Interdisciplinary Study of Acid-Meditated Tumor Invasion

描述(由申请人提供)：这项拟议的研究调查了由研究人员开发的一种新的、概念上简单的癌症侵袭机制。它的目标是通过一种跨学科的方法，通过实验室实验与数学模型的制定和分析之间的持续互动，更全面地了解肿瘤-宿主界面的结构和动力学。这项工作是由大量证据启动的，这些证据表明，肿瘤的代谢一直不同于正常组织，越来越依赖糖酵解途径来产生能量。研究人员推测，肿瘤细胞分泌的过量H+离子将扩散到肿瘤-宿主界面和邻近的正常组织，创造有利于肿瘤侵袭的酸性微环境，因为：1.正常细胞对酸性堆积的耐受性明显低于肿瘤细胞2.酸性Phe促进蛋白水解酶的释放，分解细胞外基质，促进肿瘤侵袭3.酸性Phe增加IL8和VEGF的释放，促进血管生成。这一假设通过使用耦合偏微分方程组和改进的元胞自动机方法的数学模型来形式化。实验确定了这些模型中的关键参数值，如H+产生量和扩散系数。这使得数学模型能够产生对肿瘤周围酸梯度和由此产生的肿瘤-宿主界面的形态的详细预测。这些预测已经使用背部皮肤折叠室技术进行了研究。使用荧光比率成像(FRIM)测量Phe的初步数据证实了H+离子从肿瘤边缘延伸到邻近正常组织的梯度。使用染料排斥技术，已经证实了暴露在酸性环境中的瘤周正常细胞的活力丧失--酸性环境是该假说的关键组成部分。这项拟议的研究将通过比较MCF7/S和mda-mb-435肿瘤株的瘤周Phe梯度以及由此导致的瘤周正常组织和肿瘤生长动力学的变化来扩展实验观察，这两种肿瘤株具有明显不同的产酸率和体内行为。随着更多参数值的确定，数学模型将进一步完善。将探索产生状态方程(即肿瘤生长)的行波解的减慢或反转的扰动，以预测可能的新治疗策略。

DESCRIPTION (provided by applicant): The proposed study investigates a novel, conceptually simple mechanism for cancer invasion developed by the investigators. Its goal is a fuller understanding of the structure and dynamics of the tumor-host interface through an interdisciplinary approach with continuous interaction between laboratory experiments and the formulation and analysis of mathematical models. This work was initiated by extensive evidence that tumor metabolism is consistently different from normal tissue with increased reliance on glycolytic pathways for energy production. The investigators hypothesized that excess H+ ions excreted by tumor cells would diffuse into the tumor-host interface and adjacent normal tissue creating an acidic microenvironment favorable for tumor invasion because: 1. Normal cells are significantly less tolerant to acidic pile than are tumor cells 2.acidic pHe promotes release of proteolytic enzymes breaking down extracellular matrix facilitating tumor invasion 3. acid pHe increases release of IL8 and VEGF promoting angiogenesis. This hypothesis is formalized through mathematical models using both coupled partial differential equations and a modified cellular automata approach. Critical parameter values in these models such as H+ production and diffusion coefficient have been determine experimentally. This has allowed the mathematical models to produce detailed predictions of the peritumoral acid gradient and the resulting morphology of the tumor-host interface. These predictions have been investigated using a dorsal skin fold chamber technique. Preliminary data measuring pHe using fluorescence ratio imaging (FRIM) has confirmed a gradient of H+ ions extending from the tumor edge into adjacent normal tissue. Using dye exclusion techniques loss of viability has been demonstrated in peritumoral normal cells exposed to the acidic environment - a key component of the hypothesis. The proposed study will extend the experimental observations by comparing the peritumoral pHe gradients and the resulting changes in the peritumoral normal tissue and tumor growth dynamics in the MCF7/s and MDA-mb-435 tumor lines which have markedly different acid production rates and in-vivo behavior. The mathematical models will be further refined as additional parameter values can be determined. Perturbations that produce slowing or reversal of the traveling wave solution to the state equations (ie tumor growth) will be explored to predict possible new treatment strategies.