Expression of Fibroblast Growth Factor 10 Is Correlated with Poor Prognosis in Gastric Adenocarcinoma

Abstract

Fibroblast growth factor receptor 2 (FGFR2) has been proved to be a significant prognostic factor and a potential therapeutic target in several types of cancer, including gastric cancer. FGFR2 consists two isoforms: FGFR2-IIIb and FGFR2-IIIc, which can be stimulated by different ligands and trigger different downstream signaling pathways. As a specific ligand to FGFR2-IIIb, fibroblast growth factor 10 (FGF10) is expressed in the gastric mesenchyme cell and is involved in stomach development and morphogenesis, but its expression and clinical significance is not well elucidated in gastric cancer. We analyzed FGF10 expression by immunohistochemistry in 178 samples of gastric adenocarcinoma (134 male and 44 female patients, with the average age of 63.2 years old and the average follow-up of 21.6 months). Using the arbitrarily scoring method based on positive cell percentage and staining intensity, we sub-divided the patients into FGF10 high-expression group (58 patients) and low-expression group (120 patients). We thus found that FGF10 expression is significantly associated with lymph node invasion (P = 0.004) and distant metastasis (P = 0.032). Importantly, FGF10 expression is an independent unfavorable prognostic factor (P = 0.042). Moreover, FGF10 knockdown significantly decreased the migration of cultured gastric adenocarcinoma cells, suggesting that FGF10 could promote the invasion of gastric adenocarcinoma. In conclusion, FGF10 expression was identified as a poor prognostic biomarker in gastric adenocarcinoma, and FGF10 could promote the invasion of gastric cancer cells. We suggest that FGF10 could be a potential and promising drug target in gastric adenocarcinoma.

Targeting the Oncogenic FGF-FGFR Axis in Gastric Carcinogenesis

“…At the genetic level, amplification of FGF genes may lead to their overproduction in GC, specifically, FGF10 amplification has been reported in 3% of GC and in 5.7% of gastric adenocarcinomas [82,83]. FGF10 is correlated to GC cell invasion and has been suggested as a prognostic biomarker and potential drug target in gastric adenocarcinoma [84]. In our recent study, we explored the FGF mRNA profiling in 10 GC cell lines by microarray analysis, where FGF18 showed the highest expression among all the FGF members.…”

Emerging Roles of Fibroblast Growth Factor 10 in Cancer

“…In a cohort of 961 gastric cancers from the United Kingdom, Korea and China, FGFR2 amplification was detected in 4.2–7.4% of cases and was associated with lymph node metastasis and poor overall survival ( Su et al, 2014 ). FGF10 amplification has also been detected in 3% of gastric cancers ( Ooi et al, 2015 ) and immunohistochemical analysis of 178 gastric adenocarcinoma samples revealed that FGF10 levels are correlated with poor prognosis ( Sun et al, 2015 ). Interrogation of most recent cBioPortal data suggests this could be an underestimate, with FGF10 amplifications reported in 5.7% of stomach adenocarcinoma cases ( Cerami et al, 2012 ; Gao et al, 2013 ).…”

Regulation of FGF10 Signaling in Development and Disease

“…More recently, chromosomal translocation and duplication events at the loci of the Fgf10 and Fgfr2 genes have been associated with neurological disorders such as developmental delay and autism ( Casey et al, 2012 ; Wentz et al, 2014 ). The role of single nucleotide polymorphisms and de novo point mutations causing oncogenic expression of Fgf10 and Fgfr2 are also becoming clearer, particularly in pancreatic, gastric, and breast cancers ( Jang et al, 2001 ; Theodorou et al, 2004 ; Nomura et al, 2008 ; Reintjes et al, 2013 ; Su et al, 2014 ; Sun et al, 2015 ; Ghoussaini et al, 2016 ; Coci et al, 2017 ). (D) FGF10-dependent activation of FGFR intracellular tyrosine residues (Y; insert), adaptor proteins (gray), protein kinases (red), and transcription factors (blue).…”

“…Fgf10 knockout (KO) mice die at birth with defects in multiple organ development, including the limb, lung, kidney, salivary gland and adipose tissue ( Ohuchi et al, 2000 ). Fgf10 gene mutations have been associated with diseases, such as aplasia of lacrimal and salivary glands (ALSG) ( Entesarian et al, 2007 ) and lacrimo-auriculo-dento-digital (LADD) syndrome ( Rohmann et al, 2006 ); chronic obstructive pulmonary disease ( Klar et al, 2011 ) and certain cancer types, including breast ( Theodorou et al, 2004 ; Ghoussaini et al, 2016 ), pancreatic ( Nomura et al, 2008 ), and gastric ( Sun et al, 2015 ) cancers (Figure 1C ).…”