2024

Jump to: 2021, 2020

13 pages, 3650 KiB

Open AccessArticle

FGF9, a Potent Mitogen, Is a New Ligand for Integrin αvβ3, and the FGF9 Mutant Defective in Integrin Binding Acts as an Antagonist

by Chih-Chieh Chang, Yoko K. Takada, Chao-Wen Cheng, Yukina Maekawa, Seiji Mori and Yoshikazu Takada

Cells 2024, 13(4), 307; https://doi.org/10.3390/cells13040307 - 07 Feb 2024

Viewed by 742

Abstract

FGF9 is a potent mitogen and survival factor, but FGF9 protein levels are generally low and restricted to a few adult organs. Aberrant expression of FGF9 usually results in cancer. However, the mechanism of FGF9 action has not been fully established. Previous studies [...] Read more.

FGF9 is a potent mitogen and survival factor, but FGF9 protein levels are generally low and restricted to a few adult organs. Aberrant expression of FGF9 usually results in cancer. However, the mechanism of FGF9 action has not been fully established. Previous studies showed that FGF1 and FGF2 directly bind to integrin αvβ3, and this interaction is critical for signaling functions (FGF–integrin crosstalk). FGF1 and FGF2 mutants defective in integrin binding were defective in signaling, whereas the mutants still bound to FGFR suppressed angiogenesis and tumor growth, indicating that they act as antagonists. We hypothesize that FGF9 requires direct integrin binding for signaling. Here, we show that docking simulation of the interaction between FGF9 and αvβ3 predicted that FGF9 binds to the classical ligand-binding site of αvβ3. We show that FGF9 bound to integrin αvβ3 and generated FGF9 mutants in the predicted integrin-binding interface. An FGF9 mutant (R108E) was defective in integrin binding, activating FRS2α and ERK1/2, inducing DNA synthesis, cancer cell migration, and invasion in vitro. R108E suppressed DNA synthesis and activation of FRS2α and ERK1/2 induced by WT FGF9 (dominant-negative effect). These findings indicate that FGF9 requires direct integrin binding for signaling and that R108E has potential as an antagonist to FGF9 signaling. Full article

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2021

Jump to: 2024, 2020

6 pages, 817 KiB

Open AccessBrief Report

The Use of Human Serum Samples to Study Malignant Transformation: A Pilot Study

by Andreana N. Holowatyj, Biljana Gigic, Christy A. Warby, Jennifer Ose, Tengda Lin, Petra Schrotz-King, Cornelia M. Ulrich and Jamie J. Bernard

Cells 2021, 10(10), 2670; https://doi.org/10.3390/cells10102670 - 06 Oct 2021

Cited by 1 | Viewed by 1574

Abstract

Obesity and excess adiposity account for approximately 20% of all cancer cases; however, biomarkers of risk remain to be elucidated. While fibroblast growth factor-2 (FGF2) is emerging as an attractive candidate biomarker for visceral adipose tissue mass, the role of circulating FGF2 in [...] Read more.

Obesity and excess adiposity account for approximately 20% of all cancer cases; however, biomarkers of risk remain to be elucidated. While fibroblast growth factor-2 (FGF2) is emerging as an attractive candidate biomarker for visceral adipose tissue mass, the role of circulating FGF2 in malignant transformation remains unknown. Moreover, functional assays for biomarker discovery are limited. We sought to determine if human serum could stimulate the 3D growth of a non-tumorigenic cell line. This type of anchorage-independent 3D growth in soft agar is a surrogate marker for acquired tumorigenicity of cell lines. We found that human serum from cancer-free men and women has the potential to stimulate growth in soft agar of non-tumorigenic epithelial JB6 P⁺ cells. We examined circulating levels of FGF2 in humans in malignant transformation in vitro in a pilot study of n = 33 men and women. Serum FGF2 levels were not associated with colony formation in epithelial cells (r = 0.05, p = 0.80); however, a fibroblast growth factor receptor-1 (FGFR1) selective inhibitor significantly blocked serum-stimulated transformation, suggesting that FGF2 activation of FGFR1 may be necessary, but not sufficient for the transforming effects of human serum. This pilot study indicates that the FGF2/FGFR1 axis plays a role in JB6 P⁺ malignant transformation and describes an assay to determine critical serum factors that have the potential to promote tumorigenesis. Full article

