Progress in neuro-psychopharmacology & biological psychiatry
Chang, GQ;Yasmin, N;Collier, AD;Karatayev, O;Khalizova, N;Onoichenco, A;Fam, M;Albeg, AS;Campbell, S;Leibowitz, SF;
PMID: 35176416 | DOI: 10.1016/j.pnpbp.2022.110536
Prenatal alcohol exposure (PAE) increases alcohol consumption and risk for alcohol use disorder. This phenomenon in rodents is suggested to involve a stimulatory effect of PAE, in female more than male offspring, on neurogenesis and density of neurons expressing neuropeptides in lateral hypothalamus (LH), including melanin-concentrating hormone (MCH), known to promote alcohol intake. With evidence suggesting a role for fibroblast growth factor 2 (FGF2) and its receptor FGFR1 in stimulating neurogenesis and alcohol drinking, we investigated here whether the FGF2-FGFR1 system is involved in the PAE-induced increase in MCH neurons, in postnatal offspring of pregnant rats given ethanol orally (embryonic day 10-15) at a low-moderate (2 g/kg/day) or high (5 g/kg/day) dose. Our results demonstrate that PAE at the low-moderate but not high dose stimulates FGF2 and FGFR1 gene expression and increases the density of MCH neurons co-expressing FGF2, only in females, but FGFR1 in both sexes. PAE induces this effect in the dorsal but not ventral area of the LH. Further analysis of FGF2 and FGFR1 transcripts within individual MCH neurons reveals an intracellular, sex-dependent effect, with PAE increasing FGF2 transcripts positively related to FGFR1 in the nucleus as well as cytoplasm of females but transcripts only in the cytoplasm of males. Peripheral injection of FGF2 itself (80 μg/kg, s.c.) in pregnant rats mimics these effects of PAE. Together, these results support the involvement of the FGF2-FGFR1 system in mediating the PAE-induced, sex dependent increase in density of MCH neurons, possibly contributing to increased alcohol consumption in the offspring.
Pathobiology. 2015 Jun 16;82(2):76-83.
Kwak Y, Nam SK, Seo AN, Kim DW, Kang SB, Kim WH, Lee HS.
PMID: 26088290
Abstract Objectives: Fibroblast growth factor receptor 1 (FGFR1) has been reported to be overexpressed in colorectal cancer (CRC) and suggested to be a therapeutic target. In this study, we investigated FGFR1 expression and amplification in CRC and its correlation with clinicopathologic parameters. Methods:FGFR1 dual-color fluorescence in situ hybridization and mRNA in situ hybridization were performed on tissue array blocks composed of 291 consecutive primary CRCs. Results: Of the 291 CRC cases, FGFR1 gene amplification was found in 11 (3.8%) cases, high FGFR1 polysomy in 4 (1.4%) cases, and FGFR1 gene copy number (GCN) gain (GCN >2) in 77 (26.5%) cases. FGFR1 GCN gain was significantly associated with left-sided location, lymph node metastasis, distant metastasis, and higher TNM stage (p < 0.05). FGFR1 GCN gain also correlated with poor patient survival (p = 0.015). FGFR1 mRNA overexpression (score 3-4) was present in 11.7% (34/291) of the patients and was significantly associated with FGFR1 GCN alteration (Pearson correlation coefficient, r = 0.463; p < 0.001). Conclusion:FGFR1 GCN gain was more frequently found (26.5%) than gene amplification (3.8%) and correlated with aggressive clinical behavior in consecutive CRC patients. FGFR1 GCN alteration was associated with a high FGFR1 mRNA level.
Development (Cambridge, England)
Imaimatsu, K;Hiramatsu, R;Tomita, A;Itabashi, H;Kanai, Y;
PMID: 37376880 | DOI: 10.1242/dev.201660
Temporal transcription profiles of fetal testes with Sertoli cell ablation were examined in 4-day culture using a diphtheria toxin (DT)-dependent cell knockout system in AMH-TRECK transgenic (Tg) mice. RNA analysis revealed that ovarian-specific genes, including Foxl2, were ectopically expressed in DT-treated Tg testis explants initiated at embryonic days 12.5-13.5. FOXL2-positive cells were ectopically observed in two testicular regions-near the testicular surface epithelia and around its adjacent mesonephros. The surface FOXL2-positive cells, together with ectopic expression of Lgr5 and Gng13 (markers of ovarian cords), were derived from the testis epithelia/subepithelia, whereas another FOXL2-positive population was the 3βHSD-negative stroma near the mesonephros. In addition to high expression of Fgfr1/Fgfr2 and heparan sulfate proteoglycan (a reservoir for FGF ligand) in these two sites, exogenous FGF9 additives repressed DT-dependent Foxl2 upregulation in Tg testes. These findings imply retention of Foxl2 inducibility in the surface epithelia and peri-mesonephric stroma of the testicular parenchyma, in which certain paracrine signals, including FGF9 derived from fetal Sertoli cells, repress feminization in these two sites of the early fetal testis.
