Angiogenesis regulators as a possible key to accelerated growth of secondary tumors following primary tumor resection

Resection of primary tumors is often followed by accelerated growth of metastases. Here we propose that this effect may be due to the fact that resection of primary tumor results in a decrease in the total systemic amount of angiogenesis stimulators, such as VEGF and bFGF. This in turn causes decrease in the systemic level of angiogenesis inhibitors, such as PF-4 and TSP-1, which at least temporarily relieves inhibition of secondary tumors, allowing them to grow. This construct is predicated on the notion that systemic level of angiogenesis inhibitors is regulated by the systemic level of angiogenesis stimulators, as the host is trying to maintain the homeostatic balance of stimulators to inhibitors in the body. We evaluate this hypothesis using a conceptual mathematical model and show that indeed, this mechanism can explain accelerated growth of secondary tumors following resection of a primary tumor. We also show that there exists a tradeoff between time of surgery and time to onset of metastatic growth. We conclude with a discussion of possible therapeutic approaches that may counteract this effect and reduce metastatic recurrences after surgery.