Gatenby R A, Gawlinski E T
Department of Diagnostic Imaging, College of Medicine, Temple University, Philadelphia, Pennsylvania 19122, USA.
Cancer Res. 1996 Dec 15;56(24):5745-53.
We present mathematical analyses, experimental data, and clinical observations which support our novel hypothesis that tumor-induced alteration of microenvironmental pH may provide a simple but complete mechanism for cancer invasion. A reaction-diffusion model describing the spatial distribution and temporal development of tumor tissue, normal tissue, and excess H+ ion concentration is presented. The model predicts a pH gradient extending from the tumor-host interface, which is confirmed by reanalysis of existing experimental data. Investigation of the structure and dynamics of the tumor-host interaction within the context of the model demonstrates a transition from benign to malignant growth analogous to the adenoma-carcinoma sequence. The effect of biological parameters critical to controlling this transition are supported by experimental and clinical observations. Tumor wave front velocities determined via a marginal stability analysis of the model equations are consistent with in vivo tumor growth rates. The model predicts a previously unrecognized hypocellular interstitial gap at the tumor-host interface which we demonstrate both in vivo and in vitro. A direct correlation between the interfacial morphology and tumor wave front velocity provides an explicit, testable, clinically important prediction.
我们展示了数学分析、实验数据和临床观察结果，这些均支持我们的新假说，即肿瘤诱导的微环境pH改变可能为癌症侵袭提供一种简单而完整的机制。我们提出了一个反应扩散模型，用于描述肿瘤组织、正常组织和过量H⁺离子浓度的空间分布和时间发展。该模型预测了一个从肿瘤-宿主界面延伸的pH梯度，这一点通过对现有实验数据的重新分析得到了证实。在该模型背景下对肿瘤-宿主相互作用的结构和动力学进行研究，结果表明从良性生长到恶性生长的转变类似于腺瘤-癌序列。对控制这种转变至关重要的生物学参数的影响得到了实验和临床观察的支持。通过对模型方程进行边际稳定性分析确定的肿瘤波前速度与体内肿瘤生长速率一致。该模型预测在肿瘤-宿主界面存在一个此前未被认识到的细胞减少的间质间隙，我们在体内和体外均证实了这一点。界面形态与肿瘤波前速度之间的直接相关性提供了一个明确的、可检验的、具有临床重要性的预测。
