Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, 1111 Highland Avenue, Madison, Wisconsin 53705, USA.
Lab Chip. 2020 Nov 24;20(23):4420-4432. doi: 10.1039/d0lc00252f.
Clear cell renal cell carcinoma (ccRCC) is a common genitourinary cancer associated with the development of abnormal tumor angiogenesis. Although multiple anti-angiogenic therapies have been developed, responses to individual treatment are highly variable between patients. Thus, the use of one-patient clinical trials has been suggested as an alternative to standard trials. We used a microfluidic device to generate organotypic primary patient-specific blood vessel models using normal (NEnC) and tumor-associated primary CD31+ selected cells (TEnC). Our model was able to recapitulate differences in angiogenic sprouting and vessel permeability that characterize normal and tumor-associated vessels. We analyzed the expression profile of vessel models to define vascular normalization in a patient-specific manner. Using this data, we identified actionable targets to normalize TEnC vessel function to a more NEnC-like phenotype. Finally, we tested two of these drugs in our patient-specific models to determine the efficiency in restoring vessel function showing the potential of the model for single-patient clinical trials.
透明细胞肾细胞癌 (ccRCC) 是一种常见的泌尿生殖系统癌症，与异常肿瘤血管生成的发展有关。尽管已经开发出多种抗血管生成疗法，但个体治疗的反应在患者之间差异很大。因此，有人建议使用单患者临床试验作为标准试验的替代方法。我们使用微流控装置，使用正常 (NEnC) 和肿瘤相关的原发性 CD31+选择细胞 (TEnC) 生成器官型原发性患者特异性血管模型。我们的模型能够再现正常和肿瘤相关血管特征的血管生成发芽和血管通透性差异。我们分析了血管模型的表达谱，以确定以患者特异性方式的血管正常化。使用这些数据，我们确定了可操作的靶点，将 TEnC 血管功能正常化为更类似于 NEnC 的表型。最后，我们在我们的患者特异性模型中测试了两种药物，以确定恢复血管功能的效率，显示了该模型用于单患者临床试验的潜力。
