Our data demonstrate that trans-[tetrachlorobisindazole-ruthenate(III)] complex salts are promising candidate drugs in the second-line treatment of colorectal cancers resistant to other cytostatic drugs and has been introduced into phase I clinical trials.

Fibroblast growth factors (FGFs) and their high-affinity receptors [fibroblast growth factor receptors (FGFRs)] contribute to autocrine and paracrine growth stimulation in several nonliver cancer entities. Here we report that at least one member of the FGF8 subfamily (FGF8, FGF17, and FGF18) was up-regulated in 59% of 34 human hepatocellular carcinoma (HCC) samples that we investigated. The levels of the corresponding receptors (FGFR2, FGFR3, and FGFR4) were also elevated in the great majority of the HCC cases. Overall, 82% of the HCC cases showed overexpression of at least one FGF and/or FGFR. The functional implications of the deregulated FGF/FGFR system were investigated by the simulation of an insufficient blood supply. When HCC-1.2, HepG2, or Hep3B cells were subjected to serum withdrawal or the hypoxia-mimetic drug deferoxamine mesylate, the expression of FGF8 subfamily members increased dramatically. In the serum-starved cells, the incidence of apoptosis was elevated, whereas the addition of FGF8, FGF17, or FGF18 impaired apoptosis, which was associated with phosphorylation of extracellular signal-regulated kinase 1/2 and ribosomal protein S6. In contrast, down-modulation of FGF18 by small interfering RNA (siRNA) significantly reduced the viability of the hepatocarcinoma cells. siRNA targeting FGF18 also impaired the cells' potential to form clones at a low cell density or in soft agar. With respect to the tumor microenvironment, FGF17 and FGF18 stimulated the growth of HCC-derived myofibroblasts, and FGF8, FGF17, and FGF18 induced the proliferation and tube formation of hepatic endothelial cells. Conclusion: FGF8, FGF17, and FGF18 are involved in autocrine and paracrine signaling in HCC and enhance the survival of tumor cells under stress conditions, malignant behavior, and neoangiogenesis. Thus, the FGF8 subfamily supports the development and progression of hepatocellular malignancy. (HEPATOLOGY 2011;53:854-864) H epatocellular carcinoma (HCC) is the thirdleading cause of cancer deaths worldwide. 1 Important risk factors for this disease are persistent infections with hepatitis viruses and chronic steatohepatitis due to ethanol abuse and obesity, which contribute to the increasing incidence of HCC in Abbreviations: AHR, aryl hydrocarbon receptor; AKT, protein kinase B; ERK, extracellular signal-regulated kinase; ETS, E twenty-six; FACS, fluorescenceactivated cell sorting; FBS, fetal bovine serum; FCS, fetal colf serum; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; GSK3b, glycogen synthase kinase 3b; HCC, hepatocellular carcinoma; HIF, hypoxia inducible factor; MAP, mitogen-activated protein; MF, myofibroblast; mRNA, messenger RNA; MTF, metal-responsive transcription factor; pERK, phosphorylated extracellular signal-regulated kinase; pGSK3b, phosphorylated glycogen synthase kinase 3b; pS6, phosphorylated S6; qRT-PCR, quantitative reverse-transcriptase polymerase chain reaction; siFGF18, small interfering RNA targeting fibroblast growth factor 18; siRNA, small interfering RNA;...

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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.