Local imbalance of proangiogenic and antiangiogenic factors: A potential mechanism of focal necrosis and dormancy in tumors

Solid tumors produce both stimulators and inhibitors of angiogenesis, The s uppression of metastases by some primary tumors has been attributed to the longer circulatory half-lives of the inhibitors. We propose that intrinsic differences in the physicochemical properties of these regulators may also explain focal suppression of angiogenesis within the primary tumor. We pres ent a mathematical framework that describes production, diffusion, and degr adation of these factors in tumor and host tissue and their effect on angio genesis at Local and distal sites. Results show focal suppression of angiog enesis, provide an explanation for tumor dormancy and focal necrosis, and p redict a suppressive influence of primary tumors on angiogenesis at metasta tic sites. They suggest generally that diffusible factors produced by tumor s can stimulate responses in adjacent host tissue, preparing it for further tumor invasion. This study presents a new paradigm for the development of tumor necrosis and offers new insight into angiogenesis regulation and ther apy, The framework established for modeling the competing effects of diffus ible stimulators and inhibitors can be applied more generally to growth fac tors/inhibitors and other opposing factors produced in the tumor environmen t.