Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, 1111 Highland Avenue, Madison, WI, 53705, USA; University of Wisconsin Carbone Cancer Center, Wisconsin Institutes for Medical Research, 1111 Highland Ave, Madison, WI, 53705, USA; Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI, 53705, USA.
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, 1111 Highland Avenue, Madison, WI, 53705, USA; University of Wisconsin Carbone Cancer Center, Wisconsin Institutes for Medical Research, 1111 Highland Ave, Madison, WI, 53705, USA; Department of Dermatology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI, 53705, USA.
Biomaterials. 2022 Apr;283:121454. doi: 10.1016/j.biomaterials.2022.121454. Epub 2022 Mar 11.
Renal cell carcinomas are common genitourinary tumors characterized by high vascularization and strong reliance on glycolysis. Despite the many available therapies for renal cell carcinomas, first-line targeted therapies, such as cabozantinib, and durable reaponses are seen in only a small percentage of patients. Yet, little is known about the mechanisms that drive response (or lack thereof). This dearth of knowledge can be explained by the dynamic and complex microenvironment of renal carcinoma, which remains challenging to recapitulate in vitro. Here, we present a microphysiological model of renal cell carcinoma, including a tubular blood vessel model of induced pluripotent stem cell-derived endothelial cells and an adjacent 3D carcinoma model. Our model recapitulated hypoxia, glycolic metabolism, and sprouting angiogenesis. Using our model, we showed that cabozantinib altered cancer cell metabolism and decreased sprouting angiogenesis but did not restore barrier function. This microphysiological model could be helpful to elucidate, through multiple endpoints, the contributions of the relevant environmental components in eliciting a functional response or resistance to therapy in renal cell carcinoma.
肾细胞癌是常见的泌尿生殖系统肿瘤，其特点是血管化程度高，对糖酵解的依赖性强。尽管有许多针对肾细胞癌的治疗方法，但一线靶向治疗药物，如卡博替尼，只有一小部分患者能获得持久的缓解。然而，对于驱动反应（或缺乏反应）的机制知之甚少。这种知识的匮乏可以用肾癌细胞复杂多变的微环境来解释，这种微环境在体外仍然难以重现。在这里，我们提出了一种肾细胞癌的器官芯片模型，包括诱导多能干细胞衍生的内皮细胞的管状血管模型和相邻的 3D 癌模型。我们的模型再现了缺氧、糖酵解代谢和发芽血管生成。使用我们的模型，我们表明卡博替尼改变了癌细胞的代谢，减少了发芽血管生成，但没有恢复屏障功能。这种器官芯片模型可以通过多个终点来阐明相关环境成分在诱发肾细胞癌功能反应或对治疗产生耐药性方面的作用。