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5 pages, 216 KiB

Open AccessEditorial

Roles of the FGF-FGFR Signaling System in Cancer Development and Inflammation

by Antoni Wiedlocha, Ellen Margrethe Haugsten and Malgorzata Zakrzewska

Cells 2021, 10(9), 2231; https://doi.org/10.3390/cells10092231 - 28 Aug 2021

Cited by 11 | Viewed by 2121

Abstract

For multi-cellular organisms to organize tissues, their cells must communicate with each other [...] Full article

14 pages, 890 KiB

Open AccessReview

Fibroblast Growth Factor Receptor (FGFR) Signaling in GIST and Soft Tissue Sarcomas

by Andrea Napolitano, Alexandra E. Ostler, Robin L. Jones and Paul H. Huang

Cells 2021, 10(6), 1533; https://doi.org/10.3390/cells10061533 - 17 Jun 2021

Cited by 13 | Viewed by 3168

Abstract

Sarcomas are a heterogeneous group of rare malignancies originating from mesenchymal tissues with limited therapeutic options. Recently, alterations in components of the fibroblast growth factor receptor (FGFR) signaling pathway have been identified in a range of different sarcoma subtypes, most notably gastrointestinal stromal [...] Read more.

Sarcomas are a heterogeneous group of rare malignancies originating from mesenchymal tissues with limited therapeutic options. Recently, alterations in components of the fibroblast growth factor receptor (FGFR) signaling pathway have been identified in a range of different sarcoma subtypes, most notably gastrointestinal stromal tumors, rhabdomyosarcomas, and liposarcomas. These alterations include genetic events such as translocations, mutations, and amplifications as well as transcriptional overexpression. Targeting FGFR has therefore been proposed as a novel potential therapeutic approach, also in light of the clinical activity shown by multi-target tyrosine kinase inhibitors in specific subtypes of sarcomas. Despite promising preclinical evidence, thus far, clinical trials have enrolled very few sarcoma patients and the efficacy of selective FGFR inhibitors appears relatively low. Here, we review the known alterations of the FGFR pathway in sarcoma patients as well as the preclinical and clinical evidence for the use of FGFR inhibitors in these diseases. Finally, we discuss the possible reasons behind the current clinical data and highlight the need for biomarker stratification to select patients more likely to benefit from FGFR targeted therapies. Full article

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16 pages, 2773 KiB

Open AccessArticle

Efficacy and Selectivity of FGF2-Saporin Cytosolically Delivered by PCI in Cells Overexpressing FGFR1

by Aurora K. Vikan, Michal Kostas, Ellen Margrethe Haugsten, Pål K. Selbo and Jørgen Wesche

Cells 2021, 10(6), 1476; https://doi.org/10.3390/cells10061476 - 12 Jun 2021

Cited by 2 | Viewed by 2484

Abstract

Fibroblast growth factor receptors (FGFRs) have become an attractive target in cancer research and therapy due to their implication in several cancers. Limitations of current treatment options require a need for additional, more specific and potent strategies to overcome cancers driven by FGFRs. [...] Read more.

Fibroblast growth factor receptors (FGFRs) have become an attractive target in cancer research and therapy due to their implication in several cancers. Limitations of current treatment options require a need for additional, more specific and potent strategies to overcome cancers driven by FGFRs. Photochemical internalization (PCI) is a light-controlled method for cytosolic delivery of drugs that are entrapped in endosomes and lysosomes. We here evaluated the efficacy and selectivity of PCI of FGF2-saporin (FGF-SAP) in cells overexpressing FGFR1. FGF-SAP is a conjugate of FGF2 and the highly cytotoxic ribosome-inactivating protein (RIP) saporin, which is used as payload to eliminate cancer cells. Evaluation of the targeting effect of PCI of FGF-SAP was done by comparing the cytotoxic response in osteosarcoma cells with very low levels of FGFR1 (U2OS) to cells overexpressing FGFR1 (U2OS-R1). We demonstrate that PCI greatly enhances cytotoxicity of the drug showing efficient cell killing at pM concentrations of the drug in U2OS-R1 cells. However, U2OS cells were also sensitive to the toxin after PCI. Binding experiments using confocal microscopy and Western blotting techniques indicate that FGF-SAP is taken up by cells through heparan sulfate proteoglycans (HSPGs) in U2OS cells. We further show that the cytotoxicity of FGF-SAP in U2OS cells was reduced when cells were co-treated with heparin to compete out binding to HSPG, demonstrating that the cytotoxic effect was due to internalization by HSPGs. We conclude that to prevent off-target effects of FGF-based toxins, it will be necessary to circumvent binding to HSPGs, for example by mutating the binding site of FGF2 to HSPGs. Full article

