Abstract
Cancer is a disease of cellular regulation, often initiated by genetic mutation within cells, and leading to a heterogeneous cell population within tissues. In the competition for nutrients and growth space within the tumors the phenotype of each cell determines its success. Selection in this process is imposed by both the microenvironment (neighboring cells, extracellular matrix, and diffusing substances), and the whole of the organism through for example the blood supply. In this view, the development of tumor cells is in close interaction with their increasingly changing environment: the more cells can change, the more their environment will change. Furthermore, instabilities are also introduced on the organism level: blood supply can be blocked by increased tissue pressure or the tortuosity of the tumor-neovascular vessels. This coupling between cell, microenvironment, and organism results in behavior that is hard to predict. Here we introduce a cell-based computational model to study the effect of blood flow obstruction on the micro-evolution of cells within a cancerous tissue. We demonstrate that stages of tumor development emerge naturally, without the need for sequential mutation of specific genes. Secondly, we show that instabilities in blood supply can impact the overall development of tumors and lead to the extinction of the dominant aggressive phenotype, showing a clear distinction between the fitness at the cell level and survival of the population. This provides new insights into potential side effects of recent tumor vasculature normalization approaches.
Highlights
Cancer is a disease of multicellular regulation, in which malfunctioning cells can break free of homeostatic regulations imposed by the host environment [1]
To investigate the above questions, we model a monolayer of cells using a modified cellular Potts model (CPM) based on the CompuCell3D implementation [39] which can be obtained from http://www.compucell3D.org
Cells in the CPM are represented as confluent domains on a lattice on which an integer sð~xÞ at every position ~x indicates which cell is occupying the location ~x; cell-free areas are designated by sð~xÞ 1⁄4 0
Summary
Cancer is a disease of multicellular regulation, in which malfunctioning cells can break free of homeostatic regulations imposed by the host environment [1]. One of the main characteristics of cancer is the increased proliferation and mutation of cancerous cells due to malfunctioning control of growth and proliferation [1]. As these behavioral changes typically originate from mutations in the cells’ genetic material, excessively proliferating cells accumulate further alterations, leading to a possible amplification of malignancies. Traditional studies of altered cell traits primarily focus on genetic mutations, but neglect the multicellular nature and genetic variety of tumors. Heterogeneity may even promote the collapse of tumor development by inducing a clone population that supports and enhances the growth of other clones in mice [7]. Heterogeneity questions the validity of previous whole–tumor analyses, as “the most abundant cell type might not necessarily predict the properties of mixed populations” [8], and emphasizes the need for more detailed approach
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