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. 2019 Jun 4;8(6):540.
doi: 10.3390/cells8060540.

Fibroblast Growth Factor Receptor Signaling in Skin Cancers

Free PMC article

Fibroblast Growth Factor Receptor Signaling in Skin Cancers

Malgorzata Czyz. Cells. .
Free PMC article


Fibroblast growth factor (FGF)/Fibroblast growth factor receptor (FGFR) signaling regulates various cellular processes during the embryonic development and in the adult organism. In the skin, fibroblasts and keratinocytes control proliferation and survival of melanocytes in a paracrine manner via several signaling molecules, including FGFs. FGF/FGFR signaling contributes to the skin surface expansion in childhood or during wound healing, and skin protection from UV light damage. Aberrant FGF/FGFR signaling has been implicated in many disorders, including cancer. In melanoma cells, the FGFR expression is low, probably because of the strong endogenous mutation-driven constitutive activation of the downstream mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-ERK) signaling pathway. FGFR1 is exceptional as it is expressed in the majority of melanomas at a high level. Melanoma cells that acquired the capacity to synthesize FGFs can influence the neighboring cells in the tumor niche, such as endothelial cells, fibroblasts, or other melanoma cells. In this way, FGF/FGFR signaling contributes to intratumoral angiogenesis, melanoma cell survival, and development of resistance to therapeutics. Therefore, inhibitors of aberrant FGF/FGFR signaling are considered as drugs in combination treatment. The ongoing LOGIC-2 phase II clinical trial aims to find out whether targeting the FGF/FGFR signaling pathway with BGJ398 may be a good therapeutic strategy in melanoma patients who develop resistance to v-Raf murine sarcoma viral oncogene homolog B (BRAF)/MEK inhibitors.

Keywords: FGF; FGFR; autocrine signaling; fibroblast growth factor; melanoma; resistance; seborrheic keratosis; skin; squamous and basal cell carcinoma; targeted therapy.

Conflict of interest statement

The author declares no conflict of interest.


Figure 1
Figure 1
Fibroblast growth factor receptors (FGFRs) are highly conserved transmembrane receptors consisting of three extracellular immunoglobulin-like (Ig-like) domains, a transmembrane helical region, and a cytoplasmic region with kinase activity. The fibroblast growth factor (FGF) ligand and its cofactor heparin sulfate proteoglycan (HSPG) bind to FGFR monomers, leading to dimerization and tyrosine cross-autophosphorylation of the cytoplasmic domain. This induces various signaling pathways, resulting in cellular proliferation, survival, migration, angiogenesis, and cell fate determination in embryogenesis and in response to microenvironmental signals, including therapeutics. FGF/FGFR signaling can be stimulated in a paracrine manner, mainly in physiological settings, or in an autocrine manner as demonstrated in various cancers. In melanoma, FGF/FGFR signaling is largely suppressed by mutation-driven enhanced activity of the RAS (Rat sarcoma oncogene)/BRAF (v-Raf murine sarcoma viral oncogene homolog B)/MEK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) pathway (red framed). Melanoma cells that acquire the ability to secrete FGFs and stimulate FGFR in a paracrine or autocrine manner can contribute to angiogenesis and cell-fate decisions involving transitions between different phenotypes, including phenotypes resistant to targeted therapies (grey framed). Dab, dabrafenib; DUSP, dual-specificity phosphatase; FRS2, FGFR substrate 2; GAB1, GRB2-associated binding protein 1; GRB2, growth factor receptor protein 2; JAK, Janus kinase; PKC, protein kinase C; PLC-γ, phospholipase C gamma; SOS, son of sevenless; SEF, similar expression to FGF; SPRY, Sprouty; STAT, signal transducer and activator of transcription; Tra, trametinib; Vem, vemurafenib.
Figure 2
Figure 2
A simplified schematic illustration of fibroblast growth factor 1 (FGF1)-induced resistance to BRAF (v-Raf murine sarcoma viral oncogene homolog B) inhibitors in melanoma cells. BRAF inhibitors, e.g., vemurafenib and mitogen-activated protein kinase (MEK) inhibitors, e.g., trametinib can induce diverse changes in drug-naïve melanoma cells, including apoptosis and premature senescence, while some melanoma cells remain unaffected. Thus, targeted therapy enhances the phenotypic heterogeneity of the neoplastic lesion in the tumor niche. Melanoma cells exerting the senescence-associated secretory phenotype (SASP) secrete several cytokines and growth factors, including FGF1. FGF1 released by senescent melanoma cells can stimulate melanoma cells and neighboring cells. Melanoma cells become protected from apoptosis, whereas cancer-associated fibroblasts (CAFs) are stimulated to secrete hepatocyte growth factor (HGF). Although these mechanisms are not universal and are not observed in all tested melanoma cell lines, they can contribute to drug resistance in a subset of melanomas. The scheme was prepared based on the study of Grimm et al. [143].

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