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Fibroblast Growth Factors: Pathophysiology and Therapeutics
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Fibroblast Growth Factors: Pathophysiology and Therapeutics

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Cell Signaling".

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Editor

Prof. T.K.S. Kumar

E-Mail Website1 Website2
Collection Editor
Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR 72701, USA
Interests: cytokines; cell signaling; design of novel fibroblast growth factor (FGF) variants; FGF-receptor activation, non-classical secretion of FGF1; FGF pathogenesis; drug discovery

Topical Collection Information

Dear Colleagues,

Fibroblast growth factors (FGFs) are a family of cytokines that play crucial roles in the regulation of key cellular processes such as cell proliferation, cell differentiation, tissue morphogenesis, angiogenesis, wound repair, and tumor growth. Members of the FGF family, with the exception of FGF11, FGF12, FGF13, and FGF14, elicit a cellular response by specifically binding to their cell-surface tyrosine kinase receptors and consequently activate a cascade of intracellular signaling pathways, including the PI3 kinase/AKT p, RAS/MAP kinase, and PLCγ pathways. Most members of the FGF family that bind to heparin sulfate are paracrine secretors. However, FGF19, FGF21, and FGF23 function as endocrine secretors, recruit the Klotho proteins, and activate the FGF receptors in a heparin-independent manner. These endocrine FGFs have been demonstrated to be critical regulators of glucose and lipid metabolism, vitamin D biosynthesis, and phosphate homeostasis and, hence, have attracted an immense amount of interest as therapeutics against diabetes, obesity, osteoporosis, cardiovascular and kidney diseases, and a wide array of diseases associated with the liver–gut axis. Additionally, aberrations in the FGF signaling process are the cause of many skeletal syndromes, including Kallmann syndrome, Lacrimo-auriculo-dento-digital syndrome (LADD syndrome), and cancer. Recent determination of the three-dimensional structures of the FGF signaling complex has provided us with valuable new insights into the molecular bases of a multitude of types of FGF-mediated pathogenesis. In addition, the availability of structural information on the structure–activity relationship of FGFs has opened new avenues to the rational design of drugs against FGF-mediated pathogenesis. In this context, this Topical Collection of Cells provides an exciting open-access platform for original research articles, shorter perspective articles, and comprehensive reviews on significant recent advances in FGF pathophysiology and therapeutics against the plethora of types of FGF-related pathogenesis.

Prof. T.K.S. Kumar
Collection Editor

Manuscript Submission Information

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Keywords

  • cytokines
  • structure and function of FGFs
  • FGF signaling and mitogenic activity
  • angiogensis and cardiovascular protection
  • craniofacial syndromes
  • FGF chimeras
  • parcrine and endocrine secretors
  • glucose and phosphate metabolism
  • wound healing
  • stem cells and tissue regenration
  • therapeutics against FGFs

Published Papers (15 papers)

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2023

Jump to: 2022, 2021

12 pages, 848 KiB  
Review
FGF23 in Chronic Kidney Disease: Bridging the Heart and Anemia
by Andreja Figurek, Merita Rroji and Goce Spasovski
Cells 2023, 12(4), 609; https://doi.org/10.3390/cells12040609 - 13 Feb 2023
Cited by 3 | Viewed by 2061
Abstract
Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced mainly in osteocytes. In chronic kidney disease (CKD) FGF23 levels increase due to higher production, but also as the result of impaired cleavage and reduced excretion from the body. FGF23 has a significant [...] Read more.
Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced mainly in osteocytes. In chronic kidney disease (CKD) FGF23 levels increase due to higher production, but also as the result of impaired cleavage and reduced excretion from the body. FGF23 has a significant role in disturbed bone and mineral metabolism in CKD, which leads to a higher cardiovascular risk and mortality in these patients. Current research has emphasized the expression of FGF23 in cardiac myocytes, fibroblasts, and endothelial cells, and in addition to the effects on the kidney, its primary role is in cardiac remodeling in CKD patients. Recent discoveries found a significant link between increased FGF23 levels and anemia development in CKD. This review describes the FGF23 role in cardiac hypertrophy and anemia in the setting of CKD and discusses the best therapeutical approach for lowering FGF23 levels. Full article
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2022

Jump to: 2023, 2021

10 pages, 2316 KiB  
Article
Radiosensitization by the Selective Pan-FGFR Inhibitor LY2874455
by Narisa Dewi Maulany Darwis, Eisuke Horigome, Shan Li, Akiko Adachi, Takahiro Oike, Atsushi Shibata, Yuka Hirota and Tatsuya Ohno
Cells 2022, 11(11), 1727; https://doi.org/10.3390/cells11111727 - 24 May 2022
Cited by 1 | Viewed by 1716
Abstract
Ionizing radiation activates cytoprotective pathways in cancer cells. Fibroblast growth factor receptor (FGFR) is a key player in these pathways. Thus, FGFR signaling is a potential target to induce radiosensitization. LY2874455 is an orally administrable selective pan-FGFR inhibitor. However, the radiosensitizing effects of [...] Read more.
Ionizing radiation activates cytoprotective pathways in cancer cells. Fibroblast growth factor receptor (FGFR) is a key player in these pathways. Thus, FGFR signaling is a potential target to induce radiosensitization. LY2874455 is an orally administrable selective pan-FGFR inhibitor. However, the radiosensitizing effects of LY2874455 remain unclear. In this study, we addressed this issue by using radioresistant human cancer cell lines H1703 (FGFR1 mutant), A549 (FGFR1–4 wild-type), and H1299 (FGFR1–4 wild-type). At an X-ray dose corresponding to 50%-clonogenic survival as the endpoint, 100 nM LY2874455 increased the sensitivity of H1703, A549, and H1299 cells by 31%, 62%, and 53%, respectively. The combination of X-rays and LY2874455 led to a marked induction of mitotic catastrophe, a hallmark of radiation-induced cell death. Furthermore, combination treatment suppressed the growth of A549 xenografts to a significantly greater extent than either X-rays or the drug alone without noticeable toxicity. This is the first report to show the radiosensitizing effect of a selective pan-FGFR inhibitor. These data suggest the potential efficacy of LY2874455 as a radiosensitizer, warranting clinical validation. Full article
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11 pages, 680 KiB  
Article
Decreased Concentration of Fibroblast Growth Factor 23 (FGF-23) as a Result of Supplementation with Selenium and Coenzyme Q10 in an Elderly Swedish Population: A Sub-Analysis
by Urban Alehagen, Jan Aaseth, Anders Larsson and Jan Alexander
Cells 2022, 11(3), 509; https://doi.org/10.3390/cells11030509 - 01 Feb 2022
Cited by 3 | Viewed by 1983
Abstract
There is a reduced intake of selenium in many countries due to low levels of selenium in the soil. This results in an increased cardiovascular risk. Fibroblast growth factor 23 (FGF-23) is active mainly in the metabolism of vitamin D and phosphorus. However, [...] Read more.
There is a reduced intake of selenium in many countries due to low levels of selenium in the soil. This results in an increased cardiovascular risk. Fibroblast growth factor 23 (FGF-23) is active mainly in the metabolism of vitamin D and phosphorus. However, there are indications that FGF-23 may also provide information both on cardiovascular function and prognosis. The aim of the study was to evaluate the effect of supplementation with selenium and coenzyme Q10 on the FGF-23 concentration in an elderly population with low concentrations of both selenium and coenzyme Q10 and in which the supplementation improved cardiac function and mortality. In a randomised double-blind placebo-controlled trial, FGF-23 was measured in 219 individuals at the start and after 48 months. Selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) (n = 118) or placebo (n = 101) were given as a dietary supplement. The intervention time was 48 months. t-Tests, repeated measures of variance, and ANCOVA analyses were used to evaluate the differences in FGF-23 concentration. Following supplementation with selenium and coenzyme Q10, a significantly lower level of FGF-23 could be seen (p = 0.01). Applying 10 years of follow-up, those who later died a cardiovascular death had a significantly higher FGF-23 concentration after 48 months compared with those who survived (p = 0.036), and a significantly lower FGF-23 concentration could be seen in those with a normal renal function compared to those with an impaired renal function (p = 0.027). Supplementation with selenium and coenzyme Q10 to an elderly community-living population low in both substances prevented an increase of FGF-23 and also provided a reduced cardiovascular risk. Full article
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2021

