PTEN expression and function in adult cancer stem cells and prospects for therapeutic targeting
PTEN expression and function in adult cancer stem cells and prospects for therapeutic targeting
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DOI：
10.1016/j.jbior.2014.07.002
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发表时间：
2014-01-01
影响因子：
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通讯作者：
Milella, Michele
中科院分区：
文献类型：
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作者：
Ciuffreda, Ludovica;Falcone, Italia;Milella, Michele
10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）是一种非冗余的脂质磷酸酶，它对磷脂酰肌醇 - 3 - 激酶（PI3K）信号通路起抑制和精细调节作用。PTEN与遗传性综合征有关，这些综合征易引发不同类型的癌症，并且是散发性癌症中最常失活的肿瘤抑制基因之一。实际上，PTEN功能丧失在多种人类癌症中通过多种机制发生，包括突变、缺失、转录沉默或蛋白质不稳定。PTEN通过多种机制防止肿瘤发生，并调节众多细胞过程，包括存活、增殖、能量代谢和细胞结构。此外，近期研究表明，PTEN能够离开细胞、在细胞外存在并发挥作用，以旁分泌方式抑制邻近细胞中的PI3K通路。最近，研究还表明PTEN对干细胞的维持也至关重要，PTEN缺失可导致癌症干细胞（CSC）克隆的出现和增殖。根据起源的细胞和组织环境，PTEN缺失可能导致自我更新能力增强或正常干细胞耗竭，并且在肿瘤形成之前，已在前列腺、肺、肠道和胰腺组织中报道了PTEN缺陷的干细胞和祖细胞；此外，在多种实体和血液恶性肿瘤的癌症干细胞中经常观察到可逆或不可逆的PTEN缺失，这可能有助于癌症干细胞的功能表型。在本综述中，我们将重点关注PTEN表达和功能以及下游通路激活在癌症干细胞生物学和肿瘤发生潜能调节中的作用；还将讨论PTEN在介导PI3K和MAPK通路之间的相互作用中新兴的作用，以及针对缺乏PTEN表达的肿瘤进行治疗靶向的前景。（C）2014爱思唯尔有限公司。保留所有权利。
Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a non-redundant lipid phosphatase that restrains and fine tunes the phosphatidylinositol-3-kinase (PI3K) signaling pathway. PTEN is involved in inherited syndromes, which predispose to different types of cancers and is among the most frequently inactivated tumor suppressor genes in sporadic cancers. Indeed, loss of PTEN function occurs in a wide spectrum of human cancers through a variety of mechanisms, including mutations, deletions, transcriptional silencing, or protein instability. PTEN prevents tumorigenesis through multiple mechanisms and regulates a plethora of cellular processes, including survival, proliferation, energy metabolism and cellular architecture. Moreover, recent studies have demonstrated that PTEN is able to exit, exist, and function outside the cell, allowing for inhibition of the PI3K pathway in neighboring cells in a paracrine fashion. Most recently, studies have shown that PTEN is also critical for stem cell maintenance and that PTEN loss can lead to the emergence and proliferation of cancer stem cell (CSC) clones. Depending on the cellular and tissue context of origin, PTEN deletion may result in increased self-renewal capacity or normal stem cell exhaustion and PTEN-deficient stem and progenitor cells have been reported in prostate, lung, intestinal, and pancreatic tissues before tumor formation; moreover, reversible or irreversible PTEN loss is frequently observed in CSC from a variety of solid and hematologic malignancies, where it may contribute to the functional phenotype of CSC.In this review, we will focus on the role of PTEN expression and function and downstream pathway activation in cancer stem cell biology and regulation of the tumorigenic potential; the emerging role of PTEN in mediating the crosstalk between the PI3K and MAPK pathways will also be discussed, together with prospects for the therapeutic targeting of tumors lacking PTEN expression. (C) 2014 Elsevier Ltd. All rights reserved.