A Control Engineering Model for Resolving the TGF-β Paradox in Cancer

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.