Quantifying the role of angiogenesis in malignant progression of gliomas: in silico modeling integrates imaging and histology.
Quantifying the role of angiogenesis in malignant progression of gliomas: in silico modeling integrates imaging and histology.
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DOI：
10.1158/0008-5472.can-11-1399
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发表时间：
2011-12-15
期刊：
影响因子：
11.2
通讯作者：
Anderson AR
中科院分区：
文献类型：
--
作者：
Swanson KR;Rockne RC;Claridge J;Chaplain MA;Alvord EC Jr;Anderson AR
胶质瘤是原发性脑肿瘤的致命形式，从低级别到高级别（胶质母细胞瘤）不等。虽然低级别神经胶质瘤的血管生成能力较弱，但胶质母细胞瘤是血管生成能力最强的肿瘤之一。因此，神经胶质瘤细胞与其组织微环境之间的相互作用可能在侵袭性肿瘤的形成和进展中发挥重要作用。为了定量探索肿瘤细胞如何与其组织微环境相互作用，我们将常氧神经胶质瘤细胞、缺氧神经胶质瘤细胞、血管内皮细胞、扩散性血管生成因子和坏死形成的相互作用纳入第一代基于生物学的神经胶质瘤生长和侵袭数学模型。模型模拟定量描述了通过医学成像可视化的神经胶质瘤的体内动态范围。此外，我们研究了神经胶质瘤细胞的增殖和分散如何结合起来诱导细胞结构、有丝分裂、缺氧诱导的新血管生成和坏死程度的增加，这些特征表征了“恶性”程度的增加，并且我们发现净增殖率（{小写rho}）和侵袭率（D）的变化并不总是恶性进展所必需的。因此，尽管其他因素（包括基因突变的积累）可以改变细胞表型（例如增殖和侵袭率），但这项研究表明这些因素并不是恶性进展所必需的。模拟结果置于当前世界卫生组织临床分级方案的背景下，用于研究特定患者示例。这项研究表明，通过应用所提出的肿瘤-微环境相互作用模型，可以识别与细胞表型变化（例如增殖和侵袭率）不同的神经胶质瘤组织学动态变化的可预测模式，从而提供强大的临床工具。
Gliomas are uniformly fatal forms of primary brain neoplasms that vary from low-grade to high-grade (glioblastoma). While low-grade gliomas are weakly angiogenic, glioblastomas are among the most angiogenic of tumors. Thus, interactions between glioma cells and their tissue microenvironment may play an important role in aggressive tumor formation and progression. To quantitatively explore how tumor cells interact with their tissue microenvironment, we incorporated the interactions of normoxic glioma cells, hypoxic glioma cells, vascular endothelial cells, diffusible angiogenic factors, and necrosis formation into a first-generation, biologically-based mathematical model for glioma growth and invasion. Model simulations quantitatively described the spectrum of in vivo dynamics of gliomas visualized with medical imaging. Further, we investigated how proliferation and dispersal of glioma cells combine to induce increasing degrees of cellularity, mitoses, hypoxia-induced neo-angiogenesis and necrosis, features that characterize increasing degrees of “malignancy”, and we found that changes in the net rates of proliferation ({lower case rho}) and invasion (D) are not always necessary for malignant progression. Thus, although other factors, including the accumulation of genetic mutations, can change cellular phenotype (e.g. proliferation and invasion rates), this study suggests that these are not required for malignant progression. Simulated results are placed in the context of the current clinical World Health Organization grading scheme for studying specific patient examples. This study suggests that through the application of the proposed model for tumor-microenvironment interactions, predictable patterns of dynamic changes in glioma histology distinct from changes in cellular phenotype (e.g. proliferation and invasion rates) may be identified, thus providing a powerful clinical tool.