Durymanov Mikhail, Kroll Christian, Permyakova Anastasia, O'Neill Elizabeth, Sulaiman Raed, Person Michael, Reineke Joshua
Department of Pharmaceutical Sciences, South Dakota State University, Brookings, SD.
Avera Medical Group Oncology and Hematology, Sioux Falls, SD.
Transl Oncol. 2019 Jan;12(1):180-189. doi: 10.1016/j.tranon.2018.10.003. Epub 2018 Oct 25.
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by high expression of extracellular matrix in tumor tissue, which contributes to chemoresistance and poor prognosis. Here, we developed 3D pancreatic cancer spheroids, based on pancreatic cancer cells and fibroblast co-culture, which demonstrate innate desmoplastic properties and stay poorly permeable for model nanoparticles. Our study revealed that establishment of tumors by transplantation of spheroids significantly improved subcutaneous xenograft model of PDAC, which stays the most widely used animal model for testing of new drugs and drug delivery approaches. Spheroid based tumors abundantly produced different extracellular matrix (ECM) components including collagen I, fibronectin, laminin and hyaluronic acid. These tumors were highly reproducible with excellent uniformity in terms of ECM architecture recapitulating clinical PDAC tumors, whereas in more common cell based xenografts a significant intertumor heterogeneity in extracellular matrix production was found. Moreover, spheroid based xenografts demonstrated higher expression of pro-fibrotic and pro-survival PDAC hallmarks in opposite to cell based counterparts. We believe that future development of this model will provide an effective instrument for testing of anti-cancer drugs with improved predictive value.
胰腺导管腺癌（PDAC）是一种致命疾病，其特征是肿瘤组织中细胞外基质高表达，这导致化疗耐药性和预后不良。在此，我们基于胰腺癌细胞与成纤维细胞共培养构建了三维胰腺癌球体，其表现出固有的促结缔组织增生特性，且对模型纳米颗粒的通透性较差。我们的研究表明，通过移植球体建立肿瘤显著改善了PDAC的皮下异种移植模型，该模型仍是用于测试新药和药物递送方法的最广泛使用的动物模型。基于球体的肿瘤大量产生不同的细胞外基质（ECM）成分，包括I型胶原、纤连蛋白、层粘连蛋白和透明质酸。这些肿瘤具有高度可重复性，在ECM结构方面具有出色的一致性，重现了临床PDAC肿瘤，而在更常见的基于细胞的异种移植中，发现细胞外基质产生存在显著的肿瘤间异质性。此外，与基于细胞的异种移植相比，基于球体的异种移植显示出更高的促纤维化和促生存PDAC特征表达。我们相信，该模型的未来发展将为测试具有更高预测价值的抗癌药物提供一种有效工具。
