Department of Chemical Engineering, University of Delaware, Newark, DE 19716, USA.
J R Soc Interface. 2012 Jun 7;9(71):1389-97. doi: 10.1098/rsif.2011.0799. Epub 2011 Dec 21.
TGF-β, 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-β 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-β-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-β unchanged from normal to cancer cells, we demonstrate that the observed increased level of TGF-β is an effect of cancer cell phenotypic progression (specifically, acquired TGF-β resistance), not the cause. We are thus able to explain precisely why the clinically observed correlation between elevated TGF-β levels and poor prognosis is in fact consistent with TGF-β's original (and unchanged) role as a tumour suppressor.
TGF-β 是一种关键的细胞因子，调节多种细胞过程，包括增殖和凋亡。它在正常细胞中似乎作为肿瘤抑制因子发挥作用，而在癌细胞中则作为肿瘤促进因子发挥作用，但这种矛盾作用的机制尚不清楚。特别是，鉴于这种细胞因子主要是肿瘤抑制因子，在预后最差的癌症患者的原发性癌症组织和血液样本中观察到 TGF-β 水平异常高的难题仍然没有解决。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一个 TGF-β 驱动的细胞稳态调节的机制模型。对整体系统模型的分析提供了对细胞群体如何受到调节的定量见解，使我们能够对矛盾提出合理的解释：TGF-β 的肿瘤抑制作用从正常细胞到癌细胞没有改变，我们证明观察到的 TGF-β 水平升高是癌细胞表型进展（具体来说，获得性 TGF-β 抵抗）的结果，而不是原因。因此，我们能够准确地解释为什么临床上观察到的 TGF-β 水平升高与预后不良之间的相关性实际上与 TGF-β 作为肿瘤抑制因子的原始（且未改变）作用一致。
