Sahni A, Simpson-Haidaris P J, Sahni S K, Vaday G G, Francis C W
Hematology/Oncology Division, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
J Thromb Haemost. 2008 Jan;6(1):176-83. doi: 10.1111/j.1538-7836.2007.02808.x. Epub 2007 Oct 22.
Fibroblast growth factor (FGF)-2 is a critical growth factor in normal and malignant cell proliferation and tumor-associated angiogenesis. Fibrinogen and fibrin bind to FGF-2 and modulate FGF-2 functions. Furthermore, we have shown that extrahepatic epithelial cells are capable of endogenous production of fibrinogen.
Herein we examined the role of fibrinogen and FGF-2 interactions on prostate and lung adenocarcinoma cell growth in vitro.
Cell proliferation was measured by (3)H-thymidine uptake and the specificity of FGF-2-fibrinogen interactions was measured using wild-type and mutant FGF-2s, fibrinogen gamma-chain (FGG) RNAi and co-immunoprecipitation. Metabolic labeling, immunopurification and fluorography demonstrated de novo fibrinogen production.
FGF-2 stimulated DU-145 cell proliferation, whereas neither FGF-2 nor fibrinogen affected the growth of PC-3 or A549 cells. Fibrinogen augmented the proliferative effect of FGF-2 on DU-145 cells. The role of fibrinogen in FGF-2-enhanced DNA synthesis was confirmed using an FGF-2 mutant that exhibits no binding affinity for fibrinogen. FGG transcripts were present in PC-3, A549 and DU-145 cells, but only PC-3 and A549 cells produced detectable levels of intact protein. RNAi-mediated knockdown of FGG expression resulted in decreased production of fibrinogen protein and inhibited (3)H-thymidine uptake in A549 and PC-3 cells by 60%, which was restored by exogenously added fibrinogen. FGF-2 and fibrinogen secreted by the cells were present in the medium as a soluble complex, as determined by coimmunoprecipitation studies.
These data indicate that endogenously synthesized fibrinogen promotes the growth of lung and prostate cancer cells through interaction with FGF-2.
成纤维细胞生长因子（FGF）-2是正常细胞和恶性细胞增殖以及肿瘤相关血管生成中的关键生长因子。纤维蛋白原和纤维蛋白与FGF-2结合并调节FGF-2的功能。此外，我们已经表明肝外上皮细胞能够内源性产生纤维蛋白原。
在此我们研究了纤维蛋白原与FGF-2相互作用对前列腺和肺腺癌细胞体外生长的作用。
通过³H-胸腺嘧啶核苷摄取测量细胞增殖，并使用野生型和突变型FGF-2、纤维蛋白原γ链（FGG）RNA干扰和免疫共沉淀测量FGF-2-纤维蛋白原相互作用的特异性。代谢标记、免疫纯化和荧光显影证明了纤维蛋白原的从头产生。
FGF-2刺激DU-145细胞增殖，而FGF-2和纤维蛋白原均不影响PC-3或A549细胞的生长。纤维蛋白原增强了FGF-2对DU-145细胞的增殖作用。使用对纤维蛋白原无结合亲和力的FGF-2突变体证实了纤维蛋白原在FGF-2增强的DNA合成中的作用。PC-3、A549和DU-145细胞中存在FGG转录本，但只有PC-3和A549细胞产生可检测水平的完整蛋白。RNA干扰介导的FGG表达敲低导致纤维蛋白原蛋白产生减少，并使A549和PC-3细胞中的³H-胸腺嘧啶核苷摄取抑制60%，外源性添加纤维蛋白原可使其恢复。免疫共沉淀研究确定，细胞分泌的FGF-2和纤维蛋白原以可溶性复合物形式存在于培养基中。
这些数据表明，内源性合成的纤维蛋白原通过与FGF-2相互作用促进肺癌和前列腺癌细胞的生长。
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