MYC Activation Is a Hallmark of Cancer Initiation and Maintenance
MYC Activation Is a Hallmark of Cancer Initiation and Maintenance
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DOI：
10.1101/cshperspect.a014241
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发表时间：
2014-06-01
影响因子：
5.4
通讯作者：
Felsher, Dean W.
中科院分区：
文献类型：
--
作者：
Gabay, Meital;Li, Yulin;Felsher, Dean W.
MYC原癌基因与大多数人类肿瘤的发病机制有关。在许多正常细胞中，MYC单独激活通过多种遗传和表观遗传控制的检查点机制（包括增殖抑制、细胞凋亡和细胞衰老）抑制肿瘤发生。当在允许的表观遗传和/或遗传背景下病理激活时，MYC绕过这些机制，强制执行许多癌症的“标志性”特征，包括与DNA复制和转录相关的无情肿瘤生长、细胞增殖和生长、蛋白质合成和改变的细胞代谢。MYC通过诱导细胞干性和阻断细胞衰老和分化来控制肿瘤细胞的命运。此外，MYC协调肿瘤微环境的变化，包括血管生成的激活和宿主免疫反应的抑制。刺激、短暂甚至部分抑制MYC回到其生理激活水平，可导致内在检查点机制的恢复，导致急性和持续的肿瘤消退，与肿瘤细胞经历增殖阻滞、分化、衰老和凋亡，以及肿瘤微环境的重塑、免疫应答的募集和血管生成的关闭有关。因此，肿瘤似乎对MYC“上瘾”，因为肿瘤细胞固有的、细胞自主的和宿主依赖的、免疫细胞依赖的机制。许多人类癌症的发展轨迹和持续性都需要持续的MYC激活。多尺度数学模型可能有助于预测肿瘤何时会对MYC上瘾。MYC是肿瘤发生起始和维持的标志性分子特征。
The MYC proto-oncogene has been implicated in the pathogenesis of most types of human tumors. MYC activation alone in many normal cells is restrained from causing tumorigenesis through multiple genetic and epigenetically controlled checkpoint mechanisms, including proliferative arrest, apoptosis, and cellular senescence. When pathologically activated in a permissive epigenetic and/or genetic context, MYC bypasses these mechanisms, enforcing many of the "hallmark" features of cancer, including relentless tumor growth associated with DNA replication and transcription, cellular proliferation and growth, protein synthesis, and altered cellular metabolism. MYC mandates tumor cell fate, by inducing stemness and blocking cellular senescence and differentiation. Additionally, MYC orchestrates changes in the tumor microenvironment, including the activation of angiogenesis and suppression of the host immune response. Provocatively, brief or even partial suppression of MYC back to its physiological levels of activation can result in the restoration of intrinsic checkpoint mechanisms, resulting in acute and sustained tumor regression, associated with tumor cells undergoing proliferative arrest, differentiation, senescence, and apoptosis, as well as remodeling of the tumor microenvironment, recruitment of an immune response, and shutdown of angiogenesis. Hence, tumors appear to be "addicted" to MYC because of both tumor cell-intrinsic, cell-autonomous and host-dependent, immune cell-dependent mechanisms. Both the trajectory and persistence of many human cancers require sustained MYC activation. Multiscale mathematical modeling may be useful to predict when tumors will be addicted to MYC. MYC is a hallmark molecular feature of both the initiation and maintenance of tumorigenesis.