Systems Biology of Tumor Dormancy

Khalid Boushaba PhD, Yangjin Kim, Khalid Boushaba, Kim, Yangjin, Boushaba, Khalid

Herein, a mathematical model of a molecular control system for the regulation of secondary tumors is formulated and analyzed to explore how secondary tumors can be controlled by a primary tumor with/without a surgery and the microenvironment. This control system is composed of fibroblast growth factor-2 (FGF2), urokinase-type plasminogen activator (uPA), plasmin, transforming growth factor-beta (TGFβ), latent TGFβ (LTGFβ), and tumor density. The control of secondary tumors by primary tumors was first modeled by Boushaba, Nilsen-Hamiton and Levine in [46]. The model is based on the idea that the vascularization of a secondary tumor can be suppressed by inhibitors from a larger primary tumor. The emergence of tumors at secondary sites 5-7 cm from a primary site was observed after surgical removal of the primary tumor in silico. The model supports the notion that the fate of secondary tumors after surgery depends on the distance from the primary tumor and the surrounding microenvironment. As such, the primary tumor did not influence the growth of remote secondary tumors, but it could effectively suppress the growth of the secondary tumors if they were too close to the primary tumor, even after it was removed. Thus, the model predicts the emergence of secondary tumors after the excision of the primary tumor when the distance between these tumors is in the "distance window." It also predicts that the growth behaviors of the secondary tumors depend on the local microenvironment. Based on these findings, we propose several treatment options for better clinical outcomes.