Transient alleviation of tumor hypoxia during first days of antiangiogenic therapy as a result of therapy-induced alterations in nutrient supply and tumor metabolism - Analysis by mathematical modeling.

A number of experiments on mouse tumor models, as well as certain clinical data, have demonstrated, that antiangiogenic therapy can lead to transient improvement in tumor oxygenation, that allows to increase efficiency of following radiotherapy. In the majority of works, this phenomenon has been explained by enhanced tumor perfusion due to normalization of capillaries' structure, that results in elevated oxygen inflow in tumor. However, changes in tumor perfusion often haven't been directly measured in relevant works, moreover, antiangiogenic therapy has been proven to have ambiguous effect on tumor perfusion both in mouse tumor models and in clinics. Herein, we suggest that elevation of blood perfusion may be not the only reason for transient alleviation of tumor hypoxia, and that it may manifest itself even under unchanged tumor blood flow. We propose that it may be as well caused by the decrease in tumor oxygen consumption rate (OCR) due to the reduction of tumor proliferation level, caused by nutrient shortage in result of antiangiogenic treatment. We provide detailed explanation of this hypothesis and visualize it using a specially developed mathematical model, which takes into account basic features of tumor growth and antiangiogenic therapy. We investigate the influence of the model parameters on oxygen dynamics; demonstrate, that transient alleviation of tumor hypoxia occurs in a fairly wide range of physiologically justified values of parameters; and point out the major factors, that determine oxygen dynamics during antiangiogenic therapy.

Morphogene adsorption as a Turing instability regulator: Theoretical analysis and possible applications in multicellular embryonic systems.

The Turing instability in the reaction-diffusion system is a widely recognized mechanism of the morphogen gradient self-organization during the embryonic development. One of the essential conditions for such self-organization is sharp difference in the diffusion rates of the reacting substances (morphogens). In classical models this condition is satisfied only for significantly different values of diffusion coefficients which cannot hold for morphogens of similar molecular size. One of the most realistic explanations of the difference in diffusion rate is the difference between adsorption of morphogens to the extracellular matrix (ECM). Basing on this assumption we develop a novel mathematical model and demonstrate its effectiveness in describing several well-known examples of biological patterning. Our model consisting of three reaction-diffusion equations has the Turing-type instability and includes two elements with equal diffusivity and immobile binding sites as the third reaction substance. The model is an extension of the classical Gierer-Meinhardt two-components model and can be reduced to it under certain conditions. Incorporation of ECM in the model system allows us to validate the model for available experimental parameters. According to our model introduction of binding sites gradient, which is frequently observed in embryonic tissues, allows one to generate more types of different spatial patterns than can be obtained with two-components models. Thus, besides providing an essential condition for the Turing instability for the system of morphogen with close values of the diffusion coefficients, the morphogen adsorption on ECM may be important as a factor that increases the variability of self-organizing structures.