Expression and localization of fibroblast growth factors and fibroblast growth factor receptors in the developing rat kidney

Expression and localization of fibroblast growth factors and fibroblast growth factor receptors in the developing rat kidney.BackgroundThe permanent kidney, or metanephros, develops through a complex series of reciprocal inductive events and involves branching morphogenesis, tubulogenesis, angiogenesis, and tissue remodeling. Fibroblast growth factors (FGFs) are a family of growth and differentiation factors that have been implicated in metanephric development. FGFs exert their actions through tyrosine kinase receptors, FGFRs, which are encoded by four FGFR genes (FGFR1 through FGFR4).MethodsReverse transcriptase-polymerase chain reaction was used to detect the expression of FGFs and FGFRs in rat metanephroi from embryonic day (E) 14 to E21. Nonradioactive in situ hybridization was used to localize FGF1 mRNA in E20 rat metanephroi, and immunohistochemistry was used to localize FGFRs in E15 and E20 rat metanephroi.ResultsWe detected the expression of mRNAs for FGF1 through FGF5, FGF7 through FGF10, and FGFR1 through FGFR4 (IIIb and IIIc splice variants) in rat metanephroi from E14 to E21. By in situ hybridization, FGF1 mRNA was detected in the nephrogenic zone, ureteric epithelium, and developing nephron elements. FGFR proteins were localized in a distinct pattern that altered with maturation. FGFR1 was widely distributed in developing metanephric epithelia and mesenchyme, but not in developing interstitium. FGFR2 was also widely distributed in nephron epithelia, particularly in proximal convoluted tubules, but was not detected in metanephric mesenchyme, mesenchymal condensates, or developing interstitium. FGFR3 was localized to mesenchymal condensates, nephron elements, and medullary interstitium but not proximal convoluted tubules. FGFR4 was localized mostly to maturing nephron structures and was not detected in nephrogenic mesenchyme, mesenchymal condensates, or developing interstitium.ConclusionsThese results indicate that FGFs and FGFRs are expressed in the developing rat metanephros from at least E14 and that they likely play important roles in metanephric development and maturation

RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations

Abstract Activating mutations in the Wnt pathway are a characteristic feature of colorectal cancer (CRC). The R-spondin (RSPO) family is a group of secreted proteins that enhance Wnt signaling and RSPO2 and RSPO3 gene fusions have been reported in CRC. We have previously shown that Wnt pathway blockers exhibit potent combinatorial activity with taxanes to inhibit tumor growth. Here we show that RSPO3 antagonism synergizes with paclitaxel based chemotherapies in patient-derived xenograft models (PDX) with RSPO3 fusions and in tumors with common CRC mutations such as APC, β-catenin, or RNF43. In these latter types of tumors that represent over 90% of CRC, RSPO3 is produced by stromal cells in the tumor microenvironment and the activating mutations appear to sensitize the tumors to Wnt-Rspo synergy. The combination of RSPO3 inhibition and taxane treatment provides an approach to effectively target oncogenic WNT signaling in a significant number of patients with colorectal and other intestinal cancers