Carcinogenesis Advance Access originally published online on September 22, 2007
Carcinogenesis 2008 29(1):15-24; doi:10.1093/carcin/bgm202
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FGF18 in colorectal tumour cells: autocrine and paracrine effects
Department of Medicine I, Institute of Cancer Research
1 Institute of Clinical Pathology, Medical University Vienna, Vienna, Austria
2 Department of Surgery, Social Medical Center South, Vienna 1100, Austria
3 Department of Pathology, Social Medical Center South, Vienna 1100, Austria
* To whom correspondence should be addressed. Tel: +43 1 4277 65241; Fax: +43 1 4277 9651; Email: brigitte.marian{at}meduniwien.ac.at
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.
Abbreviations: ERK, externally regulated kinase; FCS, fetal calf serum; FGF, fibroblast growth factor; GAPDH, glyceraldehyde phosphate dehydrogenase; HUVEC, human umbilical vein endothelial cell; IGF, insulin-like growth factor; MAPK, mitogen-activated protein kinase; mRNA, messenger RNA; RT–PCR, reverse transcription–polymerase chain reaction; siRNA, small interference RNA; TGF
, transforming growth factor alpha
Received May 16, 2007; revised August 10, 2007; accepted September 5, 2007.
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