Fibroblast growth factor receptor 2: expression, roles, and potential as a novel molecular target for colorectal cancer

Abstract

The fibroblast growth factor receptor (FGFR) family consists of four members, named FGFR1, 2, 3, and 4. All 4 FGFRs and their ligands, fibroblast growth factors (FGFs), are expressed in colorectal cancer (CRC). Recent studies have shown that FGFR2 plays important roles in cancer progression; therefore, it is of great interest as a novel target for cancers. Expression of FGFR2 regulates migration, invasion, and growth in CRC. Expression of the FGFR2 isoform FGFR2 IIIb was associated with well-differentiated histological types, and its specific ligand, FGF7, enhanced angiogenesis and adhesion to type-IV collagen via FGFR2 IIIb in CRC. FGFR2 IIIc is detected in CRC, but its roles have not been well elucidated. Interactions between FGFR2 IIIb and IIIc and FGFs may play important roles in CRC via autocrine and/or paracrine signaling. Several kinds of molecular-targeting agents against FGFR2 have been developed; however, it is not clear how a cancer treatment can most effectively inhibit FGFR2 IIIb or FGFR2 IIIc, or both isoforms. The aim of this paper is to summarize the roles of FGFR2 and its isoforms in CRC and clarify whether they are potent therapeutic targets for CRC.

Figure 1

Alternative splicing of FGFR2 and specific ligands of each variant. The two FGFR2 isoforms are generated by alternative splicing of exons 8 and 9. This alternative splicing determines the specific ligands for each FGFR2 isoform [19]. FOX-2 or ESRP1 and 2 bind to the ISE/ISS-3 element to enhance splicing of exon 8 and silencing of exon 9.

Figure 2

Immunohistochemical images of FGFR2 and its isoforms FGFR2 IIIb and FGFR2 IIIc in CRC. FGFR2 was expressed in the surface area of crypts in a nontumorous lesion obtained from CRC tissue (arrows). FGFR2 was also expressed in fibroblasts, inflammatory cells, and vascular endothelium (arrowheads). CRC cells exhibited marked expression of FGFR2 in the cell membrane and cytoplasm. Isoforms of FGFR2, FGFR2 IIIb, and FGFR2 IIIc were expressed in CRC cells. Original magnification: upper left panel, ×200; other panels, ×600.

Figure 3

Expression levels of FGFR2 IIIb and IIIc in CRC cell lines. All 5 CRC cell lines expressed FGFR2 IIIb and IIIc mRNAs at various levels. Quantitative RT-PCR results were expressed as the ratio of target to 18S rRNA, with the latter serving as an internal standard. Gene expression levels were measured in triplicate.

Figure 4

Immunocytochemical analysis of FGFR2 IIIb and IIIc in CRC cell lines. A human CRC cell line, LoVo, exhibited both FGFR2 IIIb and FGFR2 IIIc isoforms in the cell membrane and cytoplasm. The expression level of FGFR2 IIIb was weak, but IIIc was strong, which is consistent with their mRNA levels. Original magnification, ×1000; red, FGFR2 IIIb; green, FGFR2 IIIc; blue, DAPI.