Targeting the Oncogenic FGF-FGFR Axis in Gastric Carcinogenesis

cells Review Targeting the Oncogenic FGF-FGFR Axis in Gastric Carcinogenesis Jinglin Zhang 1,2,3, Patrick M. K. Tang 1, Yuhang Zhou 1,2,3, Alfred S. L. Cheng 4, Jun Yu 2,5, Wei Kang 1,2,3,* and Ka Fai To 1,2,3,* 1 Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; [email protected] (J.Z.); [email protected] (P.M.K.T.); [email protected] (Y.Z.) 2 Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China; [email protected] 3 Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China 4 School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; [email protected] 5 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China * Correspondence: [email protected] (W.K.); [email protected] (K.F.T.); Tel.: +(852)-3505-1505 (W.K.); Fax: +(852)-2649-7286 (W.K.) Received: 23 May 2019; Accepted: 24 June 2019; Published: 25 June 2019 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 1. Introduction Gastric cancer (GC), the third leading cause of cancer death globally, is considered a heterogeneous disease. Although the prevalence has declined over the past decades, more than half of newly diagnosed cases are found to possess local advancement or metastasis [1,2]. Late diagnosis and lack of effective therapeutics still make GC a challenge globally. For decades, researchers have been dedicated to uncover the mysteries behind GC, not only the medication strategies to alleviate or cure the disease, but the key factors for detecting the challenging disease at its early stage. It has been proven that environmental, etiological, and genetic factors largely contribute to GC development, for example, high salt diets, H. pylori infections [3], and CDH1 mutations [4,5]. Systematically, in-depth and comprehensive mechanistic studies revealed the crosstalk of oncogenic signaling pathways during GC progression as well as pre-cancerous gastric lesion development [6–9]. Of note, inactivation of the Hippo pathway has been substantially demonstrated in the pathogenesis of GC, via the accumulation of nuclear YAP1 in an uncontrollable manner [10–12]. Moreover, recent studies have further uncovered Cells 2019, 8, 637; doi:10.3390/cells8060637 www.mdpi.com/journal/cells Cells 2019, 8, 637 2 of 16 the emerging roles of fibroblast growing factors (FGFs) and their receptors (FGFRs) in the carcinogenesis of some GC subtypes, owing to their molecular characteristics [13]. It has been well documented that the FGF and FGFR families are important regulators for biological development [14,15]. Aberration of FGF-FGFR signaling substantially results in skeletal disorders as well as cancer development, including GC [16]. Since genetic aberrations of FGFR2 have been recently defined, it serves as a diagnostic marker and clinical drug target for GC [17–19]. However, development of FGFR2-targeted therapy has been largely decelerated due to recently reported disadvantages. Thus, further investigation of the FGF-FGFR must be continued in order to identify drug targets for GC therapy. This review aims to summarize the updated discoveries and discuss the further prospects of FGF-FGFR signaling in GC pathogenesis and therapy development. 2. Emerging Role of FGF-FGFR in Solid Tumors 2.1. FGF Family Induces Tumor Growth FGFRs belong to the receptor tyrosine kinases (RTKs) superfamily. Most of the RTKs are membrane receptors with high affinity to multiple growth factors, cytokines, and hormones, and they contain intracellular domains with tyrosine kinase activity. Canonically, FGFRs are monomers in their inactivation state. Dimerization of the intracellular part occurs after binding with their ligand FGFs. Functional binding of FGF and FGFR leads to cross-phosphorylation and activation of the receptor. Activated FGFRs then transduce biochemical signals into cytosolic activities [20]. Indeed, the FGF family comprises 22 secreted factors that are generally divided into seven subgroups in terms of their phylogenetic relation, homology, and biochemical function [21]. As reported, five FGF subfamilies are released in paracrine and autocrine manners, including FGF1 (FGF1, FGF2), FGF4 (FGF4, FGF5, FGF6), FGF7 (FGF3, FGF7, FGF10, FGF22), FGF8 (FGF8, FGF17, FGF18), and FGF9 (FGF9, FGF16, FGF20). In contrast, the FGF15 (FGF15, FGF19, FGF21, FGF23) subfamily is secreted through endocrine glands as a hormone for metabolic modulation with α- and β-Klotho family proteins. Nevertheless, there are intracellular FGFs (FGF11, FGF12, FGF13, FGF14) that lack secretory N-terminal peptides, which execute their functions independent of FGFRs [22]. FGFs not only show regulatory roles in cell fate and survival, but also exerts biological functions in tissue regeneration and repair [23,24]. In the last few decades, clinical reports have highlighted the importance of FGFs in tumorigenesis, including excessive cell growth and angiogenesis. For example, basic fibroblast growth factor (bFGF) promotes angiogenesis for hepatoma progression [25], and a follow-up study suggested serum bFGF as a biological indicator for invasive and recurrent hepatocellular carcinoma (HCC) [26]. The clinical significance of bFGF was first recognized in patients who received surgical removal of colorectal cancer (CRC) at serological and pathological levels, where expression of bFGF indicated the independency in lymphatic invasion [27]. In addition, FGF amplification rated 10% in human malignancies, as overproduction of FGFs enables the communication between epithelial cells and stromal cells in the tumor microenvironment for tumorigenesis [28,29]. 2.2. FGFR Family Drives Oncogenesis 2.2.1. Functional Structures of FGFR Interestingly, FGF ligands interact with only four FGFRs (FGFR1–4), which are highly conserved in mammals, although FGFs harbor many family members. In general, FGFRs can be classified into three major domains based on their location relative to the cell membrane: (1) a ternary extracellular immunoglobulin (Ig) (domain I, II, III) that is in charge of binding with ligands; (2) a signal-pass transmembrane helix that acts as a connection; and (3) an intracellular tyrosine kinase (TK) that conveys the signals [30,31]. Generally speaking, the extracellular part of the FGFR provides binding sites for ligand binding, while the intracellular part is responsible for potentiating the relevant signaling pathways. Between the extracellular domains I and II, there is an acidic box region for the FGFR to Cells 2019, 8, 637 3 of 16 interact with some molecules other than FGFs, while domains II and III possess the heparin binding site and FGF binding site [32]. The Ig domain III in FGFR1-3 has alternative splicing sites. The domain IIIa remains invariant while the other half varies according to the encoded exon IIIb or IIIc, which are based on tissue-dependent expression [33,34]. This means that the FGFRs only differ between certain parts of the Ig that governs the affinity and specificity of their ligands. There is a single-pass transmembrane domain connecting the Ig domains and the intracellular FGFR domains. The intracellular part of the FGFR includes a juxtamembrane domain for phosphotyrosine binding of adaptors, and two tyrosine kinase (TK) domains. As soon as the TK domains are phosphorylated, the downstream cascades are activated to further expand the signal [35]. Special FGFRs devoid of TK activity, namely FGFR5 or FGFRL1, have been identified and proposed as decoys, interfering with downstream signaling pathways [36]. Due to the diversity of receptor structure and transcript sequence, there are a number of FGFR variants that have been identified. For example, the FGFR2 IIIb isoform has high binding affinity to FGF3, FGF7, and FGF10, while its IIIc form is much preferable to FGF2, FGF4, and FGF20 [20,29]. Further investigation may lead to the discovery of a potential FGFR variant for GC management. 2.2.2. Mechanisms of FGFR in Driving Cancer Recently,the oncogenic roles of FGFRs have been extensively demonstrated, and somatic alterations and differential expression patterns of FGFR have been seen in different human cancers. Helsten et al. recently depicted a landscape of FGFR aberrations from a large-cohort high-throughput sequencing of cancer patients. In total, FGFR aberrations were detected in 7.1% of the malignancies, including gene amplification

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