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25 pages, 1350 KiB

Open AccessReview

Oncogenic FGFR Fusions Produce Centrosome and Cilia Defects by Ectopic Signaling

by Alexandru Nita, Sara P. Abraham, Pavel Krejci and Michaela Bosakova

Cells 2021, 10(6), 1445; https://doi.org/10.3390/cells10061445 - 09 Jun 2021

Cited by 6 | Viewed by 4064

Abstract

A single primary cilium projects from most vertebrate cells to guide cell fate decisions. A growing list of signaling molecules is found to function through cilia and control ciliogenesis, including the fibroblast growth factor receptors (FGFR). Aberrant FGFR activity produces abnormal cilia with [...] Read more.

A single primary cilium projects from most vertebrate cells to guide cell fate decisions. A growing list of signaling molecules is found to function through cilia and control ciliogenesis, including the fibroblast growth factor receptors (FGFR). Aberrant FGFR activity produces abnormal cilia with deregulated signaling, which contributes to pathogenesis of the FGFR-mediated genetic disorders. FGFR lesions are also found in cancer, raising a possibility of cilia involvement in the neoplastic transformation and tumor progression. Here, we focus on FGFR gene fusions, and discuss the possible mechanisms by which they function as oncogenic drivers. We show that a substantial portion of the FGFR fusion partners are proteins associated with the centrosome cycle, including organization of the mitotic spindle and ciliogenesis. The functions of centrosome proteins are often lost with the gene fusion, leading to haploinsufficiency that induces cilia loss and deregulated cell division. We speculate that this complements the ectopic FGFR activity and drives the FGFR fusion cancers. Full article

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22 pages, 1392 KiB

Open AccessReview

Role of FGF15 in Hepatic Surgery in the Presence of Tumorigenesis: Dr. Jekyll or Mr. Hyde?

by Albert Caballeria-Casals, Marc Micó-Carnero, Carlos Rojano-Alfonso, Cristina Maroto-Serrat, Araní Casillas-Ramírez, Ana I. Álvarez-Mercado, Jordi Gracia-Sancho and Carmen Peralta

Cells 2021, 10(6), 1421; https://doi.org/10.3390/cells10061421 - 07 Jun 2021

Cited by 1 | Viewed by 2942

Abstract

The pro-tumorigenic activity of fibroblast growth factor (FGF) 19 (FGF15 in its rodent orthologue) in hepatocellular carcinoma (HCC), as well as the unsolved problem that ischemia-reperfusion (IR) injury supposes in liver surgeries, are well known. However, it has been shown that FGF15 administration [...] Read more.

The pro-tumorigenic activity of fibroblast growth factor (FGF) 19 (FGF15 in its rodent orthologue) in hepatocellular carcinoma (HCC), as well as the unsolved problem that ischemia-reperfusion (IR) injury supposes in liver surgeries, are well known. However, it has been shown that FGF15 administration protects against liver damage and regenerative failure in liver transplantation (LT) from brain-dead donors without tumor signals, providing a benefit in avoiding IR injury. The protection provided by FGF15/19 is due to its anti-apoptotic and pro-regenerative properties, which make this molecule a potentially beneficial or harmful factor, depending on the disease. In the present review, we describe the preclinical models currently available to understand the signaling pathways responsible for the apparent controversial effects of FGF15/19 in the liver (to repair a damaged liver or to promote tumorigenesis). As well, we study the potential pharmacological use that has the activation or inhibition of FGF15/19 pathways depending on the disease to be treated. We also discuss whether FGF15/19 non-pro-tumorigenic variants, which have been developed for the treatment of liver diseases, might be promising approaches in the surgery of hepatic resections and LT using healthy livers and livers from extended-criteria donors. Full article

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18 pages, 9940 KiB

Open AccessFeature PaperReview

Negative Regulation of FGFR (Fibroblast Growth Factor Receptor) Signaling

by Patrycja Szybowska, Michal Kostas, Jørgen Wesche, Ellen Margrethe Haugsten and Antoni Wiedlocha

Cells 2021, 10(6), 1342; https://doi.org/10.3390/cells10061342 - 28 May 2021

Cited by 28 | Viewed by 4634

Abstract

FGFR (fibroblast growth factor receptor) signaling controls fundamental processes in embryonic, fetal and adult human life. The magnitude, duration, and location of FGFR signaling must be strictly controlled in order to induce the correct biological response. Uncontrolled receptor signaling has been shown to [...] Read more.

