Mathematical Modeling of Tumor-Tumor Distant Interactions Supports a Systemic Control of Tumor Growth
Mathematical Modeling of Tumor-Tumor Distant Interactions Supports a Systemic Control of Tumor Growth
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DOI：
10.1158/0008-5472.can-17-0564
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发表时间：
2017-09-15
期刊：
影响因子：
11.2
通讯作者：
Hahnfeldt, Philip
中科院分区：
文献类型：
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作者：
Benzekry, Sebastien;Lamont, Clare;Hahnfeldt, Philip
同一生物体内不同肿瘤之间的相互作用具有重大的临床意义，特别是在手术和转移性疾病的背景下。三个主要的解释理论（竞争，血管生成抑制和增殖抑制）已被提出，但确切的决定因素的现象仍然知之甚少。在这里，我们将这些理论形式化为数学模型，并进行生物实验，以经验数据来验证它们。在携带两个同时植入的肿瘤的同基因小鼠中，仅一个肿瘤的生长被显著抑制（在第15天尺寸减小61%，P <0.05）。竞争模型必须被拒绝，而血管生成抑制和增殖抑制模型能够描述数据。其他模型（包括基于远距离细胞毒性对数杀灭效应的理论）无法拟合数据。增殖抑制模型是可识别的和最小的（四个参数），其描述能力根据数据进行了验证，包括当不存在继发性肿瘤时预测单个肿瘤生长的一致性。这一理论也可能为单个癌症的生长提供新的线索，因为它提供了一个生物学上可翻译的图景，说明局部和全局作用如何联合收割机控制局部肿瘤生长，特别是肿瘤-肿瘤抑制的作用。该模型提供了一个描述伴随的阻力，提供了一个改进的理论基础，肿瘤生长控制，也可能发现实用程序的治疗计划，以避免术后转移加速。(C)2017年AACR。
Interactions between different tumors within the same organism have major clinical implications, especially in the context of surgery and metastatic disease. Three main explanatory theories (competition, angiogenesis inhibition, and proliferation inhibition) have been proposed, but precise determinants of the phenomenon remain poorly understood. Here, we formalized these theories into mathematical models and performed biological experiments to test them with empirical data. In syngeneic mice bearing two simultaneously implanted tumors, growth of only one of the tumors was significantly suppressed (61% size reduction at day 15, P < 0.05). The competition model had to be rejected, whereas the angiogenesis inhibition and proliferation inhibition models were able to describe the data. Additional models including a theory based on distant cytotoxic log-kill effects were unable to fit the data. The proliferation inhibition model was identifiable and minimal (four parameters), and its descriptive power was validated against the data, including consistency in predictions of single tumor growth when no secondary tumor was present. This theory may also shed new light on single cancer growth insofar as it offers a biologically translatable picture of how local and global action may combine to control local tumor growth and, in particular, the role of tumor-tumor inhibition. This model offers a depiction of concomitant resistance that provides an improved theoretical basis for tumor growth control and may also find utility in therapeutic planning to avoid postsurgery metastatic acceleration. (C) 2017 AACR.