Fibroblast Growth Factor Signalling: From Development to Cancer

Nicholas Turner; Richard Grose

In This Article

FGF Tumour Suppressive Effects in Cancer

As well as the wealth of evidence that links activation of FGF signalling with oncogenesis, there is unequivocal evidence from mouse models for a tumour suppressive role of FGFR2 in some contexts. Mice that specifically lack FGFR2-IIIb in keratinocytes are sensitive to carcinogenic insults to their skin.[145] In mouse models of medulloblastoma, FGF signalling inhibits Sonic Hedgehog signalling, which blocks the proliferation of cancer cells.[146] In addition, studies in a rat model of prostate cancer showed that when non-malignant epithelial cells expressing FGFR2-IIIb were mixed with stromal cells they formed non-malignant tumours. However, when the stromal cells were absent, epithelial cells underwent a splicing switch from the FGFR2-IIIb to the FGFR2-IIIc isoform, and expression of FGF2 was upregulated, potentially initiating an autocrine loop. These studies established the importance of epithelial–stromal interactions in the paracrine regulation of prostate epithelial cell proliferation.[147]

Several studies of human tumours and cancer cell lines potentially support a tumour protective effect of FGFR2 signalling. In bladder cell lines, expression of FGFR2-IIIb expression blocks proliferation.[148] FGFR2-IIIb, which is physiologically expressed in many epithelial structures, is downregulated on progression in bladder cancers,[148] prostate cancer[94] and salivary adenocarcinomas.[149] In prostate cancer cell lines, the expression of a conditionally active FGFR1 kinase domain promotes proliferation, but a conditionally active form of FGFR2 does not.[39] Finally, inactivating mutations of FGFR2 have been described in melanoma.[150]

In some circumstances FGFR2 signalling is clearly oncogenic, so what explains the potential tumour suppressive effects? In general, it is important to draw a distinction between genuine tumour suppressive effects and oncogene-induced senescence. It is well recognized that context-dependent differences in signalling can lead to either tumour promotion or senescence in response to activated FGF signalling. Similarly, the genuine tumour suppressive effects of FGFR2-IIIb are also likely to reflect context-dependent differences in signalling. Although there has been much focus on FGFR2-IIIb, as opposed to FGFR2-IIIc, being tumour protective, there is no evidence that splicing of the extracellular domain affects intracellular signalling. Therefore, it seems likely that differences in extracellular splicing reflect changes in cellular phenotype.

Other mechanisms have been proposed for the tumour suppressive function of FGFR2. FGF signalling may induce cytoprotective pathways in epithelial cells, helping to maintain genomic stability following challenge with carcinogens, reactive oxygen species or other cytotoxic stresses, as shown in mice that lack the NRF2 transcription factor — which is known to be regulated by FGF7 (Ref.[151]). Another speculative mechanism is a potential role for FGFR2-IIIb in immune surveillance. γδ-T cells release both FGF7 (Ref.[152]) and FGF10, which may signal through FGFR2-IIIb in epithelia to promote immune surveillance, and loss of epithelial FGFR2 could therefore interfere with tumour surveillance.


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