为什么一刀切的血管调节干预无法控制胶质瘤侵袭：计算机见解
Why one-size-fits-all vaso-modulatory interventions fail to control glioma invasion: in silico insights
摘要：
血管调节干预对胶质瘤侵袭的治疗潜力仍存在争议。突出的血管靶向治疗涉及功能性肿瘤相关血管恶化和正常化。前者旨在通过诱导肿瘤血管闭塞/塌陷的血管靶向剂介导的肿瘤梗死和营养剥夺。相比之下，使肿瘤血管网的异常结构和功能正常化（例如通过减轻应激诱导的血管闭塞）的治疗目的是改善化疗、免疫和放疗的功效。尽管这两种策略都显示出治疗潜力，但目前尚不清楚为什么它们常常无法控制胶质瘤侵入周围健康脑组织。为了阐明这个问题，我们提出了一个数学模型的胶质瘤侵袭集中在迁移/增殖二分法（去或生长）的胶质瘤细胞和功能肿瘤血管系统的调制之间的相互作用。通过改变血管闭塞的程度来模拟血管调节干预。我们发现存在一个临界细胞增殖/扩散比，它将胶质瘤对血管调节干预的侵袭反应分为两种不同的状态。而对于属于一个政权的肿瘤，血管调制降低肿瘤前沿速度并增加浸润宽度，对于那些在其他政权的入侵速度增加和浸润宽度减小。我们展示了这些计算机模拟结果如何用于指导血管调节治疗策略的个体化方法，从而提高成功率。
英文摘要：
There is an ongoing debate on the therapeutic potential of vaso-modulatory interventions against glioma invasion. Prominent vasculature-targeting therapies involve functional tumour-associated blood vessel deterioration and normalisation. The former aims at tumour infarction and nutrient deprivation medi- ated by vascular targeting agents that induce occlusion/collapse of tumour blood vessels. In contrast, the therapeutic intention of normalising the abnormal structure and function of tumour vascular net- works, e.g. via alleviating stress-induced vaso-occlusion, is to improve chemo-, immuno- and radiation therapy efficacy. Although both strategies have shown therapeutic potential, it remains unclear why they often fail to control glioma invasion into the surrounding healthy brain tissue. To shed light on this issue, we propose a mathematical model of glioma invasion focusing on the interplay between the mi- gration/proliferation dichotomy (Go-or-Grow) of glioma cells and modulations of the functional tumour vasculature. Vaso-modulatory interventions are modelled by varying the degree of vaso-occlusion. We discovered the existence of a critical cell proliferation/diffusion ratio that separates glioma invasion re- sponses to vaso-modulatory interventions into two distinct regimes. While for tumours, belonging to one regime, vascular modulations reduce the tumour front speed and increase the infiltration width, for those in the other regime the invasion speed increases and infiltration width decreases. We show how these in silico findings can be used to guide individualised approaches of vaso-modulatory treatment strategies and thereby improve success rates.
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