Understanding Ductal Carcinoma In Situ Invasion using a Multiscale Agent-Based Model *
Understanding Ductal Carcinoma In Situ Invasion using a Multiscale Agent-Based Model *
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使用基于多尺度代理的模型了解导管癌原位侵袭*
DOI：
10.1109/embc.2018.8513542
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Wang, Zhihui
中科院分区：
文献类型：
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作者：
Joseph Butner, D.;Cristini, Vittorio;Wang, Zhihui
导管原位癌(DCIS)是临床上常见的外科手术治疗方法。尽管存在手术切除的选择，但目前尚不清楚哪种手术是降低未来侵袭性疾病可能性的最佳选择。从疾病诊断中确定正确的手术切缘的挑战使情况更加复杂，与组织学检查相比，乳房X光成像对手术切缘的误判高达2厘米。我们已经实施了一个三维的、混合的多尺度DCIS模型来研究疾病的发生和发展。为了阐明当前围绕疾病的生物学问题和临床挑战，我们提出了该模型的改进版本，包括更多与生物相关的分子信号通路、细胞表型分级和导管结构变化。特别是，在模型中加入了细胞坏死、溶解和钙化的途径，以帮助更好地理解诊断成像和疾病侵袭的真实程度之间的关系。我们观察到，可用于促进细胞增殖的分子信号分子的不足可以通过疾病团块内表型分布的动态变化来克服。缺氧、坏死和钙化共同起到缓解缺氧的作用，观察到DCIS前缘与坏死点之间保持一致的距离，为提高手术切缘提供了洞察力。
Ductal carcinoma in situ (DCIS) is commonly treated clinically through surgical resection. Although surgical options exist for resection, it is unclear which is optimal to reduce the likelihood of future invasive disease. This is further complicated by challenges in determining correct surgical margins from disease diagnostics, with mammographic imaging misidentifying surgical margins by as much as 2 cm vs. histological examination. We have implemented a three-dimensional, hybrid multiscale model of DCIS to study disease initiation and progression. In order to shed new light on current biological questions and clinical challenges surrounding the disease, we present here an improved version of this model, with more biologically relevant molecular signaling pathways, cell phenotype hierarchies, and duct architecture variation. In particular, a cell necrosis, lysis and calcification pathway has been incorporated into the model to help better understand the relationship between diagnostic imaging and the true extent of disease invasion. We observe that deficiencies in availability of molecular signaling molecules that upregulate cell proliferation may be overcome by dynamic shifts in phenotypic distributions within the disease mass. Hypoxia, necrosis, and calcification together functioned as a hypoxia relief mechanism, and were observed to maintain a consistent distance between the DCIS leading edge and the site of necrosis onset, providing insights for improving surgical margins.