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Review
. 2014;20(17):2881-98.
doi: 10.2174/13816128113199990594.

Is fibroblast growth factor receptor 4 a suitable target of cancer therapy?

Christine Heinzle, Zeynep Erdem, Jakob Paur, Bettina Grasl-Kraupp, Klaus Holzmann, Michael Grusch, Walter Berger, Brigitte Marian  1
Affiliations
Review

Is fibroblast growth factor receptor 4 a suitable target of cancer therapy?

Christine Heinzle et al. Curr Pharm Des. 2014.

Abstract

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.

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Conflict of interest statement

Conflict of Interest

The authors confirm that this article content has no conflicts of interest.

Disclosures

No conflicting interests to disclose

Figures

Fig. (1)
Fig. (1). The gene and protein structure of FGFR4
The gene and protein structures of FGFR4 were extracted from the GenBank [219] and the nextProt [220] database and aligned to demonstrate the conserved exon protein domain relationships of the FGFR family. The figure depicts the two full-length transcripts NM002011 and NM213647, the soluble variant NM022963 that lacks exon 9 [41, 43], the soluble variant consisting of only exons 2-4 and the cytoplasmic ptd-FGFR4 variant (AF359246) [112]. Exons and protein domains are color coded to show which domain is derived from which exon.
Fig. (2)
Fig. (2). Promoter elements regulating FGFR4 gene expression
Sequences from intron 4 of the FGFR4 gene to about 1500bp up-stream of the major TSP have been investigated in the ENCODE project. TSPs are marked by red arrow heads. Transcription factor binding sites are given as boxes at the appropriate site.
Fig. (3)
Fig. (3). FGFR4 signaling options
Left: Canonic down-stream signaling pathways adapted from [3]. Right: Non-canonical signaling options related to FGFR-CAM binding as described by [221]. In cancer cells non-canonical signaling is reported to involve c-src-mediated activation of MMPs [157].
Fig. (4)
Fig. (4). the FGFR4G388R SNP
Among the many SNPs in the FGFR4 gene rs351855 has strong pathophysiological impact. It is located in the transmembrane domain of the protein.
See this image and copyright information in PMC

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