Jump to: 2023, 2022

16 pages, 18437 KiB  
Article
Establishing F1A-CreERT2 Mice to Trace Fgf1 Expression in Adult Mouse Cardiomyocytes
by Yi-Chao Hsu, Yu-Fen Chung, Mei-Shu Chen, Chi-Kuang Wang, Si-Tse Jiang and Ing-Ming Chiu
Cells 2022, 11(1), 121; https://doi.org/10.3390/cells11010121 - 30 Dec 2021
Cited by 9 | Viewed by 2565
Abstract
Fibroblast growth factor 1 (FGF1) regulates many biological and physiological processes. In mice, Fgf1 gene contains at least three upstream promoters and are alternatively spliced to the first protein coding exon, giving rise to different Fgf1 mRNA variants (1A, 1B and 1G). Among [...] Read more.
Fibroblast growth factor 1 (FGF1) regulates many biological and physiological processes. In mice, Fgf1 gene contains at least three upstream promoters and are alternatively spliced to the first protein coding exon, giving rise to different Fgf1 mRNA variants (1A, 1B and 1G). Among them, the Fgf1A transcript is predominantly expressed in the heart. FGF1 can induce cardiomyocyte regeneration and cardiogenesis in vitro and in vivo. Here, we generated a novel mouse line using the Fgf1A promoter (F1A) driving the expression of the inducible Cre recombinase (CreERT2). We firstly demonstrated that the highest mRNA expression of CreERT2 were detected in the heart specifically of F1A-CreERT2 mice, similar to that of Fgf1A mRNA. The F1A-CreERT2 mice were crossed with ROSA26 mice, and the F1 mice were analyzed. The LacZ-positive signals were detected exclusively in the heart after tamoxifen administration. The CreERT2-mediated recombination in the tissues is monitored through LacZ-positive signals, indicating the in situ localization of F1A-positive cells. Consistently, these F1A-positive cells with RFP-positive signals or LacZ-positive blue signals were co-localized with cardiomyocytes expressing cardiac troponin T, suggesting cardiomyocyte-specific activation of Fgf1A promoter. Our data suggested that the F1A-CreERT2 mouse line could be used for time-dependent and lineage tracing of Fgf1A-expressing cells in vivo. Full article
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13 pages, 1935 KiB  
Article
Up-Regulation of Fibroblast Growth Factor 23 Gene Expression in UMR106 Osteoblast-like Cells with Reduced Viability
by Sina Münz, Martina Feger, Bayram Edemir and Michael Föller
Cells 2022, 11(1), 40; https://doi.org/10.3390/cells11010040 - 23 Dec 2021
Cited by 1 | Viewed by 2595
Abstract
Fibroblast growth factor 23 (FGF23) controls vitamin D and phosphate homeostasis in the kidney and has additional paracrine effects elsewhere. As a biomarker, its plasma concentration is associated with progression of inflammatory, renal, and cardiovascular diseases. Major stimuli of FGF23 synthesis include active [...] Read more.
Fibroblast growth factor 23 (FGF23) controls vitamin D and phosphate homeostasis in the kidney and has additional paracrine effects elsewhere. As a biomarker, its plasma concentration is associated with progression of inflammatory, renal, and cardiovascular diseases. Major stimuli of FGF23 synthesis include active vitamin D and inflammation. Antineoplastic chemotherapy treats cancer by inducing cellular damage ultimately favoring cell death (apoptosis and necrosis) and causing inflammation. Our study explored whether chemotherapeutics and other apoptosis inducers impact on Fgf23 expression. Experiments were performed in osteoblast-like UMR106 cells, Fgf23 gene expression and protein synthesis were determined by qRT-PCR and ELISA, respectively. Viability was assessed by MTT assay and NFκB activity by Western Blotting. Antineoplastic drugs cisplatin and doxorubicin as well as apoptosis inducers procaspase-activating compound 1 (PAC-1), a caspase 3 activator, and serum depletion up-regulated Fgf23 transcripts while reducing cell proliferation and viability. The effect of cisplatin on Fgf23 transcription was paralleled by Il-6 up-regulation and NFκB activation and attenuated by Il-6 and NFκB signaling inhibitors. To conclude, cell viability-decreasing chemotherapeutics as well as apoptosis stimulants PAC-1 and serum depletion up-regulate Fgf23 gene expression. At least in part, Il-6 and NFκB may contribute to this effect. Full article
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17 pages, 40022 KiB  
Article
