title: A control engineering approach to understanding the TGF-β paradox in cancer.
abstract: 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.
authors.affiliation: Department of Chemical Engineering, University of Delaware, Newark, DE 19716, USA.
authors.forename: Seung-Wook
authors.initials: SW
authors.lastname: Chung
authors.forename: Carlton R
authors.initials: CR
authors.lastname: Cooper
authors.forename: Mary C
authors.initials: MC
authors.lastname: Farach-Carson
authors.forename: Babatunde A
authors.initials: BA
authors.lastname: Ogunnaike
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003198:Computer Simulation; D025461:Feedback, Physiological; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta