卵巢癌致死率居妇科肿瘤之首，主要归因于多数患者确诊时已处于晚期，其发生机制尚不清楚。血管细胞粘附分子-1（VCAM-1）隶属免疫球蛋白超家族，生物学功能是介导异种细胞间的粘附。已知肿瘤细胞能通过VLA-4与内皮或间皮细胞VCAM-1结合，参与转移，但对肿瘤细胞自身表达VCAM-1的生物学意义并不明确。我们前期研究发现，卵巢癌细胞存在VCAM-1表达并与预后差及肿瘤复发关系密切、致瘤性T29H细胞共表达VCAM-1及炎症因子、腹腔转移性癌组织含有VLA-4＋巨噬细胞、VCAM-1＋卵巢癌细胞侵袭性及增殖活性均明显增强，提示巨噬细胞可能激活卵巢癌细胞产生VCAM-1进而促进癌细胞生长及侵袭。因此，本课题拟利用细胞及分子生物学方法，通过探讨巨噬细胞-VLA-4/VCAM-1-卵巢癌细胞信号通路，阐明肿瘤炎症性微环境促进VCAM-1介导卵巢癌侵袭及腹腔转移的分子机制，为卵巢癌治疗提供可能的靶点。

Ovarian carcinoma is the most lethal gynecologic malignancy, primarily owing to most patients being diagnosed at the advanced stages of disease. Its mechanism is still unclear. Vascular cell adhesion molecule-1 (VCAM-1) belongs to the immunoglobin superfamily and plays an important role in heterogenous cell-cell adhesions. It is well known that tumor cells with VLA-4 expression can adhere to endothelial or peritoneal mesothelial cells by binding of VLA-4 to VCAM-1, taking part in the metastasis of tumors. However, biological functions that VCAM-1 is expressed in tumor cells remain to be elucidated. In the previous study, we had found that VCAM-1 expression was found in 28% of ovarian carcinoma samples and was associated with worse prognosis of patients and shorter disease-free survival duration. T29H cells, which are the tumorigenic cells, expressed both VCAM-1 and inflammatory factors. The macrophages with VLA-4 expression were found in the peritoneal metastatic ovarian carcinoma samples. VCAM-1＋ ovarian cancer cells demonstrated stronger invasiveness and higher proliferative potential than VCAM-1- tumor cells. These data proposed that macrophages may activate ovarian cancer cells produce VCAM-1 and enhance tumor progression. Therefore, in the current study, we will elucidate the mechanism on tumor inflammatory microenvironment promoting VCAM-1 to mediate invasion and peritoneal metastasis in ovarian carcinoma via the signaling pathways among macrophages, VLA-4/VCAM-1, and ovarian cancer cells, using the methods of cell and molecular biology. This may develop a novel therapeutic target for the treatment of ovarian carcinoma.

卵巢癌致死率居妇科肿瘤之首，主要归因于多数患者确诊时已处于晚期，其发生机制尚不清楚。血管细胞粘附分子-1（VCAM-1）隶属免疫球蛋白超家族，生物学功能是介导异种细胞间的粘附。已知肿瘤细胞能通过VLA-4与内皮或间皮细胞VCAM-1结合，参与肿瘤转移，但对肿瘤细胞自身表达VCAM-1的生物学意义并不明确。本课题围绕巨噬细胞—VCAM-1—卵巢癌细胞信号通路进行研究，以期阐明肿瘤炎症性微环境促进VCAM-1介导的卵巢癌侵袭及腹腔转移的具体机制。通过对人类卵巢癌组织进行原位研究，我们发现VCAM-1阳性表达主要存在于高级别浆液性癌及高级别卵巢癌组织，VCAM-1阳性表达的患者预后较差，生存时间及复发时间均明显缩短，是肿瘤复发的独立预后因素。巨噬细胞上清和TNF-alpha可显著上调VCAM-1基因启动子的转录活性，导致卵巢癌细胞VCAM-1 mRNA和蛋白表达水平升高。与空载体对照组相比，VCAM-1+卵巢癌细胞在细胞周期及迁移能力无显著差异，但细胞凋亡显著增高，细胞侵袭和克隆形成能力显著下降；巨噬细胞上清培养的VCAM-1＋卵巢癌细胞在细胞周期和凋亡方面未见显著差异，但细胞迁移、侵袭和克隆形成能力均显著增强，提示巨噬细胞能够通过上调VCAM-1表达，促进卵巢癌细胞生长、迁移和侵袭，其分子机制可能与STAT3表达和/或STAT3磷酸化有关。裸鼠体内实验结果显示，与对照组相比，VCAM-1＋卵巢癌细胞组尽管肿瘤体积和重量均显著下降，但细胞侵袭能力显著升高，较常出现骨骼肌和骨骼侵犯、远隔脏器（肺脏及胸腔淋巴结）和盆/腹腔脏器转移。本课题研究结果证实肿瘤炎症性微环境能够促进卵巢癌侵袭及转移，为未来卵巢癌临床治疗提供可能的靶点及实验依据。