Maresin-1 Prevents Liver Fibrosis by Targeting Nrf2 and NF-κB, Reducing Oxidative Stress and Inflammation
by María José Rodríguez, Matías Sabaj, Gerardo Tolosa, Francisca Herrera Vielma, María José Zúñiga, Daniel R. González and Jessica Zúñiga-Hernández
Cells 2021, 10(12), 3406; https://doi.org/10.3390/cells10123406 - 03 Dec 2021
Cited by 28 | Viewed by 3984
Abstract
Liver fibrosis is a complex process characterized by the excessive accumulation of extracellular matrix (ECM) and an alteration in liver architecture, as a result of most types of chronic liver diseases such as cirrhosis, hepatocellular carcinoma (HCC) and liver failure. Maresin-1 (MaR1) is [...] Read more.
Liver fibrosis is a complex process characterized by the excessive accumulation of extracellular matrix (ECM) and an alteration in liver architecture, as a result of most types of chronic liver diseases such as cirrhosis, hepatocellular carcinoma (HCC) and liver failure. Maresin-1 (MaR1) is derivative of ω-3 docosahexaenoic acid (DHA), which has been shown to have pro-resolutive and anti-inflammatory effects. We tested the hypothesis that the application of MaR1 could prevent the development of fibrosis in an animal model of chronic hepatic damage. Sprague-Dawley rats were induced with liver fibrosis by injections of diethylnitrosamine (DEN) and treated with or without MaR1 for four weeks. In the MaR1-treated animals, levels of AST and ALT were normalized in comparison with DEN alone, the hepatic architecture was improved, and inflammation and necrotic areas were reduced. Cell proliferation, assessed by the mitotic activity index and the expression of Ki-67, was increased in the MaR1-treated group. MaR1 attenuated liver fibrosis and oxidative stress was induced by DEN. Plasma levels of the pro-inflammatory mediators TNF-α and IL-1β were reduced in MaR1-treated animals, whereas the levels of IL-10, an anti-inflammatory cytokine, increased. Interestingly, MaR1 inhibited the translocation of the p65 subunit of NF-κB, while increasing the activation of Nrf2, a key regulator of the antioxidant response. Finally, MaR1 treatment reduced the levels of the pro-fibrotic mediator TGF-β and its receptor, while normalizing the hepatic levels of IGF-1, a proliferative agent. Taken together, these results suggest that MaR1 improves the parameters of DEN-induced liver fibrosis, activating hepatocyte proliferation and decreasing oxidative stress and inflammation. These results open the possibility of MaR1 as a potential therapeutic agent in fibrosis and other liver pathologies. Full article
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14 pages, 4572 KiB  
Article
p38 Mediates Resistance to FGFR Inhibition in Non-Small Cell Lung Cancer
by Izabela Zarczynska, Monika Gorska-Arcisz, Alexander Jorge Cortez, Katarzyna Aleksandra Kujawa, Agata Małgorzata Wilk, Andrzej Cezary Skladanowski, Aleksandra Stanczak, Monika Skupinska, Maciej Wieczorek, Katarzyna Marta Lisowska, Rafal Sadej and Kamila Kitowska
Cells 2021, 10(12), 3363; https://doi.org/10.3390/cells10123363 - 30 Nov 2021
Cited by 6 | Viewed by 2884
Abstract
FGFR signalling is one of the most prominent pathways involved in cell growth and development as well as cancer progression. FGFR1 amplification occurs in approximately 20% of all squamous cell lung carcinomas (SCC), a predominant subtype of non-small cell lung carcinoma (NSCLC), indicating [...] Read more.
FGFR signalling is one of the most prominent pathways involved in cell growth and development as well as cancer progression. FGFR1 amplification occurs in approximately 20% of all squamous cell lung carcinomas (SCC), a predominant subtype of non-small cell lung carcinoma (NSCLC), indicating FGFR as a potential target for the new anti-cancer treatment. However, acquired resistance to this type of therapies remains a serious clinical challenge. Here, we investigated the NSCLC cell lines response and potential mechanism of acquired resistance to novel selective FGFR inhibitor CPL304110. We found that despite significant genomic differences between CPL304110-sensitive cell lines, their resistant variants were characterised by upregulated p38 expression/phosphorylation, as well as enhanced expression of genes involved in MAPK signalling. We revealed that p38 inhibition restored sensitivity to CPL304110 in these cells. Moreover, the overexpression of this kinase in parental cells led to impaired response to FGFR inhibition, thus confirming that p38 MAPK is a driver of resistance to a novel FGFR inhibitor. Taken together, our results provide an insight into the potential direction for NSCLC targeted therapy. Full article
