Tumor Neoangiogenesis and Flow Congestion: A Parallel to the Braess Paradox?

Abstract

Although tumor angiogenesis is considered as a critical parameter in tumor growth, antiangiogenic monotherapy lags far behind expectations. Applying a mathematical model from route planning, known as the Braess paradox, provides an explanation by showing that in some constellations, more roads can lead to more traffic jams. It is one of the most widely accepted paradigms in tumor biology that growth of solid tumors is restricted to the ample supply of nutrients. Accordingly, it is assumed that passive diffusion is sufficient for tumor growth only to a size of ≈2 mm in diameter; thus, the tumor connects to capillaries to satisfy its hunger. It was Folkman1 who first established in 1971 the concept of a tumor that actively attracts capillaries sprouting into the tumor tissue. In this model, the hypoxia-inducible factor 1, a heterodimeric transcription factor consisting of the constitutively hypoxia-inducible factor 1β and the oxygen-sensitive hypoxia-inducible factor 1α subunit, plays a key role. Under normoxic conditions, hypoxia-inducible factor 1α is proteasomally degraded, whereas hypoxia stabilized the dimer allowing transcription of a set of genes. Among those, members of the vascular endothelial growth factor (VEGF) family are of particular importance as they direct endothelial cell migration along the hypoxic gradient.2 Together with the proliferation-inducing properties of VEGF, new blood vessels are formed connecting the tumor to the blood circulation. These findings inspired the development of antiangiogenic tumor therapy as an effective tool to combat the growth of solid tumors. As a result, >60 antiangiogenic compounds of different origin have been identified and tested in patients to date.3 In particular, antibodies directed against VEGF-A (bevacizumab) and VEGF receptor 2 (ramucirumab), as well as endogenous inhibitors of angiogenesis, such as angiostatin and endostatin, are viewed as highly potential drugs to halt vessel growth.4,5 Furthermore, regimens utilizing …