(664e) A Control Engineering Approach to Understanding the Paradoxical Roles of TGF-β in Cancer

Transforming growth factor β (TGF-β) signaling plays a critical role in maintaining tissue homeostasis by regulating a multitude of cellular and physiologic processes. The best-known function of TGF-β is to inhibit cell proliferation via cytostatic program and to induce programmed cell death in normal or pre-malignant epithelia. However, the elevated level of TGF-β is frequently detected in malignant tissues and blood samples from cancer patients with poor prognosis. Accordingly, in the late stages of tumor progression, the role of TGF-β appears to become one of tumor promotion, apparently supporting growth, avoiding immune surveillance, and facilitating the metastatic process. This has created the widely held perception that TGF-β is simultaneously a tumor suppressor under one condition and a tumor promoter under another. But how does such a single stimulus produce multiple contradictory results? This long-standing paradox of TGF-β biology remains unidentified because the role of TGF-β on cancer is too complex for qualitative description.

For a quantitative explanation of the paradoxical clinical correlation between the elevated TGF-β levels and poor prognosis, we have developed a macroscopic mechanistic model of TGF-β driven regulation of cell proliferation and death from a control theory perspective. By identifying the components of the TGF-β-mediated control system and by describing how those components are connected, the model yields quantitative insight into how cell population is regulated through communication between the cells and their surroundings. The model also allows us to predict possible dynamic behavior of the TGF-β-mediated control system in cancer tissues. Simulations of cancerous system dynamics indicate that as pre-malignant cells lose their responsiveness to TGF-β along the spectrum of tumor progression, a still-intact control system must secrete more of this ligand in a futile attempt to achieve the level of tumor suppression attainable with normal, responsive cells. In other words, the observed increased level of TGF-β is a consequence of the acquired TGF-β resistance exhibited by the cancer cells, not the cause (by switching the TGF-β roles from tumor suppressor to tumor promoter). Thus, we suggest that the correlation between increased levels of TGF-β and poor prognosis has been inadvertently misconstrued as causality, creating the apparent paradox. We also propose that the current approach of targeting TGF-β ligand therapeutically may have to be modified in favor of re-sensitizing the cells to the tumor suppressive effect of TGF-β.