Dilly, GA;Kittleman, CW;Kerr, TM;Messing, RO;Mayfield, RD;
PMID: 35859068 | DOI: 10.1038/s41398-022-02063-0
The central amygdala (CeA) contains a diverse population of cells, including multiple subtypes of GABAergic neurons, along with glia and epithelial cells. Specific CeA cell types have been shown to affect alcohol consumption in animal models of dependence and may be involved in negative affect during alcohol withdrawal. We used single-nuclei RNA sequencing to determine cell-type specificity of differential gene expression in the CeA induced by alcohol withdrawal. Cells within the CeA were classified using unbiased clustering analyses and identified based on the expression of known marker genes. Differential gene expression analysis was performed on each identified CeA cell-type. It revealed differential gene expression in astrocytes and GABAergic neurons associated with alcohol withdrawal. GABAergic neurons were further subclassified into 13 clusters of cells. Analyzing transcriptomic responses in these subclusters revealed that alcohol exposure induced multiple differentially expressed genes in one subtype of CeA GABAergic neurons, the protein kinase C delta (PKCδ) expressing neurons. These results suggest that PKCδ neurons in the CeA may be uniquely sensitive to the effects of alcohol exposure and identify a novel population of cells in CeA associated with alcohol withdrawal.
Hwang, E;Scarlett, JM;Baquero, AF;Bennett, C;Dong, Y;Chau, D;Brown, JM;Mercer, AJ;Meek, TH;Grove, KL;Phan, BAN;Morton, GJ;Williams, KW;Schwartz, MW;
PMID: 35917179 | DOI: 10.1172/jci.insight.160891
In rodent models of type 2 diabetes (T2D), central administration of fibroblast growth factor 1 (FGF1) normalizes elevated blood glucose levels in a manner that is sustained for weeks or months. Increased activity of NPY/AgRP neurons in the hypothalamic arcuate nucleus (ARC) is implicated in the pathogenesis of hyperglycemia in these animals, and the ARC is a key brain area for the antidiabetic action of FGF1. We therefore sought to determine whether FGF1 inhibits NPY/AgRP neurons, and if so whether this inhibitory effect is sufficiently durable to offer a feasible explanation for sustained diabetes remission induced by central administration of FGF1. Here we show that FGF1 inhibits ARC NPY/AgRP neuron activity, both after icv injection in vivo and when applied ex vivo in a slice preparation, and that the underlying mechanism involves increased input from presynaptic GABAergic neurons. Following central administration, the inhibitory effect of FGF1 on NPY/AgRP neurons is also highly durable, lasting for at least two weeks. To our knowledge, no precedent for such a prolonged inhibitory effect exists. Future studies are warranted to determine whether NPY/AgRP neuron inhibition contributes to the sustained antidiabetic action elicited by icv FGF1 injection in rodent models of T2D. .
Hultman K, Scarlett JM, Baquero AF, Cornea A, Zhang Y, Salinas CBG, Brown J, Morton GJ, Whalen EJ, Grove KL, Koegler FH, Schwartz MW, Mercer AJ.
PMID: 30809795 | DOI: 10.1002/cne.24668
Central activation of fibroblast growth factor (FGF) receptors regulates peripheral glucose homeostasis and reduces food intake in preclinical models of obesity and diabetes. The current work was undertaken to advance our understanding of the receptor expression, as sites of ligand action by FGF19, FGF21, and FGF1 in the mammalian brain remains unresolved. Recent advances in automated RNAscope in situ hybridization and droplet digital PCR (ddPCR) technology allowed us to interrogate central FGFR/beta klotho (Klb) system at the cellular level in the mouse, with relevant comparisons to nonhuman primate and human brain. FGFR1-3 gene expression was broadly distributed throughout the CNS in Mus musculus, with FGFR1 exhibiting the greatest heterogeneity. FGFR4 expression localized only in the medial habenula and subcommissural organ of mice. Likewise, Klb mRNA was restricted to the suprachiasmatic nucleus (SCh) and select midbrain and hindbrain nuclei. ddPCR in the rodent hypothalamus confirmed that, although expression levels are indeed low for Klb, there is nonetheless a bonafide subpopulation of Klb+ cells in the hypothalamus. In NHP and human midbrain and hindbrain, Klb + cells are quite rare, as is expression of FGFR4. Collectively, these data provide the most robust central map of the FGFR/Klb system to date and highlight central regions that may be of critical importance to assess central ligand effects with pharmacological dosing, such as the putative interactions between the endocrine FGFs and FGFR1/Klb, or FGF19 with FGFR4.
