FABP3通过刺激大网膜脂肪细胞分泌细胞因子促进卵巢癌转移

One of the most important ways to seek a breakthrough in clinic treatment for ovary cancer is to explore the molecular mechanism of metastasis, thereby providing a more potent agent for therapy. In previous study, by using the “primary-metastasis” mouse model based on SKOV3 cells, we have established ovarian cancer cell lines with high peritoneal metastasis potential and selected genes involved in metastasis, in which FABP3 is found to be over-expressed with high metastasis potential. In the following experiment of FABP3 test, it turned out that the expression level of FABP3 in tissues, blood and ascites of ovarian cancer patients were respectively significant higher than that in the normal controls. Down-regulation of FABP3 inhibited the metastasis of ovarian cancer cells in vivo. During the progress of adaptation, tumor cells also did change to the metastasis micro-environment. In the further study of FABP3, we found that this protein affected the differentiation process and secretion function of adipocytes, which implied that FABP3 might promote the metastasis of ovarian cancer through the modulation of omental adipocytes. This project is aimed at finding new clues and explore potent target for ovarian cancer treatment through investigating the expression and clinical meaning of FABP3 in ovary cancer, as well as the mechanism of promoting metastasis.

对卵巢癌的转移机制进行研究，进而设计有效的阻遏方式是寻找临床治疗突破口的重要途径之一。通过建立基于SKOV3细胞的卵巢癌原位转移模型，我们筛选得到具有腹腔高转移潜能的细胞株，并且发现FABP3基因在这些细胞株中表达明显升高。后续关于FABP3的检测结果表明，在卵巢癌病人中FABP3水平在病人组织标本，血液和腹水样本中都较正常对照组明显升高。下调FABP3表达，能够明显抑制卵巢癌的转移。癌细胞既是转移微环境的适应者，也是改造者。进一步的研究发现FABP3能够影响脂肪细胞的分化成熟和分泌功能。这提示我们FABP3可能通过对大网膜脂肪细胞的改造促进卵巢癌转移。本项目拟通过研究FABP3在卵巢癌中的表达和临床意义，以及促进转移的作用机制，为改善卵巢癌临床治疗提供新的线索和目标。

转移是导致卵巢癌死亡的主要原因。因此，找到卵巢癌早发现或者有效抑制卵巢癌转移的手段，对于改善卵巢癌患者预后至关重要。本研究发现，FABP3表达水平与卵巢癌临床分期，复发，生存预后密切相关。FABP3与CA125联合预测卵巢癌能够提高早期卵巢癌检出率。研究发现卵巢癌细胞通过分泌FABP3可以激活大网膜脂肪细胞，促进例如IL-6，IL-8, MCP-1, 和TIMP-1这些细胞因子的分泌。以上这些脂肪细胞分泌的细胞因子可以吸引肿瘤细胞向大网膜转移、增殖。因此，我们认为FABP3促进了卵巢癌细胞和大网膜脂肪细胞之间的信息沟通。进一步研究发现，靶向FABP3或者MCP1的治疗可以逆转FABP3改造大网膜“pre-metastatic niche”形成的过程，从而抑制卵巢癌腹腔转移。因此，FABP3可以作为“pre-metastatic niche”形成的一个标记，以利于我们早期发现卵巢癌的腹腔转移。靶向“pre-metastatic niche”形成相关的治疗，为卵巢癌转移的治疗提供了新的方向。