Department of Chemical and Biomolecular Engineering, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA.
Biomaterials. 2011 Dec;32(35):9308-15. doi: 10.1016/j.biomaterials.2011.08.045. Epub 2011 Sep 10.
Three dimensional (3D) tumor spheroid models are becoming important biomedical tools for both fundamental and applied cancer studies, but current models do not account for different levels of cancer malignancy. Several studies have reported that the mechanical rigidity of a hydrogel plays a significant role in regulating the phenotypes of cancer cells adhered to the gel surface. This finding suggests that matrix rigidity should also modulate the malignancy of 3D tumor spheroids. However, the role of matrix stiffness is often confounded by concurrent changes in 3D matrix permeability. This study reports an advanced strategy to assemble 3D liver tumor spheroids with controlled intercellular organization, phenotypes, and angiogenic activities using hydrogels with controlled stiffness and minimal differences in molecular diffusivity. The elastic moduli of cell-encapsulated collagen gels were increased by stiffening interconnected collagen fibers with varied amounts of poly(ethylene glycol) di-(succinic acid N-hydroxysuccinimidyl ester). Interestingly, hepatocellular carcinoma cells encapsulated in a fat-like, softer hydrogel formed malignant cancer spheroids, while cells cultured in a liver-like, stiffer gel formed compact hepatoids with suppressed malignancy. Overall, both the hydrogel and the 3D tumor spheroids developed in this study will be greatly useful to better understand and regulate the emergent behaviors of various cancer cells.
三维（3D）肿瘤球体模型正在成为基础和应用癌症研究的重要生物医学工具，但目前的模型并未考虑癌症恶性程度的不同。有几项研究报告称，水凝胶的机械硬度在调节附着在凝胶表面的癌细胞表型方面起着重要作用。这一发现表明，基质硬度也应该调节 3D 肿瘤球体的恶性程度。然而，基质硬度的作用往往因 3D 基质渗透性的同时变化而变得复杂。本研究报告了一种先进的策略，使用具有可控硬度和最小分子扩散率差异的水凝胶组装具有受控细胞间组织、表型和血管生成活性的 3D 肝肿瘤球体。通过用不同量的聚乙二醇二（琥珀酸 N-羟基琥珀酰亚胺酯）交联胶原纤维来增加细胞包封的胶原凝胶的弹性模量。有趣的是，包裹在脂肪状较软水凝胶中的肝癌细胞形成恶性肿瘤球体，而在肝状较硬凝胶中培养的细胞形成恶性程度受抑制的致密肝样细胞。总体而言，本研究中开发的水凝胶和 3D 肿瘤球体将非常有助于更好地理解和调节各种癌细胞的新兴行为。
