A control engineering approach to understanding the TGF-β paradox in cancer
A control engineering approach to understanding the TGF-β paradox in cancer
复制标题
DOI：
10.1098/rsif.2011.0799
复制
发表时间：
2012-06-07
影响因子：
3.9
通讯作者：
Ogunnaike, Babatunde A.
中科院分区：
文献类型：
--
作者：
Chung, Seung-Wook;Cooper, Carlton R.;Ogunnaike, Babatunde A.
TGF-β是调节多种细胞过程（包括增殖和凋亡）的关键细胞因子，它在正常细胞中作为肿瘤抑制因子，在癌细胞中作为肿瘤促进剂，似乎具有矛盾的功能，但这种矛盾作用背后的机制仍然未知。特别是，鉴于这种细胞因子主要是一种肿瘤抑制因子，在预后最差的癌症患者的原发癌组织和血液样本中观察到的异常高水平的TGF-β这一难题仍未解决。为了对这些矛盾的观察结果提供定量解释，我们从控制理论的角度提出了 TGF-β 驱动的细胞稳态调节的机制模型。对整个系统模型的分析可以定量地了解细胞群的调节方式，使我们能够对这个悖论提出一个合理的解释：TGF-β的肿瘤抑制作用从正常细胞到癌细胞没有变化，我们证明观察到的TGF-β水平增加是癌细胞表型进展（特别是获得性TGF-β抗性）的结果，而不是原因。因此，我们能够准确地解释为什么临床观察到的 TGF-β 水平升高与不良预后之间的相关性实际上与 TGF-β 最初（且未改变）作为肿瘤抑制因子的作用一致。
TGF-beta, a key cytokine that regulates diverse cellular processes, including proliferation and apoptosis, appears to function paradoxically as a tumour suppressor in normal cells, and as a tumour promoter in cancer cells, but the mechanisms underlying such contradictory roles remain unknown. In particular, given that this cytokine is primarily a tumour suppressor, the conundrum of the unusually high level of TGF-beta observed in the primary cancer tissue and blood samples of cancer patients with the worst prognosis, remains unresolved. To provide a quantitative explanation of these paradoxical observations, we present, from a control theory perspective, a mechanistic model of TGF-beta-driven regulation of cell homeostasis. Analysis of the overall system model yields quantitative insight into how cell population is regulated, enabling us to propose a plausible explanation for the paradox: with the tumour suppressor role of TGF-beta unchanged from normal to cancer cells, we demonstrate that the observed increased level of TGF-beta is an effect of cancer cell phenotypic progression (specifically, acquired TGF-beta resistance), not the cause. We are thus able to explain precisely why the clinically observed correlation between elevated TGF-beta levels and poor prognosis is in fact consistent with TGF-beta's original (and unchanged) role as a tumour suppressor.