透明质酸及其代谢酶在胶质瘤乏氧形成机制中的作用及影像学研究

Glioma is the most common primary malignant tumor in the CNS with poor prognosis. The formation of hypoxic microenvironment in the tumor is one of the main causes which result in the treatment failure. Recent studies have found that hyaluronic acid (HA) in the extra-cellular matrix of tumor can induce the formation of hypoxic regions by increasing the static pressure of the tumor, but related studies in glioma are rarely seen. In our previous studies, we found that hyaluronic acid synthase 2 (HAS2) and hyaluronan degrading enzyme 2 (HYAL2) were significantly expressed in gliomas, and were significantly associated with tumor malignancy and poor prognosis; and the expressions were positively correlated with the expression of HIF1A and VEGF. Based on these findings, we hypothesize that HA and metabolic enzymes in gliomas participate in the formation and progression of intra-tumoral hypoxia by mediating HA deposition. Our project aims to establish animal models with different HA expression levels by creating HAS2 overexpression and HYAL2 overexpressing U87 cell lines, and using diffusion technique combined with hypoxia imaging to observe the dynamic process of the formation and progression of hypoxia in different HA levels of glioma. By combining radiomics, HA content, hypoxia changes and prognosis information, we will construct an imaging model that can be used to reflect the HA content in human gliomas. By studying the correlation between HA and intra-tumoral hypoxia and poor prognosis, we will also testify the possibility of HA as well as its metabolic enzymes as the potential therapeutic target for gliomas.

胶质瘤作为颅内常见预后极差的恶性肿瘤，瘤内乏氧微环境形成是治疗失败的主要因素之一。有研究表明肿瘤间质内透明质酸（HA）通过增加瘤体静压，诱导乏氧区形成，但胶质瘤中相关研究少见。课题组前期研究发现透明质酸合成酶2（HAS2）及透明质酸降解酶2（HYAL2）在胶质瘤中显著高表达，与肿瘤恶性程度及患者预后显著相关；且与瘤内HIF-1ɑ及VEGF表达呈正相关。据此，我们推测胶质瘤中HA及其代谢酶，通过介导HA沉积参与瘤内乏氧形成及进展。本项目拟通过创建HAS2过表达、HYAL2过表达U87细胞株，建立不同HA表达水平的动物模型，采用MRI氧增强成像结合扩散技术观察不同HA水平胶质瘤中瘤内乏氧形成及进展的动态变化。通过影像组学、HA含量、乏氧变化及预后信息，构建无创显示胶质瘤HA含量的影像模型，同时通过研究HA与瘤内乏氧及不良预后的相关性，探讨HA及其代谢酶作为胶质瘤潜在治疗靶点的可能性。

胶质瘤是颅内常见恶性肿瘤，预后极差，瘤内乏氧微环境形成是治疗失败的主要原因之一。既往研究发现肿瘤间质内透明质酸（HA）通过增加瘤体静压，诱导乏氧区形成，但胶质瘤中相关研究少见。前期研究中本实验组发现透明质酸合成酶2（HAS-2）及透明质酸降解酶2（HYAL-2）在胶质瘤中显著表达，与肿瘤恶性程度及患者预后显著相关；且与瘤内HIF-1α表达呈正相关。据此，我们推测胶质瘤中HA及代谢酶，通过介导HA沉积参与瘤内乏氧形成及进展。在本课题中，我们通过病理染色，确认了动物脑内U87模型中HA呈显著表达，且与HIF-1α的表达显著相关；随后我们建立了HAS2欠表达U87细胞系siHAS2-U87，发现siHAS2-U87细胞活性及迁移能力无显著降低；建立体内siHAS2-U87肿瘤模型后我们发现其HA及HIF-1a表达量显著低于对照组，同时siHAS2-U87荷瘤鼠生存时间较对照组显著延长。后续通过对siHAS2-U87及U87荷瘤鼠进行IVIM及R2* Mapping MRI扫描，发现肿瘤内不同部位的R2*信号值与该部位的HIF-1a具有弱相关，siHAS2-U87组肿瘤中心区域的R2*值显著低于对照组，提示R2*值可非侵袭性地、动态地反应胶质瘤内的乏氧状态，并可部分提示细胞外基质中的HA含量。