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20 pages, 9912 KiB  
Review
The Role of Fibroblast Growth Factor (FGF) Signaling in Tissue Repair and Regeneration
by Mariya Farooq, Abdul Waheed Khan, Moon Suk Kim and Sangdun Choi
Cells 2021, 10(11), 3242; https://doi.org/10.3390/cells10113242 - 19 Nov 2021
Cited by 58 | Viewed by 10058
Abstract
Fibroblast growth factors (FGFs) are a large family of secretory molecules that act through tyrosine kinase receptors known as FGF receptors. They play crucial roles in a wide variety of cellular functions, including cell proliferation, survival, metabolism, morphogenesis, and differentiation, as well as [...] Read more.
Fibroblast growth factors (FGFs) are a large family of secretory molecules that act through tyrosine kinase receptors known as FGF receptors. They play crucial roles in a wide variety of cellular functions, including cell proliferation, survival, metabolism, morphogenesis, and differentiation, as well as in tissue repair and regeneration. The signaling pathways regulated by FGFs include RAS/mitogen-activated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)–protein kinase B (AKT), phospholipase C gamma (PLCγ), and signal transducer and activator of transcription (STAT). To date, 22 FGFs have been discovered, involved in different functions in the body. Several FGFs directly or indirectly interfere with repair during tissue regeneration, in addition to their critical functions in the maintenance of pluripotency and dedifferentiation of stem cells. In this review, we summarize the roles of FGFs in diverse cellular processes and shed light on the importance of FGF signaling in mechanisms of tissue repair and regeneration. Full article
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15 pages, 2778 KiB  
Article
Local and Systemic Cytokine, Chemokine, and FGF Profile in Bacterial Chondronecrosis with Osteomyelitis (BCO)-Affected Broilers
by Alison Ramser, Elizabeth Greene, Robert Wideman and Sami Dridi
Cells 2021, 10(11), 3174; https://doi.org/10.3390/cells10113174 - 15 Nov 2021
Cited by 4 | Viewed by 1815
Abstract
Complex disease states, like bacterial chondronecrosis with osteomyelitis (BCO), not only result in physiological symptoms, such as lameness, but also a complex systemic reaction involving immune and growth factor responses. For the modern broiler (meat-type) chickens, BCO is an animal welfare, production, and [...] Read more.
Complex disease states, like bacterial chondronecrosis with osteomyelitis (BCO), not only result in physiological symptoms, such as lameness, but also a complex systemic reaction involving immune and growth factor responses. For the modern broiler (meat-type) chickens, BCO is an animal welfare, production, and economic concern involving bacterial infection, inflammation, and bone attrition with a poorly defined etiology. It is, therefore, critical to define the key inflammatory and bone-related factors involved in BCO. In this study, the local bone and systemic blood profile of inflammatory modulators, cytokines, and chemokines was elucidated along with inflammasome and key FGF genes. BCO-affected bone showed increased expression of cytokines IL-1β, while BCO-affected blood expressed upregulated TNFα and IL-12. The chemokine profile revealed increased IL-8 expression in both BCO-affected bone and blood in addition to inflammasome NLRC5 being upregulated in circulation. The key FGF receptor, FGFR1, was significantly downregulated in BCO-affected bone. The exposure of two different bone cell types, hFOB and chicken primary chondrocytes, to plasma from BCO-affected birds, as well as recombinant TNFα, resulted in significantly decreased cell viability. These results demonstrate an expression of proinflammatory and bone-resorptive factors and their potential contribution to BCO etiology through their impact on bone cell viability. This unique profile could be used for improved non-invasive detection of BCO and provides potential targets for treatments. Full article
