Abstract
Although TGF-β is widely known to appear to function paradoxically as a tumor suppressor in normal cells, and as a tumor promoter in cancer cells, the underlying mechanisms by which a single cytokine plays such a dual—and diametrically opposed—role are unknown. In particular, it remains a mystery why the level of TGF-β is unusually high in the primary cancer tissue and blood samples of cancer patients with the poorest prognosis, given that this cytokine is primarily a tumor suppressor. To provide a quantitative explanation of these paradoxical observations, we have developed, 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 the cell population is regulated, enabling us to propose a plausible explanation for the paradox: with the tumor 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 characteristics (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 tumor suppressor.
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Chung, SW., Cooper, C.R., Farach-Carson, M.C., Ogunnaike, B.A. (2010). A Control Engineering Model for Resolving the TGF-β Paradox in Cancer. In: Lévine, J., Müllhaupt, P. (eds) Advances in the Theory of Control, Signals and Systems with Physical Modeling. Lecture Notes in Control and Information Sciences, vol 407. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-16135-3_21
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DOI: https://doi.org/10.1007/978-3-642-16135-3_21
Publisher Name: Springer, Berlin, Heidelberg
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