Ito, A;Imamura, F;
| DOI: 10.2139/ssrn.4267408
Fibroblast growth factor (FGF) signaling plays several important roles in the development of the central nervous system. During the mid-gestation stage, FGF receptors (FGFRs) are expressed in the ventricular zone of the telencephalon and regulate the proliferation and neuronal differentiation of radial glial cells (RGCs). Inhibition of FGFR signaling at this stage results in abnormal brain formation, particularly loss of FGFR1 signaling causes hypoplasia of the olfactory bulb (OB). However, how FGFR1 signaling regulates OB formation is not fully understood. In this study, we inhibited FGFR1 signaling specifically in the anterior telencephalon, where OBs develop, and examined its effects on the development of RGCs in the OB (OB RGCs) and OB formation. The results suggest that inhibition of FGFR1 signaling causes a shift in the state of OB RGCs from proliferation to neuronal differentiation, resulting in an insufficient number of OB projection neurons. Furthermore, activation of Notch signaling, which maintains the self-renewal state of OB RGCs, partially rescued the early abnormal OB formation caused by inhibition of FGFR1 signaling. In contrast, inhibition of FGFR1 signaling in lateral ganglionic eminence did not affect the production of OB interneurons or OB formation. Moreover, the early abnormal OB formation induced by inhibition of FGFR1 signaling could be rescued by overactivation of Notch signaling, which maintains the proliferative state of radial glial cells. These results suggest that FGFR1 signaling regulates normal OB formation by controlling OB RGCs to produce a normal number of OB projection neurons.
Digestion. 88(3):172–181.
Göke F, Göke A, von Mässenhausen A, Franzen A, Sharma R, Kirsten R, Böhm D, Kristiansen G, Stenzinger A, Wynes M, Hirsch FR, Weichert W, Heasley L, Buettner R, Perner S (2013).
PMID: 24135816 | DOI: 10.1159/000355018
BACKGROUND/AIMS:
Resembling a potential therapeutic drug target, fibroblast growth factor receptor 1 (FGFR1) amplification and expression was assessed in 515 human colorectal cancer (CRC) tissue samples, lymph node metastases and CRC cell lines.
METHODS:
FGFR1 amplification status was determined using fluorescence in situ hybridization. Additionally, we assessed protein levels employing Western blots and immunohistochemistry. The FGFR1 mRNA localization was analyzed using mRNA in situ hybridization. Functional studies employed the FGFR inhibitor NVP-BGJ398.
RESULTS:
Of 454 primary CRCs, 24 displayed FGFR1 amplification. 92/94 lymph node metastases presented the same amplification status as the primary tumor. Of 99 investigated tumors, 18 revealed membranous activated pFGFR1 protein. FGFR1 mRNA levels were independent of the amplification status or pFGFR1 protein occurrence. In vitro, a strong antiproliferative effect of NVP-BGJ398 could be detected in cell lines exhibiting high FGFR1 protein.
CONCLUSION:
FGFR1 is a potential therapeutic target in a subset of CRC. FGFR1 protein is likely to represent a central factor limiting the efficacy of FGFR inhibitors. The lack of correlation between its evaluation at genetic/mRNA level and its protein occurrence indicates that the assessment of the receptor at an immunohistochemical level most likely represents a suitable way to assess FGFR1 as a predictive biomarker for patient selection in future clinical trials.
Necchi A, Raggi D, Volpi CC, Giannatempo P, Colecchia M, Gloghini A.
PMID: 28855072 | DOI: 10.1016/j.euf.2017.08.002
Pan-fibroblast growth-factor receptor (FGFR) inhibitors hold promise in FGFR-altered patients, but such alterations are rare in advanced urothelial carcinoma. In order to assess whether we may increase the number of eligible patients by using different molecular techniques for detecting alterations, we pooled the results of the centralised FGFR mutation/translocation assays that were performed in Clinical Laboratory Improvement Amendments-certified laboratories within multiple phase 2 trials. At our centre, the same tissue blocks were used to analyse FGFR1-3 messenger RNA expression through messenger RNA in situ hybridisation (ISH; RNAscope 2.5 assay). From October 2016 to March 2017, 52 cases were analysed. Seventeen patients (32.7%) had an upper tract primary tumour. Ten patients (19.2%) had FGFR DNA alterations. Twenty-nine (55.8%) had positive ISH analysis: N=17 score 3, N=12 score 4. Of note, concordance between the two tests was obtained in seven out of 10 patients. Sixty percent of mutated patients had an upper tract primary tumour versus 31% of ISH-positive patients.
