胎盘生长因子（PLGF）近来被发现有显著的促肿瘤细胞转移作用，但对非小细胞肺癌（NSCLC）的作用不清。我们发现多数NSCLC患者体内PLGF升高并与转移呈正相关，并且PLGF具有激活巨噬细胞PLGF受体Flt-1、募集巨噬细胞至肿瘤部位浸润和极性改变而成为肿瘤相关巨噬细胞(TAM)作用，进而刺激肿瘤细胞分泌MMP9。我们推测：PLGF可激活TAM并通过旁分泌TGFβ，结合NSCLC细胞上的受体，反向激活P38/MAPK下游信号传导通路，并激活MMP9表达和分泌，促进肿瘤的侵袭和转移。本课题拟以PLGF为研究对象，利用种植瘤动物模型平台，使用特异性巨噬细胞杀伤剂及PLGF信号通路中关键分子的抑制剂，利用慢病毒载体对特定基因过/去表达，在一系列功能获得/丢失实验中研究PLGF促进转移的分子机理，特别是TAM被激活后进而激活MMP9的下游信号传导通路，为临床发现新的治疗靶点提供理论依据。

Recent studies have reported that placental growth factor (PLGF) may facilitate the migration of the cancer cells. However, the studies on Non-small cell lung cancer (NSCLC) is much lacking. In the preliminary study, we detected significantly higher serum PLGF levels in NSCLC patients, and PLGF levels appeared to positively correlate with cancer metastasis. PLGF was seemed to stimulate the Flt-1 receptor on macrophages and to attract and polarize macrophages into tumor-associated macrophages (TAM) via their Flt-1 receptor. TAM subsequently induced the production and secretion of matrix metalloproteinases 9 (MMP9) by NSCLC. Thus we hypothesize that TAM may release transforming growth factor β(TGFβ) to activate P38/MAPK pathway in NSCLC, and eventually activates MMP9 to promote cancer metastasis. A series of gain-of-function and loss-of-function experiments will be applied, using either specific macrophage-eliminator, pathway component inhibitors, transgenes or shRNA to modulate expression of particular genes in NSCLC by lenti vectors. This work may improve our understanding of NSCLC metastasis, especially the signal cascades downstream activation of TAM, which may eventually facilitate development of novel biomarkers and therapeutic targets for NSCLC.