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Cancer is a disease of cellular regulation, often initiated by geneticmutation within cells, and leading to a heterogeneous cell population withintissues. In the competition for nutrients and growth space within the tumorsthe phenotype of each cell determines its success. Selection in this process isimposed by both the microenvironment (neighboring cells, extracellular matrix,and diffusing substances), and the whole of the organism through for examplethe blood supply. In this view, the development of tumor cells is in closeinteraction with their increasingly changing environment: the more cells canchange, the more their environment will change. Furthermore, instabilities arealso introduced on the organism level: blood supply can be blocked by increasedtissue pressure or the tortuosity of the tumor-neovascular vessels. Thiscoupling between cell, microenvironment, and organism results in behavior thatis hard to predict. Here we introduce a cell-based computational model to studythe effect of blood flow obstruction on the micro-evolution of cells within acancerous tissue. We demonstrate that stages of tumor development emergenaturally, without the need for sequential mutation of specific genes.Secondly, we show that instabilities in blood supply can impact the overalldevelopment of tumors and lead to the extinction of the dominant aggressivephenotype, showing a clear distinction between the fitness at the cell leveland survival of the population. This provides new insights into potential sideeffects of recent tumor vasculature renormalization approaches.

Blood Vessel Tortuosity Selects against Evolution of Agressive Tumor Cells in Confined Tissue Environments: a Modeling Approach