原发中枢神经系统弥漫性大B细胞淋巴瘤(PCNS-DLBCL) 是中枢神经系统较常见的高侵袭性肿瘤，预后差且无理想治疗方案。PCNS-DLBCL肿瘤细胞呈现独特的围绕血管生长特点，但其机制及与预后关系少有报道。本研究在前期观察中发现PCNS-DLBCL肿瘤细胞围血管生长且高表达XBP1和CD44，与预后差关系密切。假设XBP1和CD44是该肿瘤围血管生长的关键分子，可能与CNS特殊微环境下的肿瘤缺氧有关。本项目拟进行：①通过扩大临床病例观察"围血管生长-XBP1和CD44-预后"之间联系；②用基因重组和RNA干扰使XBP1和CD44过表达和沉默,体外设置常氧与缺氧条件观察肿瘤细胞以及与内皮细胞间作用的变化；体内用原位裸鼠模型观察过表达和阻断XBP1和CD44对裸鼠成瘤及移植瘤围血管生长和转归的影响。旨在探讨PCNS-DLBCL围血管生长的分子机制,为临床提供预后判断指标，寻找新的治疗靶点。

Primary central nervous system lymphomas, predominantly diffuse large B-cell lymphomas (PCNS-DLBCL) are aggressive form of non-Hodgkin lymphoma whose growth are restricted to the central nervous system. The prognosis of this tumor is poor and there are not valid therapy available. In clinical pathological examination, accumulation of malignant B cells around vessels is commonly found and just the most significant histological feature of PCNS-DLBCL, but there are few reports about this feature with prognosis and pathogenesis. We have previously confirmed that PCNS-DLBCL was characterized by the aggregated malignant B cells in perivascular area and demonstrated that aggregative perivascular tumor cells with strong staining of XBP1 and CD44， which were independently associated with worse survival and could be used to better stratify the PCNS-DLBCL. Therefore, we have a hypothesis of XBP1 and CD44 could be the key molecular about tumor cell's angiotropism of PCNS-DLBCL, and could be associated with hypoxia of CNS. So the present item will take the following plans：① To analyze more clinical cases of PCNS-DLBCL about association of 'Angiotropism growth pattern- - -Expression of XBP1 and CD44- - -Prognosis' ; ② In normoxic and hypoxic condition of cell cuture after activiting and blocking XBP1 and CD44 up by gene recombination and RNA interfere technique, to observe the changes of tumor cells growth, interaction between tumor cell and endothelial cell; To investigate the effect on mice brain in situ DLBCL model. In a word, we would explore the molecular pathogenesis of the perivascular tumor cells growth feature by the mode of'clinical trial-in vitro-in vivo' in order to get a valuble histopathological prognostic parameter and new therapic target.

原发性中枢神经系统弥漫性大B细胞淋巴瘤(PCNS-DLBCL)是中枢神经系统最常见的淋巴瘤，具有独特的临床病理特征，近年来发病率明显升高，治疗效果差，预后不良。临床病理工作中我们发现，PCNS-DLBCL中肿瘤细胞呈现独特的围绕血管生长的特点，但是对其机制及与预后关系方面的研究少有报道。本研究在前期观察基础上，通过三个阶段性实验，经过体内外观察和临床病例验证，全面证实了PCNS-DLBCL肿瘤细胞围血管生长与预后差有关，中枢神经系统特殊微环境导致的缺氧诱导的内质网应激（ERS）和未折叠蛋白反应（UPR）是PCNS-DLBCL肿瘤细胞围血管生长的重要机制之一，相关微环境分子XBP1/CXCR4/CD44通路的活化及表达增高对肿瘤围血管生长和预后差的关键，是值得进一步研究和靶向治疗的切入点。