Modeling the mechanical stiffness of pancreatic ductal adenocarcinoma.
Modeling the mechanical stiffness of pancreatic ductal adenocarcinoma.
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DOI：
10.1016/j.mbplus.2022.100109
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发表时间：
2022-06
影响因子：
--
通讯作者：
Peyman SA
中科院分区：
文献类型：
--
作者：
Kpeglo D;Hughes MDG;Dougan L;Haddrick M;Knowles MA;Evans SD;Peyman SA
肿瘤组织变硬会导致肿瘤的发展、生理学和药物灌注不良。 PDAC 中的肿瘤硬度是疾病侵袭性、化疗耐药性和不良预后的核心。重要的是，3D 体外模型能够反映 PDAC 组织的微环境和机械特性，以准确开发和评估潜在的治疗方法并提高患者的生存率。 PDAC 基质僵硬强调了其恶性行为和耐药性。 3D 体外培养必须模拟 PDAC 基质才能有效发挥药物功效。 PSC 负责基质，其活性随着 TGF-β 的增加而增加。开发 PDAC 的 3D 培养模型，其中包括 PSC 和 TGF-β。评估机械刚度、胶原染色并研究吉西他滨功效。尽管对疾病生物学的认识有所提高，但胰腺导管腺癌（PDAC）仍然是胰腺中最恶性的癌症。 PDAC 占所有胰腺癌的 95%，并且对治疗具有高度耐药性。组织刚性的增加源于肿瘤微环境中丰富的纤维化基质，是疾病发展、生理学和药物灌注抵抗的核心。胰腺星状细胞 (PSC) 负责纤维化基质中细胞外基质的过量产生，而转化生长因子-β (TGF-β) 的过度表达会加剧这种情况。然而，很少有体外 PDAC 模型同时包含 PSC 和 TGF-β 或模拟体内类肿瘤硬度。在这项研究中，我们提出了一个三维体外 PDAC 模型，其中包括 PSC 和 TGF-β，并概括了 PDAC 组织的机械刚度。使用振荡剪切流变学，我们显示模型的机械刚度在培养第 21 天时处于 PDAC 组织刚度范围内，并强调基质环境对于充分捕获 PDAC 疾病至关重要。 PDAC是一种复杂的侵袭性疾病，预后较差，生物物理相关的体外PDAC模型考虑了组织力学，将为有效的治疗评估提供改进的肿瘤模型。
Tumor tissue stiffening drives tumor development, physiology, and poor drug perfusion. Tumor stiffness in PDAC is central to the disease aggressiveness, chemotherapeutic resistance, and the poor prognosis observed. It is important 3D in vitro models reflects the microenvironment and mechanical characteristic of the PDAC tissue to accurately develop and assess potential therapeutics and improve patient survival. The PDAC stroma stiffness underlines its malignant behavior and drug resistance. 3D in vitro cultures must model the PDAC stroma to effectively drug efficacy. PSCs are responsible for the stroma, and its activity is increased with TGF-β. Develop a 3D culture model of PDAC, which includes PSCs and TGF-β. Assess the mechanical stiffness, stain for collagen, and investigate gemcitabine efficacy. Despite improvements in the understanding of disease biology, pancreatic ductal adenocarcinoma (PDAC) remains the most malignant cancer of the pancreas. PDAC constitutes ∼95% of all pancreatic cancers, and it is highly resistant to therapeutics. The increased tissue rigidity, which stems from the rich fibrotic stroma in the tumor microenvironment, is central to disease development, physiology, and resistance to drug perfusion. Pancreatic stellate cells (PSCs) are responsible for overproduction of extracellular matrix in the fibrotic stroma, and this is exacerbated by the overexpression of transforming growth factor-β (TGF-β). However, there are few in vitro PDAC models, which include both PSCs and TGF-β or mimic in vivo-like tumor stiffness. In this study, we present a three-dimensional in vitro PDAC model, which includes PSCs and TGF-β, and recapitulates PDAC tissue mechanical stiffness. Using oscillatory shear rheology, we show the mechanical stiffness of the model is within range of the PDAC tissue stiffness by day 21 of culture and highlight that the matrix environment is essential to adequately capture PDAC disease. PDAC is a complex, aggressive disease with poor prognosis, and biophysically relevant in vitro PDAC models, which take into account tissue mechanics, will provide improved tumor models for effective therapeutic assessment.