PATIENT SUMMARY:
We found three-fold higher frequency of fibroblast growth-factor receptor alterations at the RNA versus DNA level in advanced urothelial carcinoma, with a different distribution according to the method used and the site of the primary tumour. The evaluation of the therapeutic response to pan-fibroblast growth-factor receptor inhibitors according to the method of assessment is warranted.
Current oncology (Toronto, Ont.)
Boudin, L;Morvan, JB;Thariat, J;Métivier, D;Marcy, PY;Delarbre, D;
PMID: 36290887 | DOI: 10.3390/curroncol29100610
Anaplastic thyroid carcinoma (ATC) are highly aggressive malignant tumors with poor overall prognosis despite multimodal therapy. As ATC are extremely rare, no randomized controlled study has been published for metastatic disease. Thyrosine kinase inhibitors, especially lenvatinib and immune checkpoint inhibitors such as pembrolizumab, are emerging drugs for ATC. Few studies have reported the efficacity of pembrolizumab and lenvatinib association, resulting in its frequent off-label use. In this review, we discuss rationale efficacy and safety evidence for the association of lenvatinib and pembrolizumab in ATC. First, we discuss preclinical rationale for pembrolizumab monotherapy, lenvatinib monotherapy and synergistic action of pembrolizumab and lenvatinib in the metastatic setting. We also discuss clinical evidence for immunotherapy and pembrolizumab in ATC through the analysis of studies evaluating immunotherapy, lenvatinib and pembrolizumab lenvatinib association in ATC. In addition, we discuss the safety of this association and potential predictive biomarkers of efficiency.
Mol Cancer Res. 2014 Oct;12(10):1460-9.
Marek LA, Hinz TK, von Mässenhausen A, Olszewski KA, Kleczko EK, Boehm D, Weiser-Evans MC, Nemenoff RA, Hoffmann H, Warth A, Gozgit JM, Perner S, Heasley LE.
PMID: 25686826
Abstract Malignant pleural mesothelioma (MPM) is associated with asbestos exposure and is a cancer that has not been significantly affected by small molecule-based targeted therapeutics. Previously, we demonstrated the existence of functional subsets of lung cancer and head and neck squamous cell carcinoma (HNSCC) cell lines in which fibroblast growth factor receptor (FGFR) autocrine signaling functions as a nonmutated growth pathway. In a panel of pleural mesothelioma cell lines, FGFR1 and FGF2 were coexpressed in three of seven cell lines and were significantly associated with sensitivity to the FGFR-active tyrosine kinase inhibitor (TKI), ponatinib, both in vitro and in vivo using orthotopically propagated xenografts. Furthermore, RNAi-mediated silencing confirmed the requirement for FGFR1 in specific mesothelioma cells and sensitivity to the FGF ligand trap, FP-1039, validated the requirement for autocrine FGFs. None of the FGFR1-dependent mesothelioma cells exhibited increased FGFR1 gene copy number, based on a FISH assay, indicating that increased FGFR1 transcript and protein expression were not mediated by gene amplification. Elevated FGFR1 mRNA was detected in a subset of primary MPM clinical specimens and like MPM cells; none harbored increased FGFR1 gene copy number. These results indicate that autocrine signaling through FGFR1 represents a targetable therapeutic pathway in MPM and that biomarkers distinct from increased FGFR1 gene copy number such as FGFR1 mRNA would be required to identify patients with MPM bearing tumors driven by FGFR1 activity. IMPLICATIONS: FGFR1 is a viable therapeutic target in a subset of MPMs, but FGFR TKI-responsive tumors will need to be selected by a biomarker distinct from increased FGFR1 gene copy number, possibly FGFR1 mRNA or protein levels.
FGF-Receptors and PD-L1 in Anaplastic and Poorly Differentiated Thyroid Cancer: Evaluation of the Preclinical Rationale
Frontiers in endocrinology
Adam, P;Kircher, S;Sbiera, I;Koehler, VF;Berg, E;Knösel, T;Sandner, B;Fenske, WK;Bläker, H;Smaxwil, C;Zielke, A;Sipos, B;Allelein, S;Schott, M;Dierks, C;Spitzweg, C;Fassnacht, M;Kroiss, M;
PMID: 34475850 | DOI: 10.3389/fendo.2021.712107
Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising.Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable.PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS.High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.
