Mimetas BV, J.H. Oortweg 19, 2333 CH Leiden, The Netherlands.
Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
Int J Mol Sci. 2019 Sep 19;20(18):4647. doi: 10.3390/ijms20184647.
Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most lethal cancers due to a high chemoresistance and poor vascularization, which results in an ineffective systemic therapy. PDAC is characterized by a high intratumoral pressure, which is not captured by current 2D and 3D in vitro models. Here, we demonstrated a 3D microfluidic interstitial flow model to mimic the intratumoral pressure in PDAC. We found that subjecting the S2-028 PDAC cell line to interstitial flow inhibits the proliferation, while maintaining a high viability. We observed increased gemcitabine chemoresistance, with an almost nine-fold higher EC50 as compared to a monolayer culture (31 nM versus 277 nM), and an alleviated expression and function of the multidrug resistance protein (MRP) family. In conclusion, we developed a 3D cell culture modality for studying intratissue pressure and flow that exhibits more predictive capabilities than conventional 2D cell culture and is less time-consuming, and more scalable and accessible than animal models. This increase in microphysiological relevance might support improved efficiency in the drug development pipeline.
胰腺导管腺癌 (PDAC) 是最致命的癌症之一，其原因是化疗耐药性高和血管生成不良，导致系统性治疗效果不佳。PDAC 的特征是肿瘤内压力高，而目前的 2D 和 3D 体外模型无法捕捉到这种压力。在这里，我们展示了一种 3D 微流控间质流模型，以模拟 PDAC 中的肿瘤内压力。我们发现，使 S2-028 PDAC 细胞系经受间质流会抑制其增殖，同时保持高活力。我们观察到吉西他滨化疗耐药性增加，与单层培养相比，EC50 几乎高出九倍 (31 nM 对 277 nM)，并且多药耐药蛋白 (MRP) 家族的表达和功能减轻。总之，我们开发了一种用于研究组织内压力和流动的 3D 细胞培养方式，与传统的 2D 细胞培养相比，它具有更高的预测能力，并且比动物模型更省时、更具可扩展性和可及性。这种微生理相关性的提高可能有助于提高药物开发管道的效率。
