Host age is a systemic regulator of gene expression impacting cancer progression.
Host age is a systemic regulator of gene expression impacting cancer progression.
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DOI：
10.1158/0008-5472.can-14-1053
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发表时间：
2015-03-15
期刊：
影响因子：
11.2
通讯作者：
Hlatky L
中科院分区：
文献类型：
--
作者：
Beheshti A;Benzekry S;McDonald JT;Ma L;Peluso M;Hahnfeldt P;Hlatky L
年龄是癌症发病率的主要决定因素，反过来，这很可能在很大程度上是由影响早期亚临床(隐匿性)癌症进展的过程决定的。然而，人们对衰老如何影响有利于癌症进展的总宿主信号的变化知之甚少。在这项研究中，我们提供了直接证据，表明衰老可以作为定义癌症进展调控过程的组织轴。作为探索这一概念的模型系统，我们使用青春期(68天)、青壮年(143天)、中年(551天)和老年(736天)C57BL/6小鼠作为Lewis肺癌移植瘤的同基因宿主，以确定信号和功能过程随宿主年龄的变化。老年宿主表现出血管生成、新陈代谢和细胞凋亡失调，所有这些都与癌症进展有关。转化生长因子β1是这些系统过程中的核心角色，在老年宿主中持续下调。我们的发现直接支持了在确定宿主肿瘤控制动态时对宿主年龄的强烈依赖性的结论。此外，我们的结果为衰老如何调节肿瘤进展提供了初步的基于机制的见解，这些方式可能对治疗或预防具有可操作性。
Aging is the major determinant of cancer incidence, which, in turn, is likely dictated in large part by processes that influence the progression of early subclinical (occult) cancers. However, there is little understanding of how aging informs changes in aggregate host signaling that favor cancer progression. In this study, we provide direct evidence that aging can serve as an organizing axis to define cancer progression-modulating processes. As a model system to explore this concept, we employed adolescent (68 days), young adult (143 days), middle-aged (551 days), and old (736 days) C57BL/6 mice as syngeneic hosts for engraftment of Lewis lung cancer to identify signaling and functional processes varying with host age. Older hosts exhibited dysregulated angiogenesis, metabolism, and apoptosis, all of which are associated with cancer progression. TGFβ1, a central player in these systemic processes, was downregulated consistently in older hosts. Our findings directly supported the conclusion of a strong host age dependence in determining the host tumor control dynamic. Furthermore, our results offer initial mechanism-based insights into how aging modulates tumor progression in ways that may be actionable for therapy or prevention.