Gabay Meital, Li Yulin, Felsher Dean W
Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, California 94305.
Cold Spring Harb Perspect Med. 2014 Jun 2;4(6):a014241. doi: 10.1101/cshperspect.a014241.
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.
MYC原癌基因与大多数类型的人类肿瘤发病机制有关。在许多正常细胞中，单独的MYC激活会通过多种遗传和表观遗传控制的检查点机制受到抑制，从而无法引发肿瘤发生，这些机制包括增殖停滞、凋亡和细胞衰老。当在允许的表观遗传和/或遗传背景下发生病理激活时，MYC会绕过这些机制，强化癌症的许多“标志性”特征，包括与DNA复制和转录、细胞增殖和生长、蛋白质合成以及细胞代谢改变相关的持续肿瘤生长。MYC通过诱导干性并阻断细胞衰老和分化来决定肿瘤细胞的命运。此外，MYC还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。具有启发性的是，将MYC短暂甚至部分抑制至其生理激活水平可导致内在检查点机制的恢复，从而导致急性和持续的肿瘤消退，这与肿瘤细胞经历增殖停滞、分化、衰老和凋亡以及肿瘤微环境的重塑、免疫反应的募集和血管生成的关闭有关。因此，由于肿瘤细胞内在的、细胞自主的以及宿主依赖的、免疫细胞依赖的机制，肿瘤似乎对MYC“成瘾”。许多人类癌症的发展轨迹和持续存在都需要持续的MYC激活。多尺度数学建模可能有助于预测肿瘤何时会对MYC成瘾。MYC是肿瘤发生起始和维持的标志性分子特征。