FGFR (fibroblast growth factor receptor) signaling controls fundamental processes in embryonic, fetal and adult human life. The magnitude, duration, and location of FGFR signaling must be strictly controlled in order to induce the correct biological response. Uncontrolled receptor signaling has been shown to lead to a variety of diseases, such as skeletal disorders and cancer. Here we review the numerous cellular mechanisms that regulate and turn off FGFR signaling, once the receptor is activated. These mechanisms include endocytosis and endocytic sorting, phosphatase activity, negative regulatory proteins and negative feedback phosphorylation events. The mechanisms act together simultaneously or sequentially, controlling the same or different steps in FGFR signaling. Although more work is needed to fully understand the regulation of FGFR signaling, it is clear that the cells in our body have evolved an extensive repertoire of mechanisms that together keep FGFR signaling tightly controlled and prevent excess FGFR signaling. Full article

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18 pages, 41353 KiB

Open AccessArticle

Effects of FGFR Tyrosine Kinase Inhibition in OLN-93 Oligodendrocytes

by Ranjithkumar Rajendran, Gregor Böttiger, Niklas Dentzien, Vinothkumar Rajendran, Bischand Sharifi, Süleyman Ergün, Christine Stadelmann, Srikanth Karnati and Martin Berghoff

Cells 2021, 10(6), 1318; https://doi.org/10.3390/cells10061318 - 25 May 2021

Cited by 7 | Viewed by 3518

Abstract

Fibroblast growth factor (FGF) signaling is involved in the pathogenesis of multiple sclerosis (MS). Data from neuropathology studies suggest that FGF signaling contributes to the failure of remyelination in MS. In MOG_35–55-induced EAE, oligodendrocyte-specific deletion of FGFR1 and FGFR2 resulted in [...] Read more.

Fibroblast growth factor (FGF) signaling is involved in the pathogenesis of multiple sclerosis (MS). Data from neuropathology studies suggest that FGF signaling contributes to the failure of remyelination in MS. In MOG_35–55-induced EAE, oligodendrocyte-specific deletion of FGFR1 and FGFR2 resulted in a less severe disease course, reduced inflammation, myelin and axon degeneration and changed FGF/FGFR and BDNF/TrkB signaling. Since signaling cascades in oligodendrocytes could not be investigated in the EAE studies, we here aimed to characterize FGFR-dependent oligodendrocyte-specific signaling in vitro. FGFR inhibition was achieved by application of the multi-kinase-inhibitor dovitinib and the FGFR1/2/3-inhibitor AZD4547. Both substances are potent inhibitors of FGF signaling; they are effective in experimental tumor models and patients with malignancies. Effects of FGFR inhibition in oligodendrocytes were studied by immunofluorescence microscopy, protein and gene analyses. Application of the tyrosine kinase inhibitors reduced FGFR1, phosphorylated ERK and Akt expression, and it enhanced BDNF and TrkB expression. Furthermore, the myelin proteins CNPase and PLP were upregulated by FGFR inhibition. In summary, inhibition of FGFR signaling in oligodendrocytes can be achieved by application of tyrosine kinase inhibitors. Decreased phosphorylation of ERK and Akt is associated with an upregulation of BDNF/TrkB signaling, which may be responsible for the increased production of myelin proteins. Furthermore, these data suggest that application of FGFR inhibitors may have the potential to promote remyelination in the CNS. Full article

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Graphical abstract

35 pages, 962 KiB

Open AccessReview

Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling

by Harriet R. Ferguson, Michael P. Smith and Chiara Francavilla

Cells 2021, 10(5), 1201; https://doi.org/10.3390/cells10051201 - 14 May 2021

Cited by 37 | Viewed by 11098

Abstract

Increasing evidence indicates that success of targeted therapies in the treatment of cancer is context-dependent and is influenced by a complex crosstalk between signaling pathways and between cell types in the tumor. The Fibroblast Growth Factor (FGF)/FGF receptor (FGFR) signaling axis highlights the [...] Read more.

