微环境促进的侵袭性肿瘤生长的元胞自动机模拟

Microenvironment-enhanced invasive tumor growth via cellular automaton simulations

肿瘤的侵袭和转移行为,常常是导致病人的死亡的原因.而人们对这些由复杂的肿瘤-宿主以及肿瘤细胞与细胞之间相互作用而产生的群体性行为知之甚少.对这一过程了解的加深,需要多学科间的合作.在本篇文章中,作者将简要回顾肿瘤物理领域的一种新手段,即近年来由作者参与的通过元胞自动机(CA)模型来研究微环境促进的实体瘤侵袭性生长的研究,该模型整合了一系列微观的肿瘤宿主相互作用,包含了肿瘤细胞对细胞外基质的降解,肿瘤细胞趋向养分的迁移,肿瘤生长导致的局部组织压力累积以及该压力对局部的肿瘤-宿主界面稳定性的影响,并且,肿瘤生长时细胞间的粘连也被明确地考虑进来.该元胞自动机模型能成功地重现出一系列的标志性的肿瘤侵袭行为,这有力地表明出该模型的有效性和预测能力.这一模型,如果能与临床数据结合,理论上能够拓展从医学数据中得到的现有结论,帮助设计新的实验,检验假说,并且在实验难以检测到的情形下,预测肿瘤的行为,协助癌症的早期诊断和预后,并针对不同病人,提出最优的个体化医疗方案.

Emergence of invasive and metastatic behavior in malignant tumors can often lead to fatal outcomes for patients. The collective malignant tumor behavior resulting from the complex tumor-host interactions and the interactions between the tumor cells are currently poorly understood. Progress towards such an understanding necessarily requires an interdis-ciplinary and collaborative effort. In this paper, we review a state-of-art simulation technique, i.e., a cellular automaton （CA） model which has been developed by the authors over the past few years to investigate microenvironment-enhanced invasive growth of avascular solid tumors. This CA model incorporates a variety of microscopic-scale tumor-host in-teractions, including the degradation of the extracellular matrix by the malignant cells, nutrient-driven cell migration, pressure build-up due to the deformation of the microenvironment by the growing tumor and its effect on the local tumor-host interface stability. Moreover, the effects of cell-cell adhesion on tumor growth are also explicitly taken into account. A number of bench-mark collective invasion behaviors have been successfully reproduced via the CA model, including the emergence of elongated invasion branches characterized by homotype attraction and least resistance path, development of rough tumor surface in a high-pressure confined environment, as well as reduced invasion due to strong cell-cell adhesion. Such simulated bench-mark behaviors strongly indicate the validity and predictive power of the CA model. In addition, the CA model allows one to investigate the role of various different microenvironment factors in the progression of the neoplasm, in particular, the promotion and enhancement of tumor malignancy. As an example, a “phase diagram” that summarizes the dependency of tumor invasive behavior on extracellular matrix （ECM） rigidity （density） and strength of cell-cell adhesion is constructed based on comprehensive simulations. In this simple phase diagram, a clear transition from non-invasive to invasive behaviors of the tumor can be achieved by increasing ECM rigidity and/or decreasing the strength of cell-cell adhesion. This model, when properly combined with clinical data, in principle enables one to broaden the conclusions drawn from existing medical data, suggest new experiments, test hypotheses, predict behavior in experimentally unobservable situations, be employed for early detection and prognosis, and to suggest optimized treatment strategy for individual patient.