Purpose: Besides the tumor cells themselves, solid tumors are comprised of numerous cell types including infiltrating immune cells such as tumor-associated macrophages (TAMs). TAMs are vital stromal components of host immune system and play a critical role in the development of cancer. TAMs can be divided into two subtypes: M1 tumor-suppressive macrophage and M2 tumor-supportive macrophage. To better address the observations of TAMs functional performance, we describe an in vitro system that mimics the populations of TAMs infiltrated into the tumor mass by using our disintegrable supramolecular gelatin (DSG) hydrogels, which are physically crosslinked by host-guest complexations.
Materials and Methods: The host–guest interaction was adopted between the aromatic groups of gelatin and the photocrosslinkable acrylated β-cyclodextrins (Ac-β-CDs) to form the DSG hydrogels. The convenient macrophage/endometrial cancer cells heterospheroid 3D model was set up by DSG hydrogels. RT-PCR and Western blot assays were developed to evaluate the efficiencies of inducers on the macrophages. The ELISA and oxygen saturation assays were performed to measure the secretion of VEGF and consumption of oxygen of tumor and/or macrophages, respectively. To determine the antitumor effects of M2 reprogrammed macrophages in vitro and in vivo, migration assay and tumor xenograft model were used, respectively.
Results: The host-guest complexations of DSG hydrogels were controllably broken efficiently by soaking into the solution of competitive guest monomers 1-adamantanamine hydrochloride. The DSG hydrogels help IFN-γ reprogram the M2 to M1 and then decrease the tumor/M2 reprogrammed macrophage cells heterospheroid secretion of VEGF and increase the relative oxygen saturation. Significantly, the co-cultural tumor/M2 reprogrammed group from the disintegrated DSG hydrogels reduced the migration of cancer cells in vitro and the tumor growth in vivo.
Conclusion: We obtain a TAMs/tumor microenvironment-responsive 3D model based on the novel DSG hydrogels, and will be of utility in cancer therapy and drug discovery.

Keywords: supramolecular hydrogel, disintegration, host-guest complexations, tumor mimic model, tumor-associated macrophages, TAMs


中文翻译：

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模拟子宫内膜癌肿瘤微环境以重编程可崩解超分子明胶水凝胶中的肿瘤相关巨噬细胞。

目的：除了肿瘤细胞本身，实体瘤还由多种细胞类型组成，包括浸润性免疫细胞，如肿瘤相关巨噬细胞 (TAM)。TAMs 是宿主免疫系统的重要基质成分，在癌症的发展中发挥着关键作用。TAM 可分为两种亚型：M1 肿瘤抑制性巨噬细胞和 M2 肿瘤支持性巨噬细胞。为了更好地观察 TAM 的功能性能，我们描述了一种体外系统，该系统通过使用我们的可分解超分子明胶 (DSG) 水凝胶来模拟浸润到肿瘤块中的 TAM 群体，这些水凝胶通过主客体络合进行物理交联。
材料和方法：明胶的芳族基团与可光交联的丙烯酸酯化β-环糊精（Ac-β-CDs）之间采用主客体相互作用形成DSG水凝胶。通过DSG水凝胶建立了方便的巨噬细胞/子宫内膜癌细胞异质体3D模型。开发了 RT-PCR 和蛋白质印迹分析来评估诱导剂对巨噬细胞的效率。进行ELISA和氧饱和度测定以分别测量VEGF的分泌和肿瘤和/或巨噬细胞的氧消耗。为了确定 M2 重编程巨噬细胞在体外和体内的抗肿瘤作用，分别使用迁移测定和肿瘤异种移植模型。
结果：通过浸泡在竞争性客体单体 1-金刚胺盐酸盐溶液中，DSG 水凝胶的主客体络合物被可控有效地破坏。DSG 水凝胶帮助 IFN-γ 将 M2 重编程为 M1，然后减少肿瘤/M2 重编程的巨噬细胞异球体分泌 VEGF 并增加相对氧饱和度。值得注意的是，来自解体的 DSG 水凝胶的共培养肿瘤/M2 重编程组减少了体外癌细胞的迁移和体内肿瘤的生长。
结论：我们获得了基于新型 DSG 水凝胶的 TAMs/肿瘤微环境响应 3D 模型，可用于癌症治疗和药物发现。

关键词：超分子水凝胶, 崩解, 主客复合, 肿瘤模拟模型, 肿瘤相关巨噬细胞, TAM