| Transforming growth factor beta (TGF-beta) signaling regulates a wide range of cellular and physiologic processes including proliferation, cell survival, differentiation, migration, angiogenesis, and immune surveillance. During the early stages of epithelial tumorigenesis, TGF-beta functions as a potent tumor suppressor primarily by inhibiting cell proliferation and by inducing apoptosis. On the other hand, in the late phases of tumor progression when tumor cells become resistant to growth inhibition by TGF-beta, the role of TGF-beta appears to become one of tumor promotion, facilitating invasion, epithelial to mesenchymal transition (EMT), and angiogenesis. In spite of the prominent roles of the TGF-beta pathway in tumor progression and metastasis, the mechanisms of how TGF-beta induces such a diverse array of responses during cancer progression remain poorly understood. To help us understand these disparate, contradictory roles of TGF-beta in cancer progression, we have built an integrated mathematical model of TGF-beta signaling in normal epithelial cells via Smad transcription factors, the major intracellular mediators of the pathway. Our model, which incorporates both signal transduction and transmission, is used to investigate the dynamics of nuclear accumulation of the ligand-induced Smads that ultimately control expression of TGF-beta-targeted genes, and how the nuclear retention of the Smads is regulated. We predicted and analyzed possible system behavior of the TGF-beta pathway through several computational experiments under various conditions in which parameter values of some important steps were modulated based on the parameter sensitivity analysis. We found that the intensity and/or duration of TGF-beta-induced transcription may be greatly affected by the active state of ligand-activated receptor complex and its association with Smad, nuclear complex formation between Smad proteins, and the processes for Smad inactivation (i.e. proteasomal degradation and dephosphorylation of phosphorylated Smad). Moreover, through in-silico mutations, we predicted and characterized the dynamic behavior of cancerous TGF-beta signaling, and generated several testable hypotheses regarding potential mechanisms of how TGF-beta tumor-suppressive roles morph into tumor-promoting roles. We suggest that further investigations into (i) differences in expression profiles and thresholds of anti-growth and pro-oncogenic genes induced by TGF-beta, (ii) changes in the degradation mechanisms of the signaling components in the pathway during cancer progression, and (iii) an imbalance between tumor-suppressing responses by Smad4 and tumor-promoting responses by potential binding factors, may all facilitate comprehension of the paradox of TGF-beta in cancer. |
