泌尿系梗阻性力学因素激活肿瘤相关成纤维细胞介导细胞外基质重塑的分子机制研究

When obstruction occurs in the urinary system, changes in biomechanical factors have important effects on the biological behavior of urothelial carcinoma, but the mechanism is not yet clear. In previous study, we found that urothelial carcinoma with urinary obstruction was characterized by high degree of malignancy, poor prognosis, low survival rate, hard tissue stiffness, elevated levels of extracellular matrix proteins (COL1, COL4 and LAMA1) and increasing in the distribution of cancer-associated fibroblast (CAF). Therefore, we speculate that mechanical factors related to urinary obstruction may affect the remodeling of extracellular matrix by activating CAF and promote malignant progression of urothelial carcinoma. To test this hypothesis, we elucidate the molecular mechanisms underlying the urinary tract resistance factors that are involved in the malignant growth of urothelial cancer cells by activating CAF. So, we intend to study the effect of urinary obstruction on biological characteristics of cancer and prognosis in patients with urothelial carcinoma. Using organ microfluidic culture system and transwell co-culture system, we simulate shrinkage stress caused by compensation of Peristalsis and compress stress by hydronephrosis due to urinary tract obstruction, respectively. Furthermore, we would reveal the mechanism of activation of CAF by mechanical factors and explore the role of CAF activation in the regulation of extracellular matrix remodeling. This study provides new ideas for finding therapeutic targets and prognosis monitoring of urothelial carcinoma.

泌尿系统发生梗阻时，生物力学因素变化对于尿路上皮癌生物学行为产生重要影响, 但机制尚不清楚。申请人前期研究发现：梗阻型尿路上皮肿瘤恶性程度高、预后差、生存率低、组织刚度大、细胞外基质蛋白COL1、COL4和LAMA1含量升高，而且肿瘤相关成纤维细胞CAF分布显著增加。由此我们推测：梗阻相关力学因素可能通过激活CAF影响细胞外基质重塑，促进肿瘤恶性进展。为验证此假说，本项目拟深入阐明泌尿系梗阻力学因素通过激活CAF参与尿路上皮癌细胞恶性生长的分子机制。为此，申请人拟研究泌尿系梗阻对尿路上皮癌患者肿瘤生长及预后的影响；通过器官芯片微流控培养系统和Transwell共培养系统，分别模拟尿路梗阻所致管腔代偿蠕动引起的收缩拉力和尿路梗阻所致积液引起的膨胀压力，揭示力学因素激活CAF的作用机制并探讨CAF活化对于细胞外基质重塑的调节作用。本研究为寻找尿路上皮癌治疗靶点和预后监测提供新思路。

泌尿系统发生梗阻时，生物力学因素变化对于尿路上皮癌生物学行为产生重要影响, 但机制尚不清楚。申请人前期研究发现：梗阻型尿路上皮肿瘤恶性程度高、预后差、生存率低、组织刚度大、细胞外基质蛋白COL1、COL4和LAMA1含量升高，而且肿瘤相关成纤维细胞CAF分布显著增加。由此我们推测：梗阻相关力学因素可能通过激活CAF影响细胞外基质重塑，促进肿瘤恶性进展。为验证此假说，本项目拟深入阐明泌尿系梗阻力学因素通过激活CAF参与尿路上皮癌细胞恶性生长的分子机制。为此，申请人拟研究泌尿系梗阻对尿路上皮癌患者肿瘤生长及预后的影响；通过器官芯片微流控培养系统和Transwell共培养系统，分别模拟尿路梗阻所致管腔代偿蠕动引起的收缩拉力和尿路梗阻所致积液引起的膨胀压力，揭示力学因素激活CAF的作用机制并探讨CAF活化对于细胞外基质重塑的调节作用。本研究为寻找尿路上皮癌治疗靶点和预后监测提供新思路。