Since their description and identification in leukemias and solid tumors, cancer stem cells (CSC) have been the subject of intensive research in translational oncology. Indeed, recent advances have led to the identification of CSC markers, CSC targets, and the preclinical and clinical evaluation of the CSC-eradicating (curative) potential of various drugs. However, although diverse CSC markers and targets have been identified, several questions remain, such as the origin and evolution of CSC, mechanisms underlying resistance of CSC against various targeted drugs, and the biochemical basis and function of stroma cell-CSC interactions in the so-called ‘stem cell niche.’ Additional aspects that have to be taken into account when considering CSC elimination as primary treatment-goal are the genomic plasticity and extensive subclone formation of CSC. Notably, various cell fractions with different combinations of molecular aberrations and varying proliferative potential may display CSC function in a given neoplasm, and the related molecular complexity of the genome in CSC subsets is considered to contribute essentially to disease evolution and acquired drug resistance. In the current article, we discuss new developments in the field of CSC research and whether these new concepts can be exploited in clinical practice in the future.

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.

Deregulation of fibroblast growth factor receptor 3 (FGFR3) is involved in several malignancies. Its role in colorectal cancer has not been assessed before. Expression of FGFR3 in human colorectal tumour specimens was analysed using splice variant-specific real-time reverse transcriptase PCR assays. To analyse the impact of FGFR3-IIIc expression on tumour cell biology, colon cancer cell models overexpressing wild-type (WT-3b and WT3c) or dominant-negative FGFR3 variants (KD3c and KD3b) were generated by either plasmid transfection or adenoviral transduction. Although FGFR3 mRNA expression is downregulated in colorectal cancer, alterations mainly affected the FGFR3-IIIb splice variant, resulting in an increased IIIc/IIIb ratio predominantly in a subgroup of advanced tumours. Overexpression of WT3c increased proliferation, survival and colony formation in all colon cancer cell models tested, whereas WT3b had little activity. In addition, it conferred sensitivity to autocrine FGF18-mediated growth and migration signals in SW480 cells with low endogenous FGFR3-IIIc expression. Disruption of FGFR3-IIIc-dependent signalling by dominant-negative FGFR3-IIIc or small interfering RNA-mediated FGFR3-IIIc knockdown resulted in inhibition of cell growth and induction of apoptosis, which could not be observed when FGFR3-IIIb was blocked. In addition, KD3c expression blocked colony formation and migration and distinctly attenuated tumour growth in SCID mouse xenograft models. Our data show that FGFR3-IIIc exerts oncogenic functions by mediating FGF18 effects in colorectal cancer and may constitute a promising new target for therapeutic interventions.

Fibroblast growth factors (FGF) and their tyrosine kinase receptors (FGFR) support cell proliferation, survival and migration during embryonic development, organogenesis and tissue maintenance and their deregulation is frequently observed in cancer development and progression. Consequently, increasing efforts are focusing on the development of strategies to target FGF/FGFR signaling for cancer therapy. Among the FGFRs the family member FGFR4 is least well understood and differs from FGFRs1-3 in several aspects. Importantly, FGFR4 deletion does not lead to an embryonic lethal phenotype suggesting the possibility that its inhibition in cancer therapy might not cause grave adverse effects. In addition, the FGFR4 kinase domain differs sufficiently from those of FGFRs1-3 to permit development of highly specific inhibitors. The oncogenic impact of FGFR4, however, is not undisputed, as the FGFR4-mediated hormonal effects of several FGF ligands may also constitute a tissue-protective tumor suppressor activity especially in the liver. Therefore it is the purpose of this review to summarize all relevant aspects of FGFR4 physiology and pathophysiology and discuss the options of targeting this receptor for cancer therapy.