Cancer cell angiogenic capability is regulated by 3D culture and integrin engagement
Cancer cell angiogenic capability is regulated by 3D culture and integrin engagement
复制标题
DOI：
10.1073/pnas.0808932106
复制
发表时间：
2009-01-13
影响因子：
11.1
通讯作者：
Mooney, David J.
中科院分区：
文献类型：
--
作者：
Fischbach, Claudia;Kong, Hyun Joon;Mooney, David J.
三维培养改变了癌细胞信号传导;然而，这些变化对肿瘤血管形成的潜在机制和重要性仍不清楚。使用水凝胶系统来检查从2D到3D培养的转变（有和没有整合素参与）对癌细胞血管生成能力的作用。三维培养重建肿瘤微环境线索，并导致增强白细胞介素8（IL-8）的分泌，这取决于整合素与粘附肽耦合到聚合物。与此相反，血管内皮生长因子（VEGF）的分泌不受3D培养或无基板粘附。与VEGF相比，IL-8扩散的距离更远，并且在体循环中的浓度更高。将聚合物IL-8递送系统植入GFP骨髓移植小鼠中揭示了局部IL-8上调对于体内肿瘤血管形成的局部和全身控制都是至关重要的。总之，肿瘤微环境中的3D整合素参与调节癌细胞血管生成信号传导，并且IL-8和VEGF信号传导的受控局部和全身阻断可以改善抗血管生成疗法。
Three-dimensional culture alters cancer cell signaling; however, the underlying mechanisms and importance of these changes on tumor vascularization remain unclear. A hydrogel system was used to examine the role of the transition from 2D to 3D culture, with and without integrin engagement, on cancer cell angiogenic capability. Three-dimensional culture recreated tumor microenvironmental cues and led to enhanced interleukin 8 (IL-8) secretion that depended on integrin engagement with adhesion peptides coupled to the polymer. In contrast, vascular endothelial growth factor (VEGF) secretion was unaffected by 3D culture with or without substrate adhesion. IL-8 diffused greater distances and was present in higher concentrations in the systemic circulation, relative to VEGF. Implantation of a polymeric IL-8 delivery system into GFP bone marrow-transplanted mice revealed that localized IL-8 up-regulation was critical to both the local and systemic control of tumor vascularization in vivo. In summary, 3D integrin engagement within tumor microenvironments regulates cancer cell angiogenic signaling, and controlled local and systemic blockade of both IL-8 and VEGF signaling may improve antiangiogenic therapies.