Fibroblast Growth Factor Signalling: From Development to Cancer

Nicholas Turner; Richard Grose

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In This Article

Oncogenic Mechanisms of FGF Signalling

FGF signalling can promote cancer development by affecting a range of major downstream biological processes. The following sections highlight examples for which particular aspects of FGF signalling affect various cancer cell behaviours in different tumour types.

FGF and Proliferation

Excessive cell proliferation is one of the hallmarks of cancer, and many cell-based studies and mouse models have demonstrated that FGF signalling promotes tumour cell proliferation (Box 3). Studies of the FGFR translocations of human haematological malignancies (Table 1) have shown that the mechanism driving a proliferative response to FGF signalling differs depending on context. The zinc finger 198 (ZNF198; also known as ZMYM2)–FGFR1 fusion proteins identified in 8p11 myeloproliferative syndrome delete the FRS2-binding site of FGFR1, and require PLCγ binding at Y766 along with STAT5 activation for proliferation.[76,77] By contrast, the breakpoint cluster region (BCR)–FGFR1 fusion proteins of chronic myelogenous leukaemia (CML) activate GRB2 through FGFR1-mediated phosphorylation of a BCR tyrosine residue,[76,77] and the ETV6–FGFR3 fusion proteins found in peripheral T cell lymphoma are oncogenic, at least partly though PI3K signalling.[114] These data demonstrate an important principle, in which the signal transduction pathways initiating FGFR-dependent oncogenesis differ depending on cellular context.

Mouse studies have further added to our understanding of how FGFs can influence proliferation (Box 3). FGF10 overexpression in the stromal compartment of the murine prostate resulted in epithelial hyperproliferation, which was concomitant with the upregulation of the androgen receptor.[115] FGF10 signalling was potentially dependent on FGFR1 as a dominant-negative FGFR1-IIIc construct attenuated cancer development,[116] although this construct might also inhibit FGFR2 signalling through receptor heterodimerization. Expression of activated AKT in prostate epithelium combined with the high FGF10 expression in the stroma to further promote tumorigenesis.[116] Similarly, in an independent study, Pten deficiency in prostate epithelium (which results in increased phospho-AKT levels) synergized with autocrine overexpression of FGF8, leading to prostate adenocarcinoma.[117] Finally, ablation of Frs2 inhibited prostate cancer development in the mouse.[118] These data emphasize the potential importance of FGF signalling for prostate cancer development, but also suggest that a second hit in the PI3K–AKT pathway might be required to enhance the oncogenic potential of FGF signalling.

FGF and Survival

The mitogenic effects of FGF signalling may also be enhanced by pro-survival signalling. FGF signalling has the potential, depending on the cell type, to activate anti-apoptotic pathways through either the activation of PI3K–AKT or STAT signalling. This prosurvival effect has also been linked to resistance to chemotherapy. FGF2 has been suggested to play an important part in small-cell lung cancer, in which high levels of serum FGF2 are associated with a poor prognosis.[119] Studies have suggested that FGF2 mediates a cytoprotective effect by upregulating the expression of the anti-apoptotic proteins BCL-2, BCL-X L, X-linked inhibitor of apoptosis (XIAP) and inhibitor of apoptosis 1 (IAP1; also known as BIRC3) through an S6 kinase (S6K2 and RSK2)-mediated pathway, therefore promoting resistance to chemotherapy.[120–122]

Additional evidence supporting the importance of the S6K2 pathway in FGFR-driven cancer came from a breast carcinoma model, in which non-transformed MCF-10A breast cancer cells expressing conditionally activated FGFR1 became transformed in an S6K2-dependent manner. Inhibition of S6K2 by small interfering RNA or small molecule inhibitors caused the death of FGFR1-transformed cells, whereas non-transformed parental cells were unaffected.[123]

The RSK2 and PI3K pathways are not the only ones to mediate FGF-dependent survival signalling. Evidence from studies of FGFR1, which is expressed in addition to FGFR3 in bladder cancer, suggested that the increased expression of FGFR1 in normal and cancerous urothelial cell lines promotes FGF2-induced proliferation and decreased apoptosis.[124] These effects were transduced by MAPK signalling through FRS2 and PLCγ, and mediated by cyclin D1 (which promotes proliferation), MCL1 and phospho-BAD (which promotes survival). Some urothelial cancer cell lines also showed FGFR1-dependent growth in soft agar.[124] Together, these data confirm that cell survival is a major readout of FGF signalling, and multiple pathways can result in similar outcomes.

