The objective of this study is to design a cancer invasion model by making use of cancer-associated fibroblasts (CAF) or tumor-associated macrophages (TAM) and gelatin hydrogel microspheres (GM) for the sustained release of drugs. The GM containing adenosine (A) (GM-A) were prepared and cultured with TAM to obtain three-dimensional (3D) TAM aggregates incorporating GM-A (3D TAM-GM-A). The GM-A incorporation enabled TAM to enhance the secretion level of vascular endothelial growth factor. When co-cultured with HepG2 liver cancer cells in an invasion assay, the 3D TAM-GM-A promoted the invasion rate of cancer cells. In addition, the E-cadherin expression level decreased to a significantly greater extent compared with that co-cultured with TAM aggregates incorporating GM, whereas the significantly higher expression of N-cadherin and Vimentin was observed. This indicates that the epithelial-mesenchymal transition event was induced. The GM containing transforming growth factor-β1 (TGF-β1) were prepared to incorporate into 3D CAF (3D CAF-GM-TGF-β1). Following a co-culture of mixed 3D CAF-GM-TGF-β1 and 3D TAM-GM-A and every HepG2, MCF-7 breast cancer cell, or WA-hT lung cancer cell, the invasion rate of every cancer cell enhanced depending on the mixing ratio of 3D TAM-GM-A and 3D CAF-GM-TGF-β1. The amount of matrix metalloproteinase-2 (MMP-2) secreted also enhanced, and the enhancement was well corresponded with that of cancer cell invasion rate. The higher MMP secretion assists the breakdown of basement membrane, leading to the higher rate of cancer cell invasion. This model is a promising 3D culture system to evaluate the invasion ability of various cancer cells in vitro.

中文翻译：

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三维肿瘤相关巨噬细胞和三维肿瘤相关成纤维细胞的共培养系统结合生物分子释放用于癌细胞迁移。

本研究的目的是通过利用癌症相关成纤维细胞 (CAF) 或肿瘤相关巨噬细胞 (TAM) 和明胶水凝胶微球 (GM) 来设计一种癌症侵袭模型，用于药物的持续释放。制备含有腺苷的 GM (A) (GM-A) 并与 TAM 一起培养以获得包含 GM-A (3D TAM-GM-A) 的三维 (3D) TAM 聚集体。GM-A 的掺入使 TAM 能够提高血管内皮生长因子的分泌水平。在侵袭试验中与 HepG2 肝癌细胞共培养时，3D TAM-GM-A 促进了癌细胞的侵袭率。此外，与与含有 GM 的 TAM 聚集体共培养相比，E-cadherin 的表达水平显着降低，而观察到 N-钙粘蛋白和波形蛋白的表达显着更高。这表明诱导了上皮-间充质转化事件。制备含有转化生长因子-β1 (TGF-β1) 的 GM 以掺入 3D CAF (3D CAF-GM-TGF-β1)。将混合的 3D CAF-GM-TGF-β1 和 3D TAM-GM-A 与每个 HepG2、MCF-7 乳腺癌细胞或 WA-hT 肺癌细胞共培养后，每个癌细胞的侵袭率增强，具体取决于关于 3D TAM-GM-A 和 3D CAF-GM-TGF-β1 的混合比例。基质金属蛋白酶2（MMP-2）的分泌量也有所增加，且与癌细胞侵袭率的增加有很好的对应关系。较高的 MMP 分泌有助于基底膜的分解，导致癌细胞侵袭率较高。体外。