Fibroblast growth factor receptor promotes progression of cutaneous squamous cell carcinoma

Abstract

Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte‐derived invasive and metastatic tumor of the skin. It is the second‐most commonly diagnosed form of skin cancer striking 200 000 Americans annually. Further, in organ transplant patients, there is a 65‐ to 100‐fold increased incidence of cSCC compared to the general population. Excision of cSCC of the head and neck results in significant facial disfigurement. Therefore, increased understanding of the mechanisms involved in the pathogeneses of cSCC could identify means to prevent, inhibit, and reverse this process. In our previous studies, inhibition of fibroblast growth factor receptor (FGFR) significantly decreased ultraviolet B‐induced epidermal hyperplasia and hyperproliferation in SKH‐1 mice, suggesting an important role for FGFR signaling in skin cancer development. However, the role of FGFR signaling in the progression of cSCC is not yet elucidated. Analysis of the expression of FGFR in cSCC cells and normal epidermal keratinocytes revealed protein overexpression and increased FGFR2 activation in cSCC cells compared to normal keratinocytes. Further, tumor cell‐specific overexpression of FGFR2 was detected in human cSCCs, whereas the expression of FGFR2 was low in premalignant lesions and normal skin. Pretreatment with the pan‐FGFR inhibitor; AZD4547 significantly decreased cSCC cell‐cycle traverse, proliferation, migration, and motility. Interestingly, AZD4547 also significantly downregulated mammalian target of rapamycin complex 1 and AKT activation in cSCC cells, suggesting an important role of these signaling pathways in FGFR‐mediated effects. To further bolster the in vitro studies, NOD.Cg‐Prkdcscid Il2rgtm1Wjl/SzJ mice with SCC12A tumor xenografts treated with AZD4547 (15 mg/kg/bw, twice weekly oral gavage) exhibited significantly decreased tumor volume compared to the vehicle‐only treatment group. The current studies provide mechanistic evidence for the role of FGFR and selectively FGFR2 in the early progression of cSCC and identifies FGFR as a putative therapeutic target in the treatment of skin cancer.

Molecular Alterations in Cutaneous Squamous Cell Carcinoma in Immunocompetent and Immunosuppressed Hosts—A Systematic Review

“…The expression of CDC258 and CDC25C was increased in cSCC compared to normal skin ( p ≤ 0.001) and led to the suppression of apoptosis in cSCC cells by stimulating Pl3K/Akt signaling and survivin expression [ 18 ]. FGFR2 activation and protein expression was increased in cSCC cells and found to be low in premalignant lesions and normal skin [ 19 ]. In a large study which sought to identify genetic variants in the HLA class II region associated with the risk of cSCC, the authors found that cSCC risk was associated with rs28535317 (OR = 1.20, p = 9.88 × 10 −11 ), which corresponded to an amino-acid change from phenylalanine to leucine at codon 26 of HLA-DRB1 (OR = 1.17, p = 2.48 × 10 −10 ).…”

A Panel of Potential Serum Markers Related to Angiogenesis, Antioxidant Defense and Hypoxia for Differentiating Cutaneous Squamous Cell Carcinomas from Actinic Keratoses

“…The FGF receptor family consists of four members (FGFR-1, FGFR-2, FGFR-3 and FGFR-4), which are mainly involved in collagen synthesis [44,45]. Dysregulation of FGFRs' functions seems to be involved in numerous cancers; evidence indicates that FGF contributes to cSCC development [46].…”

Targeting receptor tyrosine kinase signaling: Avenues in the management of cutaneous squamous cell carcinoma

“…Fibroblast growth factor receptor (FGFR) is over-expressed in cSCC samples when compared to normal skin and pre-malignant lesions 18 ; moreover, cSCC cells also over-express FGF10, an FGFR binding ligand. Inhibition of FGFR by pan-FGFR inhibitor, AZD4547, decreases tumor growth in immunocompromised mice injected with SCC12 cells.…”