Katoh Masuko, Katoh Masaru
M&M Medical BioInformatics, Hongo 113-0033, Japan.
Int J Oncol. 2006 Jul;29(1):163-8.
Fibroblast growth factor (FGF) signals are transduced through FGF receptors (FGFRs) and FRS2/FRS3- SHP2 (PTPN11)-GRB2 docking protein complex to SOS-RAS-RAF-MAPKK-MAPK signaling cascade and GAB1/GAB2-PI3K-PDK-AKT/aPKC signaling cascade. The RAS approximately MAPK signaling cascade is implicated in cell growth and differentiation, the PI3K approximately AKT signaling cascade in cell survival and cell fate determination, and the PI3K approximately aPKC signaling cascade in cell polarity control. FGF18, FGF20 and SPRY4 are potent targets of the canonical WNT signaling pathway in the gastrointestinal tract. SPRY4 is the FGF signaling inhibitor functioning as negative feedback apparatus for the WNT/FGF-dependent epithelial proliferation. Recombinant FGF7 and FGF20 proteins are applicable for treatment of chemotherapy/radiation-induced mucosal injury, while recombinant FGF2 protein and FGF4 expression vector are applicable for therapeutic angiogenesis. Helicobacter pylori, a causative pathogen for peptic ulcer diseases, chronic atrophic gastritis and gastric cancer, injects bacterial proteins into gastric epithelial cells by using Type IV secretion system, which leads to FGF signaling activation through FGF2 upregulation as well as CagA-dependent SHP2 activation. FGFR2 gene is preferentially amplified and overexpressed in diffuse-type gastric cancer. PD173074 is a small-molecule inhibitor for FGFR, while RO4396686 and SU6668 are small-molecule inhibitors for FGFR and other tyrosine kinases. Cocktail therapy using multiple protein kinase inhibitors could enhance the therapeutic effects for gastrointestinal cancer through the reduction of recurrence associated with somatic mutations of drug-target genes. Single nucleotide polymorphism (SNP) and copy number polymorphism (CNP) of genes encoding FGF signaling molecules will be identified as novel risk factors of gastrointestinal cancer. Personalized prevention and personalized medicine based on the combination of genetic screening and novel therapeutic agents could dramatically improve the prognosis of cancer patients.
成纤维细胞生长因子（FGF）信号通过FGF受体（FGFRs）以及FRS2/FRS3-SHP2（PTPN11）-GRB2对接蛋白复合物转导至SOS-RAS-RAF-MAPKK-MAPK信号级联和GAB1/GAB2-PI3K-PDK-AKT/aPKC信号级联。RAS-MAPK信号级联与细胞生长和分化有关，PI3K-AKT信号级联与细胞存活和细胞命运决定有关，而PI3K-aPKC信号级联与细胞极性控制有关。FGF18、FGF20和SPRY4是胃肠道中经典WNT信号通路的有效靶点。SPRY4是FGF信号抑制剂，作为WNT/FGF依赖性上皮增殖的负反馈机制发挥作用。重组FGF7和FGF20蛋白适用于治疗化疗/放疗引起的黏膜损伤，而重组FGF2蛋白和FGF4表达载体适用于治疗性血管生成。幽门螺杆菌是消化性溃疡疾病、慢性萎缩性胃炎和胃癌的致病病原体，它通过IV型分泌系统将细菌蛋白注入胃上皮细胞，这会通过FGF2上调以及CagA依赖性SHP2激活导致FGF信号激活。FGFR2基因在弥漫型胃癌中优先扩增并过度表达。PD173074是一种FGFR小分子抑制剂，而RO4396686和SU6668是FGFR和其他酪氨酸激酶的小分子抑制剂。使用多种蛋白激酶抑制剂的联合疗法可通过减少与药物靶点基因体细胞突变相关的复发来增强对胃肠道癌症的治疗效果。编码FGF信号分子的基因的单核苷酸多态性（SNP）和拷贝数多态性（CNP）将被确定为胃肠道癌症的新危险因素。基于基因筛查和新型治疗药物相结合的个性化预防和个性化医疗可显著改善癌症患者的预后。