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16 pages, 1778 KiB  
Article
Pharmacological Inhibition of Wee1 Kinase Selectively Modulates the Voltage-Gated Na+ Channel 1.2 Macromolecular Complex
by Nolan M. Dvorak, Cynthia M. Tapia, Timothy J. Baumgartner, Jully Singh, Fernanda Laezza and Aditya K. Singh
Cells 2021, 10(11), 3103; https://doi.org/10.3390/cells10113103 - 10 Nov 2021
Cited by 3 | Viewed by 1774
Abstract
Voltage-gated Na+ (Nav) channels are a primary molecular determinant of the action potential (AP). Despite the canonical role of the pore-forming α subunit in conferring this function, protein–protein interactions (PPI) between the Nav channel α subunit and its auxiliary [...] Read more.
Voltage-gated Na+ (Nav) channels are a primary molecular determinant of the action potential (AP). Despite the canonical role of the pore-forming α subunit in conferring this function, protein–protein interactions (PPI) between the Nav channel α subunit and its auxiliary proteins are necessary to reconstitute the full physiological activity of the channel and to fine-tune neuronal excitability. In the brain, the Nav channel isoforms 1.2 (Nav1.2) and 1.6 (Nav1.6) are enriched, and their activities are differentially regulated by the Nav channel auxiliary protein fibroblast growth factor 14 (FGF14). Despite the known regulation of neuronal Nav channel activity by FGF14, less is known about cellular signaling molecules that might modulate these regulatory effects of FGF14. To that end, and building upon our previous investigations suggesting that neuronal Nav channel activity is regulated by a kinase network involving GSK3, AKT, and Wee1, we interrogate in our current investigation how pharmacological inhibition of Wee1 kinase, a serine/threonine and tyrosine kinase that is a crucial component of the G2-M cell cycle checkpoint, affects the Nav1.2 and Nav1.6 channel macromolecular complexes. Our results show that the highly selective inhibitor of Wee1 kinase, called Wee1 inhibitor II, modulates FGF14:Nav1.2 complex assembly, but does not significantly affect FGF14:Nav1.6 complex assembly. These results are functionally recapitulated, as Wee1 inhibitor II entirely alters FGF14-mediated regulation of the Nav1.2 channel, but displays no effects on the Nav1.6 channel. At the molecular level, these effects of Wee1 inhibitor II on FGF14:Nav1.2 complex assembly and FGF14-mediated regulation of Nav1.2-mediated Na+ currents are shown to be dependent upon the presence of Y158 of FGF14, a residue known to be a prominent site for phosphorylation-mediated regulation of the protein. Overall, our data suggest that pharmacological inhibition of Wee1 confers selective modulatory effects on Nav1.2 channel activity, which has important implications for unraveling cellular signaling pathways that fine-tune neuronal excitability. Full article
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21 pages, 10545 KiB  
Article
FGFR1 Overexpression Induces Cancer Cell Stemness and Enhanced Akt/Erk-ER Signaling to Promote Palbociclib Resistance in Luminal A Breast Cancer Cells
by Qiong Cheng, Zhikun Ma, Yujie Shi, Amanda B. Parris, Lingfei Kong and Xiaohe Yang
Cells 2021, 10(11), 3008; https://doi.org/10.3390/cells10113008 - 04 Nov 2021
Cited by 11 | Viewed by 2775
Abstract
Resistance to CDK4/6 inhibitors (CDKis) is emerging as a clinical challenge. Identification of the factors contributing to CDKi resistance, with mechanistic insight, is of pivotal significance. Recent studies linked aberrant FGFR signaling to CDKi resistance. However, detailed mechanisms are less clear. Based on [...] Read more.
Resistance to CDK4/6 inhibitors (CDKis) is emerging as a clinical challenge. Identification of the factors contributing to CDKi resistance, with mechanistic insight, is of pivotal significance. Recent studies linked aberrant FGFR signaling to CDKi resistance. However, detailed mechanisms are less clear. Based on control and FGFR1 overexpressing luminal A cell line models, we demonstrated that FGFR1 overexpression rendered the cells resistant to palbociclib. FGFR1 overexpression abolished palbociclib-mediated cell cycle arrest, as well as the attenuated palbociclib-induced inhibition of G1/S transition regulators (pRb, E2F1, and cyclin D3) and factors that promote G2/M transition (cyclin