Increasing evidence indicates that success of targeted therapies in the treatment of cancer is context-dependent and is influenced by a complex crosstalk between signaling pathways and between cell types in the tumor. The Fibroblast Growth Factor (FGF)/FGF receptor (FGFR) signaling axis highlights the importance of such context-dependent signaling in cancer. Aberrant FGFR signaling has been characterized in almost all cancer types, most commonly non-small cell lung cancer (NSCLC), breast cancer, glioblastoma, prostate cancer and gastrointestinal cancer. This occurs primarily through amplification and over-expression of FGFR1 and FGFR2 resulting in ligand-independent activation. Mutations and translocations of FGFR1-4 are also identified in cancer. Canonical FGF-FGFR signaling is tightly regulated by ligand-receptor combinations as well as direct interactions with the FGFR coreceptors heparan sulfate proteoglycans (HSPGs) and Klotho. Noncanonical FGFR signaling partners have been implicated in differential regulation of FGFR signaling. FGFR directly interacts with cell adhesion molecules (CAMs) and extracellular matrix (ECM) proteins, contributing to invasive and migratory properties of cancer cells, whereas interactions with other receptor tyrosine kinases (RTKs) regulate angiogenic, resistance to therapy, and metastatic potential of cancer cells. The diversity in FGFR signaling partners supports a role for FGFR signaling in cancer, independent of genetic aberration. Full article

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22 pages, 1146 KiB

Open AccessReview

Targeting the Fibroblast Growth Factor Receptor (FGFR) Family in Lung Cancer

by Laura Pacini, Andrew D. Jenks, Nadia Carvalho Lima and Paul H. Huang

Cells 2021, 10(5), 1154; https://doi.org/10.3390/cells10051154 - 10 May 2021

Cited by 22 | Viewed by 9197

Abstract

Lung cancer is the most common cause of cancer-related deaths globally. Genetic alterations, such as amplifications, mutations and translocations in the fibroblast growth factor receptor (FGFR) family have been found in non-small cell lung cancer (NSCLC) where they have a role in cancer [...] Read more.

Lung cancer is the most common cause of cancer-related deaths globally. Genetic alterations, such as amplifications, mutations and translocations in the fibroblast growth factor receptor (FGFR) family have been found in non-small cell lung cancer (NSCLC) where they have a role in cancer initiation and progression. FGFR aberrations have also been identified as key compensatory bypass mechanisms of resistance to targeted therapy against mutant epidermal growth factor receptor (EGFR) and mutant Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) in lung cancer. Targeting FGFR is, therefore, of clinical relevance for this cancer type, and several selective and nonselective FGFR inhibitors have been developed in recent years. Despite promising preclinical data, clinical trials have largely shown low efficacy of these agents in lung cancer patients with FGFR alterations. Preclinical studies have highlighted the emergence of multiple intrinsic and acquired resistance mechanisms to FGFR tyrosine kinase inhibitors, which include on-target FGFR gatekeeper mutations and activation of bypass signalling pathways and alternative receptor tyrosine kinases. Here, we review the landscape of FGFR aberrations in lung cancer and the array of targeted therapies under clinical evaluation. We also discuss the current understanding of the mechanisms of resistance to FGFR-targeting compounds and therapeutic strategies to circumvent resistance. Finally, we highlight our perspectives on the development of new biomarkers for stratification and prediction of FGFR inhibitor response to enable personalisation of treatment in patients with lung cancer. Full article

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15 pages, 2148 KiB

Open AccessReview

FGF/FGFR Pathways in Multiple Sclerosis and in Its Disease Models

by Ranjithkumar Rajendran, Gregor Böttiger, Christine Stadelmann, Srikanth Karnati and Martin Berghoff

