Involvement of tumor macrophage HIFs in chemotherapy effectiveness: mathematical modeling of oxygen, pH, and glutathione.
Involvement of tumor macrophage HIFs in chemotherapy effectiveness: mathematical modeling of oxygen, pH, and glutathione.
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DOI：
10.1371/journal.pone.0107511
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Friedman A
中科院分区：
文献类型：
--
作者：
Chen D;Bobko AA;Gross AC;Evans R;Marsh CB;Khramtsov VV;Eubank TD;Friedman A
与正常组织相比，低氧、酸性、高谷胱甘肽（GSH）浓度和快速还原速率（氧化还原）这四个变量是实体瘤明显而多样的特征。这些参数是实体瘤代谢和生理的最重要因素之一，无论其类型或来源如何。低氧张力有助于抑制癌细胞增殖和肿瘤的治疗抵抗；细胞外pH值低，与正常细胞相反，主要增强肿瘤侵袭；而失调的谷胱甘肽和癌细胞内的氧化还原电位有利于它们的增殖。事实上，这些微环境条件下的癌细胞明显改变了肿瘤对细胞毒性抗癌治疗的反应。最近的实验在小鼠乳腺癌模型中测量了这四个参数与肿瘤发展的体内纵向数据，以及相应的肿瘤巨噬细胞HIF-1α或HIF-2α的存在和缺失。在本文中，我们提出了一个基于数学模型的（普通和偏）微分方程系统，通过氧水平、pH和细胞内GSH浓度来监测肿瘤生长和对标准化疗的易感性。我们首先证明我们的模型模拟与相应的实验一致，然后我们使用我们的模型来建议通过改变肿瘤微环境中的这四个参数来治疗肿瘤。例如，该模型定性地预测GSH耗竭可以使活性氧（ROS）水平升高到毒性阈值以上，从而抑制肿瘤生长。
The four variables, hypoxia, acidity, high glutathione (GSH) concentration and fast reducing rate (redox) are distinct and varied characteristics of solid tumors compared to normal tissue. These parameters are among the most significant factors underlying the metabolism and physiology of solid tumors, regardless of their type or origin. Low oxygen tension contributes to both inhibition of cancer cell proliferation and therapeutic resistance of tumors; low extracellular pH, the reverse of normal cells, mainly enhances tumor invasion; and dysregulated GSH and redox potential within cancer cells favor their proliferation. In fact, cancer cells under these microenvironmental conditions appreciably alter tumor response to cytotoxic anti-cancer treatments. Recent experiments measured the in vivo longitudinal data of these four parameters with tumor development and the corresponding presence and absence of tumor macrophage HIF-1α or HIF-2α in a mouse model of breast cancer. In the current paper, we present a mathematical model-based system of (ordinary and partial) differential equations to monitor tumor growth and susceptibility to standard chemotherapy with oxygen level, pH, and intracellular GSH concentration. We first show that our model simulations agree with the corresponding experiments, and then we use our model to suggest treatments of tumors by altering these four parameters in tumor microenvironment. For example, the model qualitatively predicts that GSH depletion can raise the level of reactive oxygen species (ROS) above a toxic threshold and result in inhibition of tumor growth.
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DOI：
10.1073/pnas.89.7.3070
发表时间：
1992-04-01
影响因子：
11.1
作者：
GODWIN, AK;MEISTER, A;ANDERSON, ME
通讯作者：
ANDERSON, ME
影响因子：
3.3
作者：
Bobko, Andrey A.;Eubank, Timothy D.;Voorhees, Jeffrey L.;Efimova, Olga V.;Kirilyuk, Igor A.;Petryakov, Sergey;Trofimiov, Dmitrii G.;Marsh, Clay B.;Zweier, Jay L.;Grigor'ev, Igor A.;Samouilov, Alexandre;Khramtsov, Valery V.
通讯作者：
Khramtsov, Valery V.
影响因子：
3.5
作者：
Chen, Duan;Roda, Julie M.;Marsh, Clay B.;Eubank, Timothy D.;Friedman, Avner
通讯作者：
Friedman, Avner
影响因子：
11.2
作者：
Eubank TD;Roberts RD;Khan M;Curry JM;Nuovo GJ;Kuppusamy P;Marsh CB
通讯作者：
Marsh CB
影响因子：
20.3
作者：
Eubank, Tim D.;Roda, Julie M.;Marsh, Clay B.
通讯作者：
Marsh, Clay B.