Targeting the Oncogenic FGF-FGFR Axis in Gastric Carcinogenesis

Jinglin Zhang, Patrick M K Tang, Yuhang Zhou, Alfred S L Cheng, Jun Yu, Wei Kang, Ka Fai To, Jinglin Zhang, Patrick M K Tang, Yuhang Zhou, Alfred S L Cheng, Jun Yu, Wei Kang, Ka Fai To

Abstract

Gastric cancer (GC) is one of the most wide-spread malignancies in the world. The oncogenic role of signaling of fibroblast growing factors (FGFs) and their receptors (FGFRs) in gastric tumorigenesis has been gradually elucidated by recent studies. The expression pattern and clinical correlations of FGF and FGFR family members have been comprehensively delineated. Among them, FGF18 and FGFR2 demonstrate the most prominent driving role in gastric tumorigenesis with gene amplification or somatic mutations and serve as prognostic biomarkers. FGF-FGFR promotes tumor progression by crosstalking with multiple oncogenic pathways and this provides a rational therapeutic strategy by co-targeting the crosstalks to achieve synergistic effects. In this review, we comprehensively summarize the pathogenic mechanisms of FGF-FGFR signaling in gastric adenocarcinoma together with the current targeted strategies in aberrant FGF-FGFR activated GC cases.

Keywords: FGF; FGFR; gastric cancer; monoclonal antibody; small molecule.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The FGF-FGFR cascade interplays with the downstream signaling network in GC progression. Firstly, FGFR is aberrantly activated in GC cells. FGFs can be released mainly in two ways, in a paracrine manner by gastric fibroblasts, and in an autocrine manner from cancer cells. Gene amplification of FGFs and FGFRs leads to overproduction of FGFs and FGFRs. FGFs are stabilized and bind to FGFR via HSPG. Alternative splicing of FGFR induces two isoforms that highly are expressed in GC. The isoforms show different affinity to FGFs and contribute to diverse cellular processes. The intracellular region of the FGFR has tyrosine kinase (TK) activity. FGF stimulation leads to dimerization, phosphorylation, and activation of FGFR. The inhibitory effect of SEF is attenuated in GC cells. Secondly, after FGFR activation, adaptor proteins are recruited and also activated by phosphorylation. FRS2 further recruits GRB2, GAB1, and SOS to form a complex. The complex activates RAS-MAPK and PI3K-Akt-mTOR signaling pathways and transduces FGF stimulation into transcriptional regulation to forward tumorigenesis. The inhibitory effects of SPRY and MKP3 are abrogated in GC cells. PLCγ hydrolyzes PIP2 to IP3, increases Ca2+ levels, triggers DAG-PKC signaling, and phosphorylates GSK3β. Then, GSK3β is decreased and β-catenin is released to the nuclei. β-catenin and other EMT transcription factors, SNAIL and TWIST, initiate expression of oncogenes that are required for GC progression. Besides, JAK-STAT3 is activated by FGFR and contributes to transcriptional regulation of GC progression. (Arrows represent the activation or release routes; dash dots indicate the weakening of inhibitory effects).

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