B1, cdc2/CDK1, and cdc25). Importantly, FGFR1-induced palbociclib resistance was associated with promotion of cancer cell stemness and the upregulation of Wnt/β-catenin signaling. We found that palbociclib may function as an ER agonist in MCF-7/FGFR1 cells. Upregulation of the ER-mediated transcription in MCF-7/FGFR1 cells was associated with ERα phosphorylation and enhanced receptor tyrosine kinase signaling. The combination of palbociclib with FGFR-targeting AZD4547 resulted in remarkable synergistic effects on MCF-7/FGFR1 cells, especially for the inhibition of cancer cell stemness. Our findings of FGFR1-induced palbociclib resistance, promotion of cancer stem cells and associated molecular changes advance our mechanistic understanding of CDKi resistance, which will facilitate the development of strategies targeting CDKi resistance in breast cancer treatment. Full article
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13 pages, 1201 KiB  
Article
The Mitochondrial Biomarkers FGF-21 and GDF-15 in Patients with Episodic and Chronic Migraine
by Philipp Burow, Marc Haselier, Steffen Naegel, Leila Motlagh Scholle, Charly Gaul and Torsten Kraya
Cells 2021, 10(9), 2471; https://doi.org/10.3390/cells10092471 - 18 Sep 2021
Cited by 5 | Viewed by 2348
Abstract
Mitochondrial processes may play a role in the pathophysiology of migraine. Serum levels of two biomarkers, Fibroblast-growth-factor 21 (FGF-21) and Growth-differentiation-factor 15 (GDF-15), are typically elevated in patients with mitochondrial disorders. The study investigated whether the presence of migraine may influence FGF-21 and [...] Read more.
Mitochondrial processes may play a role in the pathophysiology of migraine. Serum levels of two biomarkers, Fibroblast-growth-factor 21 (FGF-21) and Growth-differentiation-factor 15 (GDF-15), are typically elevated in patients with mitochondrial disorders. The study investigated whether the presence of migraine may influence FGF-21 and GDF-15 serum levels considering vascular and metabolic disorders as possible confounders. A cross-sectional study in two headache centers was conducted analyzing GDF-15 and FGF-21 serum concentration in 230 patients with episodic and chronic migraine compared to a control group. Key clinical features of headache were evaluated, as well as health-related life quality, anxiety and depression using SF-12 and HADS-questionnaires. Elevated GDF-15 values were detected in the migraine group compared to the control group (506.65 ± 275.87 pg/mL vs. 403.34 ± 173.29 pg/mL, p < 0.001, Mann–Whitney U test). A strong correlation between increasing age and higher GDF-15 levels was identified (p < 0.001, 95%-CI elevation of GDF-15 per year 5.246–10.850 pg/mL, multiple linear regression). Mean age was different between the groups, and this represents a confounding factor of the measurements. FGF-21 levels did not differ between migraine patients and controls (p = 0.635, Mann–Whitney U test) but were significantly influenced by increasing BMI (p = 0.030, multiple linear regression). Neither biomarker showed correlation with headache frequency. Higher FGF-21 levels were associated with a higher mean intensity of headache attacks, reduced health-related life quality and anxiety. When confounding factors were considered, increased serum levels of FGF-21 and GDF-15 were not detected in migraine patients. However, the results show an age-dependence of GDF-15 in migraine patients, and this should be considered in future studies. Similar findings apply to the relationship between FGF-21 and BMI. Previous studies that did not adjust for these factors should be interpreted with caution. Full article
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38 pages, 8296 KiB  
Review
The Saga of Endocrine FGFs
by Phuc Phan, Bibhuti Ballav Saikia, Shivakumar Sonnaila, Shilpi Agrawal, Zeina Alraawi, Thallapuranam Krishnaswamy Suresh Kumar and Shilpa Iyer
Cells 2021, 10(9), 2418; https://doi.org/10.3390/cells10092418 - 14 Sep 2021
Cited by 25 | Viewed by 4094
Abstract
Fibroblast growth factors (FGFs) are cell-signaling proteins with diverse functions in cell development, repair, and metabolism. The human FGF family consists of 22 structurally related members, which can be classified into three separate groups based on their action of mechanisms, namely: intracrine, paracrine/autocrine, [...] Read more.