Cells 2021, 10(4), 884; https://doi.org/10.3390/cells10040884 - 13 Apr 2021

Cited by 26 | Viewed by 4578

Abstract

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) affecting more than two million people worldwide. In MS, oligodendrocytes and myelin sheaths are destroyed by autoimmune-mediated inflammation, while remyelination is impaired. Recent investigations of post-mortem tissue [...] Read more.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) affecting more than two million people worldwide. In MS, oligodendrocytes and myelin sheaths are destroyed by autoimmune-mediated inflammation, while remyelination is impaired. Recent investigations of post-mortem tissue suggest that Fibroblast growth factor (FGF) signaling may regulate inflammation and myelination in MS. FGF2 expression seems to correlate positively with macrophages/microglia and negatively with myelination; FGF1 was suggested to promote remyelination. In myelin oligodendrocyte glycoprotein (MOG)_35–55-induced experimental autoimmune encephalomyelitis (EAE), systemic deletion of FGF2 suggested that FGF2 may promote remyelination. Specific deletion of FGF receptors (FGFRs) in oligodendrocytes in this EAE model resulted in a decrease of lymphocyte and macrophage/microglia infiltration as well as myelin and axon degeneration. These effects were mediated by ERK/Akt phosphorylation, a brain-derived neurotrophic factor, and downregulation of inhibitors of remyelination. In the first part of this review, the most important pharmacotherapeutic principles for MS will be illustrated, and then we will review recent advances made on FGF signaling in MS. Thus, we will suggest application of FGFR inhibitors, which are currently used in Phase II and III cancer trials, as a therapeutic option to reduce inflammation and induce remyelination in EAE and eventually MS. Full article

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14 pages, 2380 KiB

Open AccessReview

Dissecting FGF Signalling to Target Cellular Crosstalk in Pancreatic Cancer

by Edward P. Carter, Abigail S. Coetzee, Elena Tomas Bort, Qiaoying Wang, Hemant M. Kocher and Richard P. Grose

Cells 2021, 10(4), 847; https://doi.org/10.3390/cells10040847 - 08 Apr 2021

Cited by 16 | Viewed by 3453

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with a 5 year survival rate of less than 8%, and is predicted to become the second leading cause of cancer-related death by 2030. Alongside late detection, which impacts upon surgical treatment, PDAC tumours are [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with a 5 year survival rate of less than 8%, and is predicted to become the second leading cause of cancer-related death by 2030. Alongside late detection, which impacts upon surgical treatment, PDAC tumours are challenging to treat due to their desmoplastic stroma and hypovascular nature, which limits the effectiveness of chemotherapy and radiotherapy. Pancreatic stellate cells (PSCs), which form a key part of this stroma, become activated in response to tumour development, entering into cross-talk with cancer cells to induce tumour cell proliferation and invasion, leading to metastatic spread. We and others have shown that Fibroblast Growth Factor Receptor (FGFR) signalling can play a critical role in the interactions between PDAC cells and the tumour microenvironment, but it is clear that the FGFR signalling pathway is not acting in isolation. Here we describe our current understanding of the mechanisms by which FGFR signalling contributes to PDAC progression, focusing on its interaction with other pathways in signalling networks and discussing the therapeutic approaches that are being developed to try and improve prognosis for this terrible disease. Full article

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20 pages, 628 KiB

Open AccessReview

Crk and CrkL as Therapeutic Targets for Cancer Treatment

by Taeju Park

Cells 2021, 10(4), 739; https://doi.org/10.3390/cells10040739 - 27 Mar 2021

Cited by 23 | Viewed by 3615

Abstract

Crk and CrkL are cellular counterparts of the viral oncoprotein v-Crk. Crk and CrkL are overexpressed in many types of human cancer, correlating with poor prognosis. Furthermore, gene knockdown and knockout of Crk and CrkL in tumor cell lines suppress tumor cell functions, [...] Read more.

Crk and CrkL are cellular counterparts of the viral oncoprotein v-Crk. Crk and CrkL are overexpressed in many types of human cancer, correlating with poor prognosis. Furthermore, gene knockdown and knockout of Crk and CrkL in tumor cell lines suppress tumor cell functions, including cell proliferation, transformation, migration, invasion, epithelial-mesenchymal transition, resistance to chemotherapy drugs, and in vivo tumor growth and metastasis. Conversely, overexpression of tumor cells with Crk or CrkL enhances tumor cell functions. Therefore, Crk and CrkL have been proposed as therapeutic targets for cancer treatment. However, it is unclear whether Crk and CrkL make distinct or overlapping contributions to tumor cell functions in various cancer types because Crk or CrkL have been examined independently in most studies. Two recent studies using colorectal cancer and glioblastoma cells clearly demonstrated that Crk and CrkL need to be ablated individually and combined to understand distinct and overlapping roles of the two proteins in cancer. A comprehensive understanding of individual and overlapping roles of Crk and CrkL in tumor cell functions is necessary to develop effective therapeutic strategies. This review systematically discusses crucial functions of Crk and CrkL in tumor cell functions and provides new perspectives on targeting Crk and CrkL in cancer therapy. Full article

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14 pages, 996 KiB

Open AccessFeature PaperReview

Targeting Aberrant FGFR Signaling to Overcome CDK4/6 Inhibitor Resistance in Breast Cancer

by Navid Sobhani, Anne Fassl, Giuseppina Mondani, Daniele Generali and Tobias Otto

Cells 2021, 10(2), 293; https://doi.org/10.3390/cells10020293 - 01 Feb 2021

Cited by 29 | Viewed by 7359

Abstract

Breast cancer (BC) is the most common cause of cancer-related death in women worldwide. Therapies targeting molecular pathways altered in BC had significantly enhanced treatment options for BC over the last decades, which ultimately improved the lives of millions of women worldwide. Among [...] Read more.

