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Carcinogenesis Advance Access published online on September 22, 2007
Carcinogenesis, doi:10.1093/carcin/bgm202
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FGF18 in Colorectal Tumour Cells: Autocrine and Paracrine Effects

Gudrun Sonvilla1, Sigrid Allerstorfer1, Stefan Stättner3, Josef Karner3, Martin Klimpfinger3, Hendrik Fischer1, Bettina Grasl-Kraupp1, Klaus Holzmann1, Walter Berger1, Friedrich Wrba2, Brigitte Marian1 and Michael Grusch1

1 Institute of Cancer Research, Department of Medicine 1
2 Institute of Clinical Pathology, Medical University Vienna
3 Social Medical Center South, Vienna

Address for correspondence: Brigitte Marian Institute of Cancer Research tel: +43 1 4277 65241, Department of Medicine 1 fax: +43 1 4277 9651, Medical University Vienna e-mail: brigitte.marian{at}meduniwien.ac.at Borschkegasse 8a 1090 Vienna Austria

Fibroblast growth factors (FGF) and their high affinity receptors contribute to autocrine growth stimulation in several human malignancies. Here we describe that FGF18 expression is upregulated 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-tumourigenic and pro-metastatic way. Addition of recombinant FGF18 to culture media of slowly growing colorectal tumour cell lines LT97 and Caco-2 stimulated proliferation. Phosphorylation of ERK1/2 and S6 was increased already 5 minutes 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 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 HUVEC vascular 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 overexpressed in colon cancer and exerts pro-tumourigenic effects both in the epithelial and the stromal compartments by stimulating growth and survival of tumour cells, migration of fibroblasts and neovascularisation. Together these data strongly support an oncogenic role of FGF18 in colorectal cancer.

Grant support: this work was supported by the Austrian Science Fund project P17630 [GenBank] -B12

Received May 16, 2007; revised August 10, 2007; accepted September 5, 2007.


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