Fibroblast Growth Factor Receptor Signaling in Skin Cancers

Abstract

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.

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

“…Analysis of whole-exome sequencing data revealed only a few mutations previously identified as associated with acquired resistance to targeted drugs. It is in line with the current view that in parallel to genetic alterations, melanoma cell-autonomous mechanisms of resistance can rely on complex transcriptomic adaptations supported by epigenetic regulations, including miRNA-mediated mechanisms, and extended by the interplay between tumor and stromal cells that involves cell-cell interactions, paracrine stimulation and extracellular vesicles to create a resistance-permissive niche [39][40][41][42][43][44][45][46]. Mechanisms of resistance primarily directed to support proliferation and survival of cancer cells implicate a plethora of transcriptional regulators, adaptive responses, and feedback loops that extensively affect melanoma cell phenotype enabling the expansion of distinct cell subpopulations in the presence of drug(s) [27,[47][48][49][50][51][52].…”

The FGF/FGFR System in Breast Cancer: Oncogenic Features and Therapeutic Perspectives

“…In this context, the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system has recently attracted increasing interest due to its role in tumor growth, metastasis, and resistance to anti-cancer therapies [ 7 , 8 ]. For instance, aberrant FGF/FGFR activation may occur in both a ligand-dependent and ligand-independent manner in several tumors, including breast cancer [ 8 , 9 , 10 , 11 , 12 , 13 ]. Experimental and clinical evidence has also shown that deregulated FGF/FGFR signaling may elicit an oncogenic action [ 14 , 15 , 16 , 17 ], though some reports have indicated that the FGF/FGFR axis may exert an anticancer action in certain contexts [ 18 , 19 ].…”

Fibroblast growth factor‐2 and interleukin‐4 synergistically induce eotaxin‐1 expression in adipose tissue‐derived stromal cells

“…FGFRs are a subfamily of tyrosine kinase receptors; the family has four members (FGFR‐1–4) in mice, and these proteins are expressed in a wide variety of cell types (Eswarakumar et al, 2005; Czyz, 2019; Dai et al, 2019). To measure the expression levels of FGFR‐1–4 in ASCs, we examined FGFR messenger RNA (mRNA) expression in the presence of different concentrations of FGF‐2.…”

“…FGF‐2 binds to FGFR‐1–4 to mediate downstream signaling through pathways such as mitogen‐activated protein kinase (MAPK) signaling (Eswarakumar et al, 2005; Czyz, 2019), thereby regulating cellular proliferation, differentiation, and migration. To examine the downstream effectors of FGFR signaling in the regulation of ASCs, the phosphorylation of ERK1/2, p38α, and JNK1/2/3 was examined after the addition of 5 ng/mL FGF‐2 into the medium.…”