受限Tissue环境中血管迂曲度对侵袭性肿瘤细胞演化的影响
Blood Vessel Tortuosity Selects against Evolution of Agressive Tumor Cells in Confined Tissue Environments: a Modeling Approach
摘要：
癌症是一种细胞调节疾病，通常由细胞内的基因突变引发，并导致组织内的异质细胞群。在肿瘤内营养和生长空间的竞争中，每个细胞的表型决定了其成功。这个过程中的选择是由微环境（相邻细胞，细胞外基质和扩散物质）和整个生物体（例如血液供应）施加的。从这个角度来看，肿瘤细胞的发展与其日益变化的环境密切相关：细胞变化越多，其环境变化也就越大。此外，在生物体水平上也引入了不稳定性：血液供应可以被增加的组织压力或肿瘤新生血管的迂曲度阻断。细胞、微环境和有机体之间的这种耦合导致了难以预测的行为。在这里，我们介绍了一个基于细胞的计算模型来研究血流阻塞对癌组织内细胞微观演变的影响。我们证明了肿瘤发展的各个阶段是自然出现的，而不需要特定基因的连续突变。其次，我们发现血液供应的不稳定性会影响肿瘤的整体发展，并导致显性侵袭性表型的灭绝，这表明细胞水平的适应性和群体的存活率之间存在明显的区别。这为最近的肿瘤血管重整方法的潜在副作用提供了新的见解。
英文摘要：
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 renormalization approaches.
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