D'Angelo Edoardo, Marangio Asia, Sensi Francesca, Zanrè Eleonora, Steffan Agostino, Repetto Ombretta, Rampado Riccardo, Giomo Monica, Fassan Matteo, Spolverato Gaya, Cimetta Elisa, Agostini Marco
General Surgery 3, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; NanoInspired biomedicine lab, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy; Biobanca di Ricerca, Azienda Ospedale-Università di Padova, Padova, Italy.
General Surgery 3, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
Biomater Adv. 2025 Aug 5;178:214438. doi: 10.1016/j.bioadv.2025.214438.
Colorectal cancer (CRC) is among the most prevalent cancers globally and is associated with a high mortality rate, particularly in advanced stages. In the realm of drug discovery, the use of innovative and highly translational pre-clinical CRC models is essential. Currently, the most relevant in vitro tumor approaches are three dimensional (3D) models. However, most 3D models of solid tumors are based either on synthetic materials or animal-derived commercial hydrogels, which fail to accurately mimic the biology of native tissues and originate from non-human sources. In contrast, hydrogels derived from human decellularized extracellular matrix (ECM) retain signaling cues from native tissue and represent a bioactive mechanical structure that can foster tumor cell growth in a tissue-specific 3D in vitro environment. Here, we demonstrated that patient-derived decellularized colon ECM can be processed into a hydrogel, producing the CologEM. CologEM formulation process preserved key ECM proteins, such as collagens, glycosaminoglycans and secreted bioactive molecules belonging to the family of cytokine, chemokine, interleukin, growth factors and ECM-remodeling enzyme. CologEM displayed a fibrous ultrastructure with interconnected pores, with notable differences observed between 1 % and 3 % (w/v) CologEM. Both 1 % and 3 % CologEM showed good biocompatibility, with 3 % CologEM demonstrating a higher propensity to induce a mesenchymal phenotype and resistance to antitumor drugs. In conclusion, CologEM is a suitable scaffold for 3D CRC models as it replicates critical characteristics of the tumor microenvironment. This model holds promise for facilitating the discovery and development of chemotropic drugs for cancer treatment.
结直肠癌（CRC）是全球最常见的癌症之一，死亡率很高，尤其是在晚期。在药物研发领域，使用创新且高度可转化的临床前CRC模型至关重要。目前，最相关的体外肿瘤研究方法是三维（3D）模型。然而，大多数实体瘤的3D模型要么基于合成材料，要么基于动物来源的商业水凝胶，这些模型无法准确模拟天然组织的生物学特性，且来源于非人类。相比之下，源自人脱细胞细胞外基质（ECM）的水凝胶保留了来自天然组织的信号线索，代表了一种生物活性机械结构，能够在组织特异性的3D体外环境中促进肿瘤细胞生长。在此，我们证明了患者来源的脱细胞结肠ECM可以加工成水凝胶，即CologEM。CologEM的制备过程保留了关键的ECM蛋白，如胶原蛋白、糖胺聚糖以及属于细胞因子、趋化因子、白细胞介素、生长因子和ECM重塑酶家族的分泌生物活性分子。CologEM呈现出具有相互连接孔隙的纤维超微结构，1%和3%（w/v）的CologEM之间存在显著差异。1%和3%的CologEM均显示出良好的生物相容性，3%的CologEM表现出更高的诱导间充质表型和抗抗肿瘤药物的倾向。总之，CologEM是3D CRC模型的合适支架，因为它复制了肿瘤微环境的关键特征。该模型有望促进用于癌症治疗的趋化药物的发现和开发。