FGF and Migration and Invasion

In addition to effects on proliferation and survival, FGF signalling can promote cell migration in several ways. Simple in vitro models, such as the invasion of pancreatic cancer cells through Matrigel-coated Transwell filters, have shown FGF10- and FGFR2-IIIb-dependent invasion.[125] In a breast cancer model with a membrane-tethered chemically inducible FGFR1 kinase domain,[126] activation of FGFR1 in the mammary epithelium in adult mice induced MAPK- and AKT-dependent proliferation and ultimately led to invasive mammary lesions.[126]In vitro studies of the same inducible construct in three-dimensional cultures of HC11 mouse mammary epithelial cells demonstrated that, as well as increasing cell proliferation and survival, constitutive FGFR1 signalling led to the loss of polarity and the gain of a matrix metalloproteinase 3 (MMP3)-dependent invasive phenotype.[127] Interestingly, this effect was specific to the FGFR1 kinase domain, and an identical FGFR2 construct showed no effect on cell survival and invasion.[38]

The same inducible FGFR1 construct induced prostatic intraepithelial neoplasia when expressed and chemically activated in the mouse prostate.[40] Interestingly, in this model prostatic intraepithelial neoplasia progressed over the course of 1 year to a transitional sarcomatoid-type carcinoma, suggesting that EMT had occurred. This EMT phenotype was accompanied by upregulation of both Sox9 , an FGF target gene associated with EMT,[128] and the pro-angiogenic factor angiopoietin 2 (ANG2).[129] EMT is important in cancer cell metastasis, disrupting cell–cell contacts and promoting tumour cell invasion,[130] and these data therefore suggest that activation of FGFR1 signalling can both initiate cancer development and promote invasion and metastasis.

SOX9 was also upregulated in a study of androgen-induced prostate carcinogenesis, in which the FGF and Wnt signalling pathways were significantly upregulated. This study potentially uncovered a reactivation of signalling pathways used in the embryo for both proliferation and invasion in prostate cancer progression.[131] In development, Wnt–β-catenin and FGF signalling function in concert to coordinate collective cell migration during morphogenesis through differential regulation of the chemokine receptors CXCR4b and CXCR7b, and a similar molecular mechanism could theoretically regulate the collective cell migration that underpins metastasis.[132]

FGF in Angiogenesis

Alongside embryogenesis, one of the first areas in which FGF signalling was shown to be important in terms of cell proliferation and migration was during wound healing.[133] Initial studies showed a key role for FGF signalling in epithelial repair but some FGF members, in particular FGF2, are known to be important for new blood vessel growth at the wound site (reviewed in Ref.[134]). Angiogenesis is key to the repair process, delivering nutrients and oxygen to support the energy-consuming process of tissue remodelling.[134] If a tumour is to grow more than 1 mm3 and metastasize, it must establish its own blood supply to provide oxygen and nutrients,[135] and FGFs have also been implicated in tumour angiogenesis.[93,136]

Endothelial cells express high levels of FGFR1-IIIc, as well as FGFR2-IIIc in some circumstances, and both FGF1 and FGF2 (and to a lesser extent FGF4 and FGF8b) are potent pro-angiogenic growth factors.[93] FGFs stimulate new vessel formation and vessel maturation by driving endothelial cell proliferation, promoting extracellular matrix degradation, altering intercellular adhesion and communication by affecting cadherins and gap junctions, respectively, and modulating integrin expression (reviewed in Ref.[93]). Although most of these effects are transduced through MAPK activation, PKC activation is also required for FGF-induced endothelial cell proliferation[137] and migration.[138] Furthermore, a model of FGFR1-mediated chemotaxis was dependent on PI3K signalling to drive endothelial cell motility, with wortmannin (a PI3K inhibitor) treatment blocking migration independently of receptor tyrosine kinase activity.[139]

Evidence for a role of FGFs in tumour angiogenesis includes the increased mobilization of FGF ligands from the extracellular matrix, as has been shown for FGF-binding protein,[140] the paracrine release of FGF2 from tumour cells acting on endothelial cells to initiate angiogenesis,[89] FGF1 expression in ovarian cancer[90] and the autocrine release of FGF2 from capillary endothelial cells.[141] Autocrine FGF2 signalling might also be important in the growth of endothelial tumours such as Kaposi's sarcoma.[142] Finally there is substantial crosstalk between FGFR and vascular endothelial growth factor receptor (VEGFR) signalling in angiogenesis, and the FGFR system may mediate resistance to VEGFR targeting in some situations.[143,144]

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