Sonvilla Gudrun, Allerstorfer Sigrid, Stättner Stefan, Karner Josef, Klimpfinger Martin, Fischer Hendrik, Grasl-Kraupp Bettina, Holzmann Klaus, Berger Walter, Wrba Friedrich, Marian Brigitte, Grusch Michael
Department of Medicine I, Institute of Cancer Research, Medical University Vienna, Vienna, Austria.
Carcinogenesis. 2008 Jan;29(1):15-24. doi: 10.1093/carcin/bgm202. Epub 2007 Sep 22.
Fibroblast growth factors (FGFs) and their high-affinity receptors contribute to the autocrine growth stimulation in several human malignancies. Here, we describe that FGF18 expression is up-regulated in 34/38 colorectal tumours and is progressively enhanced during colon carcinogenesis reaching very high levels in carcinoma. Moreover, our data suggest that FGF18 affects both tumour cells and tumour microenvironment in a pro-tumorigenic and pro-metastatic way. Addition of recombinant FGF18 to the culture media of slowly growing colorectal tumour cell lines LT97 and Caco-2 stimulated proliferation. Phosphorylation of externally regulated kinase 1/2 and S6 was increased already 5 min after growth factor addition. SW480 cells, endogenously producing large amounts of FGF18, were not affected in this setting, but recombinant FGF18 supported tumour cell survival under conditions of serum starvation. Down-modulation of endogenous FGF18 production by small interference RNA (siRNA) significantly reduced clonogenicity of SW480 cells and restored sensitivity to exogenous FGF18. With respect to the tumour microenvironment, both recombinant and tumour-derived FGF18 stimulated growth of colon-associated fibroblasts at 0.1 ng/ml and migration at 10 ng/ml. In addition, recombinant FGF18 (10 ng/ml) induced tube formation in human umbilical vein endothelial cells. siRNA knock down demonstrated that tube-forming activity of colon cancer cell supernatants depended to a large part on tumour cell-derived FGF18. In summary, this study demonstrates that FGF18 is almost generally over-expressed in colon cancer and exerts pro-tumorigenic effects both in the epithelial and the stromal compartments by stimulating growth and survival of tumour cells, migration of fibroblasts and neovascularization. Together, these data strongly support an oncogenic role of FGF18 in colorectal cancer.
成纤维细胞生长因子（FGFs）及其高亲和力受体在多种人类恶性肿瘤中参与自分泌生长刺激。在此，我们描述FGF18在38例结直肠肿瘤中的34例中表达上调，且在结肠癌发生过程中逐渐增强，在癌组织中达到非常高的水平。此外，我们的数据表明FGF18以促肿瘤发生和促转移的方式影响肿瘤细胞和肿瘤微环境。将重组FGF18添加到生长缓慢的结直肠肿瘤细胞系LT97和Caco-2的培养基中可刺激细胞增殖。添加生长因子5分钟后，细胞外调节激酶1/2和S6的磷酸化水平就已升高。内源性产生大量FGF18的SW480细胞在此条件下未受影响，但重组FGF18可在血清饥饿条件下支持肿瘤细胞存活。通过小干扰RNA（siRNA）下调内源性FGF18的产生可显著降低SW480细胞的克隆形成能力，并恢复对外源性FGF18的敏感性。关于肿瘤微环境，重组FGF18和肿瘤来源的FGF18在0.1 ng/ml时均可刺激结肠相关成纤维细胞生长，在10 ng/ml时可刺激其迁移。此外，重组FGF18（10 ng/ml）可诱导人脐静脉内皮细胞形成管腔结构。siRNA敲低实验表明，结肠癌细胞上清液的管腔形成活性在很大程度上依赖于肿瘤细胞来源的FGF18。总之，本研究表明FGF18在结肠癌中几乎普遍过度表达，并通过刺激肿瘤细胞生长和存活、成纤维细胞迁移和新血管形成，在上皮和基质成分中发挥促肿瘤发生作用。这些数据共同有力地支持了FGF18在结直肠癌中的致癌作用。
