An integrated computational/experimental model of tumor invasion
An integrated computational/experimental model of tumor invasion
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DOI：
10.1158/0008-5472.can-05-3166
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发表时间：
2006-02-01
期刊：
影响因子：
11.2
通讯作者：
Cristini, V
中科院分区：
文献类型：
--
作者：
Frieboes, HB;Zheng, X;Cristini, V
在体内，控制肿瘤生长和侵袭的细胞内和细胞外动力学仍然知之甚少。细胞基因型和表型，以及营养、氧和生长因子浓度是关键变量。在以前的工作中，使用基于直接描述肿瘤细胞周期和生物学的变量的反应扩散数学模型，我们制定了肿瘤形态由空间扩散梯度引起的异质细胞增殖之间的竞争决定的假设，例如，细胞营养素的影响，驱动形状不稳定性和侵入性肿瘤形态，以及稳定机械力，例如，细胞与细胞和细胞与基质的粘附。为了验证这一假设，我们在这里获得基于变量的统计输入到数学模型，从体外人类和大鼠胶质母细胞瘤文化。模型的线性稳定性分析预测，胶质瘤球体形态是勉强稳定的。与该预测一致，对于一系列变量值，在体外观察到肿瘤块的无限生长和环境的侵袭。侵袭的机制是肿瘤活性边缘的递归亚球体成分的发展和与母球体的分离。数学模型的计算机模拟结果与体外模型中肿瘤细胞的形态和空间排列非常相似。我们提出，体内肿瘤形态发生可能是由细胞营养物质、氧气和生长因子的空间变化引起的边缘稳定的环境条件的函数，并且通过降低空间梯度来控制这些条件可以有益于治疗结果，而目前的治疗，特别是抗血管生成治疗，可能引发空间异质性（例如，局部缺氧），从而引起侵入性不稳定。
The intracellular and extracellular dynamics that govern tumor growth and invasiveness in Vivo remain poorly understood. Cell genotype and phenotype, and nutrient, oxygen, and growth factor concentrations are key variables. In previous work, using a reaction-diffusion mathematical model based on variables that directly describe tumor cell cycle and biology, we formulated the hypothesis that tumor morphology is determined by the competition between heterogeneous cell proliferation caused by spatial diffusion gradients, e.g., of cell nutrients, driving shape instability and invasive tumor morphologies, and stabilizing mechanical forces, e.g., cell-to-cell and cell-to-matrix adhesion. To test this hypothesis, we here obtain variable-based statistics for input to the mathematical model from in vitro human and rat glioblastoma cultures. A linear stability analysis of the model predicts that glioma spheroid morphology is marginally stable. In agreement with this prediction, for a range of variable values, unbounded growth of the tumor mass and invasion of the environment are observed in vitro. The mechanism of invasion is recursive subspheroid component development at the tumor viable rim and separation from the parent spheroid. Results of computer simulations of the mathematical model closely resemble the morphologies and spatial arrangement of tumor cells from the in vitro model. We propose that tumor morphogenesis in vivo may be a function of marginally stable environmental conditions caused by spatial variations in cell nutrients, oxygen, and growth factors, and that controlling these conditions by decreasing spatial gradients could benefit treatment outcomes, whereas current treatment, and especially antiangiogenic therapy, may trigger spatial heterogeneity (e.g., local hypoxia), thus causing invasive instability.