Morphologic instability and cancer invasion
Morphologic instability and cancer invasion
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DOI：
10.1158/1078-0432.ccr-05-0852
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发表时间：
2005-10-01
影响因子：
11.5
通讯作者：
Sinek, J
中科院分区：
文献类型：
--
作者：
Cristini, V;Frieboes, HB;Sinek, J
目的：实体瘤嵌入宿主组织是细胞和细胞外基质的三维排列，作为氧气和细胞营养物质的汇，从而建立扩散梯度。这以及血管密度和血流的变化通常会导致肿瘤内缺氧和酸中毒，并可能导致空间上不同的细胞增殖和迁移。在这里，我们提出假设，通过这些机制，微环境底物梯度可能通过从肿瘤边缘分离细胞簇并渗透到周围正常组织来驱动形态不稳定性。实验设计：我们使用计算机模拟和体外实验。结果：我们提供了证据表明，在体内，空间均匀的氧气和营养供应可以抑制形态不稳定性，因为常氧条件既通过减少梯度，也通过增加细胞黏附，从而通过维持明确的肿瘤边界的机械力来发挥作用。一个正常工作的肿瘤微血管可以通过最小化氧气和营养梯度来帮助维持致密的非浸润性肿瘤形态。相反，通过增加微环境的异质性，抗肿瘤治疗可能会促进形态的不稳定性，甚至在肿瘤整体质量缩小的情况下也会导致侵袭模式。结论：我们得出结论：仅专注于降低血管密度的治疗策略可能会矛盾地增加侵袭行为。这一理论模型解释了在多个临床试验中抗血管生成治疗的高度可变的结果。我们认为，如果旨在使血管系统“正常化”，并与增加细胞黏附的治疗相结合，从而抑制形态不稳定，并强制实施致密、非侵入性的肿瘤形态，抗血管生成策略将更加成功。
Purpose: A solid tumor embedded in host tissue is a three-dimensional arrangement of cells and extracellular matrix that acts as a sink of oxygen and cell nutrients, thus establishing diffusional gradients. This and variations in vascular density and blood flow typically produce intratumoral regions of hypoxia and acidosis, and may result in spatially heterogeneous cell proliferation and migration. Here, we formulate the hypothesis that through these mechanisms, microenvironmental substrate gradients may drive morphologic instability with separation of cell clusters from the tumor edge and infiltration into surrounding normal tissue.Experimental Design: We used computer simulations and in vitro experiments.Results: We provide evidence that morphologic instability could be suppressed in vivo by spatially homogeneous oxygen and nutrient supply because normoxic conditions act both by decreasing gradients and increasing cell adhesion and, therefore, the mechanical forces that maintain a well-defined tumor boundary. A properly working tumor microvasculature can help maintain compact noninfiltrating tumor morphologies by minimizing oxygen and nutrient gradients. In contrast, antiarigiogenic therapy, by increasing microenvironmental heterogeneity, may promote morphologic instability, leading to invasive patterns even under conditions in which the overall tumor mass shrinks.Conclusions: We conclude that therapeutic strategies focused solely on reduction of vascular density may paradoxically increase invasive behavior. This theoretical model accounts for the highly variable outcome of antiangiogenic therapy in multiple clinical trials. We propose that antiangiogenic strategies will be more consistently successful when aimed at "normalizing" the vasculature and when combined with therapies that increase cell adhesion so that morphologic instability is suppressed and compact, noninvasive tumor morphologies are enforced.