Computational Approaches to Resolving the TGF-β Paradox in Cancer

Friday, October 15, 2010 - 12:45pm
Babatunde A. Ogunnaike, Ph.D.

Department of Chemical Engineering
University of Delaware

Computational Approaches to Resolving the TGF-β Paradox in Cancer

Abstract: 
Transforming growth factor β (TGF-β) signaling regulates a wide range of cellular and physiologic processes including proliferation, apoptosis, differentiation, migration, angiogenesis, and immune surveillance. During the early stages of epithelial tumorigenesis, TGF-β functions as a potent tumor suppressor primarily by inhibiting cell proliferation and by inducing apoptosis. However, the level of this cytokine, TGF-β, is frequently elevated in malignant tissues and blood from cancer patients with poor prognosis. Accordingly, in the late phases of tumor progression, the role of TGF-β appears to become one of tumor promotion, apparently supporting growth, subverting the immune system, and also facilitating epithelial to mesenchymal transition (EMT), invasion and angiogenesis. 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 a single stimulus produce multiple contradictory results? This long-standing enigma of TGF-β biology remains poorly understood because the role of TGF- β on cancer is too complex for qualitative description. In this presentation, we will discuss the development, validation and analysis of microscopic (Smad-mediated pathway) and macroscopic (control theory perspective of TGF-β regulation of prostate cell population) mathematical models that allow us to predict possible dynamic characteristics of healthy and abnormal cells, and provide physiologically sound explanations of the paradoxical clinical observation that unusually high levels of TGF-β correlate with poor prognosis in prostate cancer.