A 3D in vitro model of patient-derived prostate cancer xenograft for controlled interrogation of in vivo tumor-stromal interactions.
A 3D in vitro model of patient-derived prostate cancer xenograft for controlled interrogation of in vivo tumor-stromal interactions.
复制标题
DOI：
10.1016/j.biomaterials.2015.10.059
复制
发表时间：
2016-01
期刊：
影响因子：
14
通讯作者：
Farach-Carson MC
中科院分区：
文献类型：
--
作者：
Fong EL;Wan X;Yang J;Morgado M;Mikos AG;Harrington DA;Navone NM;Farach-Carson MC
患者来源的异种移植物（PDX）模型比传统细胞系更好地代表人类癌症。然而，复杂的体内环境使得采用PDX模型来研究肿瘤-基质相互作用具有挑战性，例如介导前列腺癌（PCa）骨转移的肿瘤-基质相互作用。因此，我们设计了一种定义的三维（3D）水凝胶系统，能够支持PCa PDX细胞和成骨细胞的共培养，以在体外骨转移微环境中重现PCa-成骨细胞单位。我们的3D模型不仅保持了细胞活力，而且保留了PCa PDX细胞的典型成骨表型。此外，与单独培养的任一种细胞类型相比，共培养细胞结构得以维持，这表明PCa-成骨细胞串扰支持骨中的PCa进展，如假设在前列腺骨转移患者中发生的那样。引人注目的是，与PCa PDX类肿瘤共培养的成骨细胞在类肿瘤周围组织，密切模仿骨中PCa转移的结构。最后，由成纤维细胞生长因子轴介导的肿瘤间质信号传导与体内对应物紧密相关。总之，这些发现表明，这种3D PCa PDX模型概括了PCa骨转移的重要病理学特性，并验证了该模型用于复杂的体内肿瘤-基质相互作用的受控和系统性询问的用途。
Patient-derived xenograft (PDX) models better represent human cancer than traditional cell lines. However, the complex in vivo environment makes it challenging to employ PDX models to investigate tumor-stromal interactions, such as those that mediate prostate cancer (PCa) bone metastasis. Thus, we engineered a defined three-dimensional (3D) hydrogel system capable of supporting the co-culture of PCa PDX cells and osteoblastic cells to recapitulate the PCa-osteoblast unit within the bone metastatic microenvironment in vitro. Our 3D model not only maintained cell viability but also preserved the typical osteogenic phenotype of PCa PDX cells. Additionally, co-culture cellularity was maintained over that of either cell type cultured alone, suggesting that the PCa-osteoblast cross-talk supports PCa progression in bone, as is hypothesized to occur in patients with prostatic bone metastasis. Strikingly, osteoblastic cells co-cultured with PCa PDX tumoroids organized around the tumoroids, closely mimicking the architecture of PCa metastases in bone. Finally, tumor-stromal signaling mediated by the fibroblast growth factor axis tightly paralleled that in the in vivo counterpart. Together, these findings indicate that this 3D PCa PDX model recapitulates important pathological properties of PCa bone metastasis, and validate the use of this model for controlled and systematic interrogation of complex in vivo tumor-stromal interactions.