A computer algorithm describing the process of vessel formation and maturation, and its use for predicting the effects of anti-angiogenic and anti-maturation therapy on vascular tumor growth.
A computer algorithm describing the process of vessel formation and maturation, and its use for predicting the effects of anti-angiogenic and anti-maturation therapy on vascular tumor growth.
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DOI：
10.1023/a:1023841921971
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发表时间：
2002-01-01
期刊：
影响因子：
9.8
通讯作者：
Agur, Z.
中科院分区：
文献类型：
--
作者：
Arakelyan, L.;Vainstein, V.;Agur, Z.
我们提出了一种算法，描述了影响肿瘤和脉管系统动力学的三个主要相互关联的子过程：（i）肿瘤细胞增殖（ii）血管生成，即未成熟血管（IV）的形成和消退，以及（iii）成熟，即成熟血管（MV）的形成和不稳定。该算法考虑了这些子过程在分子、细胞和器官水平上发生的关键定量相互作用。在计算机模型中实现这一复杂的算法，人们可以评估影响血管生成的各种因素之间的相关性及其在任何给定时刻对肿瘤进展的影响。此外，计算机模拟可以分析药物对肿瘤、未成熟和成熟血管的生长和腐烂以及对一系列相关生长因子（如血管生成素-1 (Ang1)、血管生成素-2 (Ang2)）的诱导的多种影响。血管内皮生长因子（VEGF）和血小板衍生生长因子（PDGF）。模拟结果表明，血管的成熟和 MV 的不稳定将原本非线性增长的系统驱动到一个非常动态的区域，在所有相关量的某些渐近值周围具有不规则的、尺度不变的波动。不稳定本身充分解释了实验观察到的肿瘤生长的最终减少，无需暗示其他假设，例如新的肿瘤生长抑制或抗血管生成因素。我们的结果进一步表明，单独使用单一疗法可以减缓肿瘤生长，但不能完全消除肿瘤。相反，抗血管生成和抗成熟药物的联合治疗会导致肿瘤生长的长期抑制和平均肿瘤大小的显着线性减小。实验室实验可以验证我们的预测并提供体内评估参数。
We put forward an algorithm describing the three principal interconnected sub-processes that influence tumor and vasculature dynamics: (i) tumor cell proliferation (ii) angiogenesis, that is, the formation and regression of immature vessels (IV), and (iii) maturation, i.e., the formation and destabilization of mature vessels (MV). This algorithm takes account of the crucial quantitative interactions of these sub-processes, occurring across the molecular, cellular and organ levels. Implementing this complex algorithm in a computer model, one can evaluate the correlations between various factors influencing angiogenesis and their influence on tumor progression at any given moment. Moreover, the computer simulations enable analysis of the versatile effects of drugs on the growth and decay of both the tumor and the immature and mature blood vessels, as well as on the induction of an array of relevant growth factors such as angiopoietin-1 (Ang1), angiopoietin-2 (Ang2). vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). Simulation results suggest that vessel maturation and destabilization of MV drive the otherwise non-linearly growing system into a very dynamic region, having irregular, scale-invariant, fluctuations, around certain asymptotic values of all the involved quantities. Destabilization itself adequately explains the experimentally observed eventual decrease of tumor growth, with no need to implicate additional assumptions, such as a new tumor growth inhibitory, or anti-angiogenic, factors. Our results further suggest that mono-therapy alone can slow tumor growth, but is not capable of eliminating it altogether. In contrast, the combined treatment of anti-angiogenic and anti-maturation drugs causes prolonged suppression of tumor growth and a significant linear decrease in average tumor size. Laboratory experiments are warranted for validating our predictions and for providing in vivo evaluated parameters.