Breast cancer (BC) is the most common cause of cancer-related death in women worldwide. Therapies targeting molecular pathways altered in BC had significantly enhanced treatment options for BC over the last decades, which ultimately improved the lives of millions of women worldwide. Among various molecular pathways accruing substantial interest for the development of targeted therapies are cyclin-dependent kinases (CDKs)—in particular, the two closely related members CDK4 and CDK6. CDK4/6 inhibitors indirectly trigger the dephosphorylation of retinoblastoma tumor suppressor protein by blocking CDK4/6, thereby blocking the cell cycle transition from the G1 to S phase. Although the CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib gained FDA approval for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative BC as they significantly improved progression-free survival (PFS) in randomized clinical trials, regrettably, some patients showed resistance to these therapies. Though multiple molecular pathways could be mechanistically responsible for CDK4/6 inhibitor therapy resistance, one of the most predominant ones seems to be the fibroblast growth factor receptor (FGFR) pathway. FGFRs are involved in many aspects of cancer formation, such as cell proliferation, differentiation, and growth. Importantly, FGFRs are frequently mutated in BC, and their overexpression and/or hyperactivation correlates with CDK4/6 inhibitor resistance and shortened PFS in BC. Intriguingly, the inhibition of aberrant FGFR activity is capable of reversing the resistance to CDK4/6 inhibitors. This review summarizes the molecular background of FGFR signaling and discusses the role of aberrant FGFR signaling during cancer development in general and during the development of CDK4/6 inhibitor resistance in BC in particular, together with other possible mechanisms for resistance to CDK4/6 inhibitors. Subsequently, future directions on novel therapeutic strategies targeting FGFR signaling to overcome such resistance during BC treatment will be further debated. Full article

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2020

Jump to: 2024, 2021

12 pages, 1561 KiB

Open AccessArticle

The Relationship between Leptin, the Leptin Receptor and FGFR1 in Primary Human Breast Tumors

by Wyatt Boothby-Shoemaker, Vanessa Benham, Shreya Paithankar, Rama Shankar, Bin Chen and Jamie J. Bernard

Cells 2020, 9(10), 2224; https://doi.org/10.3390/cells9102224 - 01 Oct 2020

Cited by 11 | Viewed by 2534

Abstract

Obesity is associated with increased breast cancer risk and poorer cancer outcomes; however, the precise etiology of these observations has not been fully identified. Our previous research suggests that adipose tissue-derived fibroblast growth factor-2 (FGF2) promotes the malignant transformation of epithelial cells through [...] Read more.

Obesity is associated with increased breast cancer risk and poorer cancer outcomes; however, the precise etiology of these observations has not been fully identified. Our previous research suggests that adipose tissue-derived fibroblast growth factor-2 (FGF2) promotes the malignant transformation of epithelial cells through the activation of fibroblast growth factor receptor-1 (FGFR1). FGF2 is increased in the context of obesity, and increased sera levels have been associated with endocrine-resistant breast cancer. Leptin is a marker of obesity and promotes breast carcinogenesis through several mechanisms. In this study, we leverage public gene expression datasets to evaluate the associations between FGFR1, leptin, and the leptin receptor (LepR) in breast cancer. We show a positive association between FGFR1 and leptin protein copy number in primary breast tumors. These observations coincided with a positive association between Janus kinase 2 (Jak2) mRNA with both leptin receptor (LepR) mRNA and FGFR1 mRNA. Moreover, two separate Jak2 inhibitors attenuated both leptin+FGF2-stimulated and mouse adipose tissue-stimulated MCF-10A transformation. These results demonstrate how elevated sera FGF2 and leptin in obese patients may promote cancer progression in tumors that express elevated FGFR1 and LepR through Jak2 signaling. Therefore, Jak2 is a potential therapeutic target for FGFR1 amplified breast cancer, especially in the context of obesity. Full article

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