后的肿瘤形成;然而，在AR缺失的CARN中，Pten缺失和致癌Kras的激活组合导致具有局灶性神经内分泌分化的肿瘤。我们的研究结果表明，AR调节CARN的特定祖细胞特性，包括它们作为前列腺癌起源细胞的能力。大多数前列腺肿瘤依赖于雄性激素-称为雄激素-生存。侵袭性前列腺癌通常用阻断雄激素的药物治疗，这通常会导致前列腺肿瘤缩小。其中一类药物通过与前列腺癌细胞上的雄激素受体蛋白结合并使其失活而起作用。然而，侵袭性前列腺肿瘤通常会对这些抗雄激素治疗产生耐药性。目前尚不清楚耐药的癌细胞来自哪里。2009年，研究人员发现，正常前列腺含有一些似乎不依赖于雄激素的细胞。这些细胞的一个子集-也称为CARN-可以作为干细胞或祖细胞，可以在损伤后修复前列腺。这些正常的雄激素非依赖性细胞也可能是前列腺肿瘤产生的细胞。在这里，Chua等人-包括2009年研究的一名研究人员-研究了当雄激素受体被删除时这些卡恩细胞的行为。当雄激素受体在其他健康小鼠的卡恩细胞中被遗传去除时，卡恩细胞的行为不受影响。当雄激素受体与一种通常抑制肿瘤形成的蛋白质一起被删除时，它保护了小鼠免受前列腺癌的侵害。然而，Chua等人也观察到，当存在两个致癌突变时，删除雄激素受体不能阻止肿瘤生长。这些肿瘤与抗雄激素治疗耐药的人前列腺肿瘤相似。由于卡恩细胞也可能存在于人类中，这种在小鼠中制造前列腺癌的新方法可能被用来研究这些耐药性如何在患者中产生。更好地了解前列腺肿瘤如何发展可能会导致新的治疗方法，其中雄激素受体与其他新的蛋白质靶点结合被阻断。
Master regulatory genes of tissue specification play key roles in stem/progenitor cells and are often important in cancer. In the prostate, androgen receptor (AR) is a master regulator essential for development and tumorigenesis, but its specific functions in prostate stem/progenitor cells have not been elucidated. We have investigated AR function in CARNs (CAstration-Resistant Nkx3.1-expressing cells), a luminal stem/progenitor cell that functions in prostate regeneration. Using genetically--engineered mouse models and novel prostate epithelial cell lines, we find that progenitor properties of CARNs are largely unaffected by AR deletion, apart from decreased proliferation in vivo. Furthermore, AR loss suppresses tumor formation after deletion of the Pten tumor suppressor in CARNs; however, combined Pten deletion and activation of oncogenic Kras in AR-deleted CARNs result in tumors with focal neuroendocrine differentiation. Our findings show that AR modulates specific progenitor properties of CARNs, including their ability to serve as a cell of origin for prostate cancer. Most prostate tumors rely on male hormones – called androgens – to survive. Aggressive prostate cancer is often treated with drugs that block androgens, which usually cause the prostate tumors to shrink. One class of the drugs works by binding to and inactivating the androgen receptor protein on prostate cancer cells. However, aggressive prostate tumors can often become resistant to these anti-androgen therapies. It is not clear where the resistant cancer cells come from. In 2009, researchers showed that the normal prostate contains some cells that appear to be independent of androgens. A subset of these cells – also known as CARNs – can act as stem or progenitor cells that can repair the prostate after injury. These normal androgen-independent cells can also be the cells from which prostate tumors arise. Here, Chua et al. – including one of the researchers from the 2009 study – investigated how these CARN cells behave when the androgen receptor is deleted. When the androgen receptor was genetically removed in CARN cells of otherwise healthy mice, the behavior of CARN cells was unaffected. When the androgen receptor was deleted together with a protein that normally suppresses the formation of tumors, it protected the mice from prostate cancer. However, Chua et al. also observed that deleting the androgen receptor could not prevent the tumor from growing when two cancer-causing mutations were present. These tumors were similar to human prostate tumors that are resistant to anti-androgen therapy. Since CARN cells may also exist in humans, this new way of making prostate cancers in mice may be used to study how these resistances arise in patients. A better understanding of how prostate tumors develop might lead to new treatments in which the androgen receptor is blocked in combination with other new protein targets.