Mathematical Modeling of Cellular Cross-Talk Between Endothelial and Tumor Cells Highlights Counterintuitive Effects of VEGF-Targeted Therapies
Mathematical Modeling of Cellular Cross-Talk Between Endothelial and Tumor Cells Highlights Counterintuitive Effects of VEGF-Targeted Therapies
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DOI：
10.1007/s11538-017-0273-6
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发表时间：
2018-05-01
影响因子：
3.5
通讯作者：
Jackson, Trachette
中科院分区：
文献类型：
--
作者：
Jain, Harsh;Jackson, Trachette
肿瘤的生长和进展严重依赖于血管支持系统的建立。这通常是通过促血管生成生长因子的表达来实现的，包括血管内皮生长因子（VEGF）家族配体的成员。VEGF配体在多种实体肿瘤中过度表达，因此，抑制VEGF通路的不同轴（单独或联合）将代表对大多数癌症类型的强大的抗血管生成疗法，这让人感到乐观。当考虑针对VEGF及其受体的治疗时，很难通过实验梳理出所有组合的抗血管生成和抗肿瘤效果的差异，因为肿瘤细胞和血管内皮细胞参与了一个动态的串扰，影响肿瘤发生的关键方面，独立于血管生成。在这里，我们建立了一个数学模型，将负责内皮细胞和肿瘤细胞增殖和死亡的细胞内信号与群体水平的癌症生长和血管生成联系起来。我们利用该模型在体外和体内研究内皮细胞和肿瘤细胞之间的双向通讯对靶向VEGF及其受体的治疗的影响。我们的结果强调了这样一个事实，即体外治疗结果并不总是转化为体内的情况。例如，我们的模型预测，某些治疗组合导致体内拮抗作用，而体外未观察到。在这个方向上的数学建模可以揭示实验观察背后的机制，即操纵VEGF及其受体在某些情况下是成功的，但在其他情况下则令人失望。
Tumor growth and progression are critically dependent on the establishment of a vascular support system. This is often accomplished via the expression of pro-angiogenic growth factors, including members of the vascular endothelial growth factor (VEGF) family of ligands. VEGF ligands are overexpressed in a wide variety of solid tumors and therefore have inspired optimism that inhibition of the different axes of the VEGF pathway-alone or in combination-would represent powerful anti-angiogenic therapies for most cancer types. When considering treatments that target VEGF and its receptors, it is difficult to tease out the differential anti-angiogenic and anti-tumor effects of all combinations experimentally because tumor cells and vascular endothelial cells are engaged in a dynamic cross-talk that impacts key aspects of tumorigenesis, independent of angiogenesis. Here we develop a mathematical model that connects intracellular signaling responsible for both endothelial and tumor cell proliferation and death to population-level cancer growth and angiogenesis. We use this model to investigate the effect of bidirectional communication between endothelial cells and tumor cells on treatments targeting VEGF and its receptors both in vitro and in vivo. Our results underscore the fact that in vitro therapeutic outcomes do not always translate to the in vivo situation. For example, our model predicts that certain therapeutic combinations result in antagonism in vivo that is not observed in vitro. Mathematical modeling in this direction can shed light on the mechanisms behind experimental observations that manipulating VEGF and its receptors is successful in some cases but disappointing in others.