Modeling the effects of vasculature evolution on early brain tumor growth
Modeling the effects of vasculature evolution on early brain tumor growth
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DOI：
10.1016/j.jtbi.2006.07.002
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发表时间：
2006-12-21
影响因子：
2
通讯作者：
Torquato, Salvatore
中科院分区：
文献类型：
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作者：
Gevertz, Jana L.;Torquato, Salvatore
肿瘤生长和血管生成的数学建模在过去几十年中一直是活跃的研究领域。这样的模型可以分为两类之一：那些分析的血管重建，而忽略了肿瘤质量的变化，和那些预测肿瘤扩张的存在下，一个非进化的血管。然而，公认的是血管重塑和肿瘤生长强烈地相互依赖。因为这个原因，我们已经开发了早期脑肿瘤生长的二维混合细胞自动机模型，其将微脉管系统的重塑与肿瘤块的演变相结合。已经开发了一个反应扩散方程系统来跟踪血管内皮生长因子（VEGF）、Ang-1、Ang-2、它们的受体和它们的复合物在空间和时间上的浓度。血管系统的特性以及每个细胞的特性由这些关键血管生成因子的相对浓度决定。该模型表现出与血管生成上调的实验观察一致的血管生成开关。特别是，我们表明，如果产生和响应VEGF和血管生成素的途径功能正常，血管生成开始，肿瘤可以生长到宏观尺寸。然而，如果VEGF途径被抑制，则不会发生血管生成，并且肿瘤生长在尺寸上超过1-2 mm时受到阻碍。此外，我们表明，即使血管生成受到抑制，肿瘤扩张也可能发生在血管化良好的环境中，这表明抗血管生成疗法可能不足以消除活跃分裂的恶性细胞群。(c)2006爱思唯尔有限公司保留所有权利。
Mathematical modeling of both tumor growth and angiogenesis, have been active areas of research for the past several decades. Such models can be classified into one of two categories: those that analyze the remodeling of the vasculature while ignoring changes ill the tumor mass, and those that predict tumor expansion in the presence of a non-evolving vasculature. However, it is well accepted that vasculature remodeling and tumor growth strongly depend on one another. For this reason., we have developed a two-dimensional hybrid cellular automaton model of early brain tumor growth that couples the remodeling of the microvasculature with the evolution of the tumor mass. A system of reaction-diffusion equations has been developed to track the concentration of vascular endothelial growth factor (VEGF), Ang-1 Ang-2, their receptors and their complexes in space and time. The properties of the vasculature and hence of each cell are determined by the relative concentrations of these key angiogenic factors. The model exhibits an angiogenic switch consistent with experimental observations on the upregulation of angiogenesis. Particularly, we show that if the pathways that produce and respond to VEGF and the angiopoietins are properly functioning, angiogenesis is initiated and a tumour can grow to a macroscopic size. However, if the VEGF pathway is inhibited, angiogenesis does not occur and tumor growth is thwarted beyond 1-2 mm in size. Furthermore, we show that tumor expansion can occur in well-vascularized environments even when angiogenesis is inhibited, suggesting that anti-angiogenic therapies may not be sufficient to eliminate a population of actively dividing malignant cells. (c) 2006 Elsevier Ltd. All rights reserved.