Fibroblast growth factors (FGFs) are cell-signaling proteins with diverse functions in cell development, repair, and metabolism. The human FGF family consists of 22 structurally related members, which can be classified into three separate groups based on their action of mechanisms, namely: intracrine, paracrine/autocrine, and endocrine FGF subfamilies. FGF19, FGF21, and FGF23 belong to the hormone-like/endocrine FGF subfamily. These endocrine FGFs are mainly associated with the regulation of cell metabolic activities such as homeostasis of lipids, glucose, energy, bile acids, and minerals (phosphate/active vitamin D). Endocrine FGFs function through a unique protein family called klotho. Two members of this family, α-klotho, or β-klotho, act as main cofactors which can scaffold to tether FGF19/21/23 to their receptor(s) (FGFRs) to form an active complex. There are ongoing studies pertaining to the structure and mechanism of these individual ternary complexes. These studies aim to provide potential insights into the physiological and pathophysiological roles and therapeutic strategies for metabolic diseases. Herein, we provide a comprehensive review of the history, structure–function relationship(s), downstream signaling, physiological roles, and future perspectives on endocrine FGFs. Full article
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21 pages, 1459 KiB  
Review
Functional Roles of FGF Signaling in Early Development of Vertebrate Embryos
by Vijay Kumar, Ravi Shankar Goutam, Soochul Park, Unjoo Lee and Jaebong Kim
Cells 2021, 10(8), 2148; https://doi.org/10.3390/cells10082148 - 20 Aug 2021
Cited by 18 | Viewed by 6824
Abstract
Fibroblast growth factors (FGFs) comprise a large family of growth factors, regulating diverse biological processes including cell proliferation, migration, and differentiation. Each FGF binds to a set of FGF receptors to initiate certain intracellular signaling molecules. Accumulated evidence suggests that in early development [...] Read more.
Fibroblast growth factors (FGFs) comprise a large family of growth factors, regulating diverse biological processes including cell proliferation, migration, and differentiation. Each FGF binds to a set of FGF receptors to initiate certain intracellular signaling molecules. Accumulated evidence suggests that in early development and adult state of vertebrates, FGFs also play exclusive and context dependent roles. Although FGFs have been the focus of research for therapeutic approaches in cancer, cardiovascular disease, and metabolic syndrome, in this review, we mainly focused on their role in germ layer specification and axis patterning during early vertebrate embryogenesis. We discussed the functional roles of FGFs and their interacting partners as part of the gene regulatory network for germ layer specification, dorsal–ventral (DV), and anterior-posterior (AP) patterning. Finally, we briefly reviewed the regulatory molecules and pharmacological agents discovered that may allow modulation of FGF signaling in research. Full article
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19 pages, 1078 KiB  
Review
Cellular Mechanisms of FGF-Stimulated Tissue Repair
by Igor Prudovsky
Cells 2021, 10(7), 1830; https://doi.org/10.3390/cells10071830 - 20 Jul 2021
Cited by 25 | Viewed by 3828
Abstract
Growth factors belonging to the FGF family play important roles in tissue and organ repair after trauma. In this review, I discuss the regulation by FGFs of the aspects of cellular behavior important for reparative processes. In particular, I focus on the FGF-dependent [...] Read more.
Growth factors belonging to the FGF family play important roles in tissue and organ repair after trauma. In this review, I discuss the regulation by FGFs of the aspects of cellular behavior important for reparative processes. In particular, I focus on the FGF-dependent regulation of cell proliferation, cell stemness, de-differentiation, inflammation, angiogenesis, cell senescence, cell death, and the production of proteases. In addition, I review the available literature on the enhancement of FGF expression and secretion in damaged tissues resulting in the increased FGF supply required for tissue repair. Full article
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