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FGF/FGFR Signaling Pathway in Development and Human Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 33045

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Prof. Dr. Roberto Ronca

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Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
Interests: tumor microenvironment; angiogenesis; endothelial cells; FGF/FGFR system; growth factors; cancer therapy

Special Issue Information

Dear Colleagues,

Due to their pleiotropic nature, FGFs and FGFRs play important roles in different physiological and pathological settings, and contribute to cancer progression not only by triggering a pro-angiogenic response but also by acting directly on tumor cells via paracrine and autocrine loops of stimulation. Recently, new roles have been attributed to the FGF/FGFR system in the complex cross-talk existing among different cell populations that are present in the tumor microenvironment. Moreover, FGF/FGFR signaling has been associated with other cancer hallmarks such as stemness, invasiveness, metabolic rewiring, and resistance to therapies.

Even though the characterization of the biological function of the FGF/FGFR system in cancer is proceeding, its diagnostic and therapeutic exploitation is ongoing in preclinical and clinical studies with some promising and other contradictory results.

In an attempt to add new hints and make a “state of the art” point, this Special Issue “FGF/FGFR Signaling Pathway in Development and Human Diseases” will cover a selection of recent research topics and current review articles in the field of FGF/FGFR biology applied to development and diseases research.

Prof. Dr. Roberto Ronca
Guest Editor

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Keywords

FGFs and FGFRs in cancer biology
Tumor microenvironment
Cancer therapy
Target therapy
Resistance and recurrence
Angiogenesis and metabolism
Invasiveness, metastasis, and EMT
Stemness and cancer stem cells
Cancer diagnosis and prognosis
FGF/FGFR signaling

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Published Papers (7 papers)

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Research

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12 pages, 3158 KiB

Open AccessArticle

Inhibition of the FGF/FGFR System Induces Apoptosis in Lung Cancer Cells via c-Myc Downregulation and Oxidative Stress

by Arianna Giacomini, Sara Taranto, Sara Rezzola, Sara Matarazzo, Elisabetta Grillo, Mattia Bugatti, Alessia Scotuzzi, Jessica Guerra, Martina Di Trani, Marco Presta and Roberto Ronca

Int. J. Mol. Sci. 2020, 21(24), 9376; https://doi.org/10.3390/ijms21249376 - 9 Dec 2020

Cited by 24 | Viewed by 2904

Abstract

Lung cancer represents an extremely diffused neoplastic disorder with different histological/molecular features. Among the different lung tumors, non-small-cell lung cancer (NSCLC) is the most represented histotype, characterized by various molecular markers, including the expression/overexpression of the fibroblast growth factor receptor-1 (FGFR1). Thus, FGF/FGFR blockade by tyrosine kinase inhibitors (TKi) or FGF-ligand inhibitors may represent a promising therapeutic approach in lung cancers. In this study we demonstrate the potential therapeutic benefit of targeting the FGF/FGFR system in FGF-dependent lung tumor cells using FGF trapping (NSC12) or TKi (erdafitinib) approaches. The results show that inhibition of FGF/FGFR by NSC12 or erdafitinib induces apoptosis in FGF-dependent human squamous cell carcinoma NCI-H1581 and NCI-H520 cells. Induction of oxidative stress is the main mechanism responsible for the therapeutic/pro-apoptotic effect exerted by both NSC12 and erdafitinib, with apoptosis being abolished by antioxidant treatments. Finally, reduction of c-Myc protein levels appears to strictly determine the onset of oxidative stress and the therapeutic response to FGF/FGFR inhibition, indicating c-Myc as a key downstream effector of FGF/FGFR signaling in FGF-dependent lung cancers. Full article

(This article belongs to the Special Issue FGF/FGFR Signaling Pathway in Development and Human Diseases)

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12 pages, 1859 KiB

Open AccessArticle

Cell Density-Dependent Fibroblast Growth Factor-2 Signaling Regulates Syndecan-4 Expression in Cultured Vascular Endothelial Cells

by Takato Hara, Shiori Yabushita, Chika Yamamoto and Toshiyuki Kaji

Int. J. Mol. Sci. 2020, 21(10), 3698; https://doi.org/10.3390/ijms21103698 (registering DOI) - 24 May 2020

Cited by 11 | Viewed by 2802

Abstract

Syndecan-4 is a member of the syndecan family of transmembrane heparan sulfate proteoglycans, and is involved in cell protection, proliferation, and the blood coagulation-fibrinolytic system in vascular endothelial cells. Heparan sulfate chains enable fibroblast growth factor-2 (FGF-2) to form a complex with its receptor and to transduce the cell growth signal. In the present study, bovine aortic endothelial cells were cultured, and the intracellular signal pathways that mediate the regulation of syndecan-4 expression in dense and sparse cultures by FGF-2 were analyzed. We demonstrated the cell density-dependent differential regulation of syndecan-4 expression. Specifically, we found that FGF-2 upregulated the synthesis of syndecan-4 in vascular endothelial cells via the MEK1/2-ERK1/2 pathway in dense cell cultures, with only a transcriptional induction of syndecan-4 at a low cell density via the Akt pathway. This study highlights a critical mechanism underlying the regulation of endothelial cell functions by proteoglycans. Full article

(This article belongs to the Special Issue FGF/FGFR Signaling Pathway in Development and Human Diseases)

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15 pages, 3034 KiB

Open AccessArticle

Targeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations

by Nadia Carvalho Lima, Eliza Atkinson, Tom D. Bunney, Matilda Katan and Paul H. Huang

Int. J. Mol. Sci. 2020, 21(9), 3214; https://doi.org/10.3390/ijms21093214 - 1 May 2020

Cited by 12 | Viewed by 4416

Abstract

Selective FGFR inhibitors such as infigratinib (BGJ398) and erdafitinib (JNJ-42756493) have been evaluated in clinical trials for cancers with FGFR3 molecular alterations, particularly in urothelial carcinoma patients. However, a substantial proportion of these patients (up to 50%) display intrinsic resistance to these drugs and receive minimal clinical benefit. There is thus an unmet need for alternative therapeutic strategies to overcome primary resistance to selective FGFR inhibitors. In this study, we demonstrate that cells expressing cancer-associated activating FGFR3 mutants and the FGFR3-TACC3 fusion showed primary resistance to infigratinib in long-term colony formation assays in both NIH-3T3 and urothelial carcinoma models. We find that expression of these FGFR3 molecular alterations resulted in elevated constitutive Src activation compared to wildtype FGFR3 and that cells co-opted this pathway as a means to achieve intrinsic resistance to infigratinib. Targeting the Src pathway with low doses of the kinase inhibitor dasatinib synergistically sensitized multiple urothelial carcinoma lines harbouring endogenous FGFR3 alterations to infigratinib. Our data provide preclinical rationale that supports the use of dasatinib in combination with selective FGFR inhibitors as a means to overcome intrinsic drug resistance in the salvage therapy setting in urothelial cancer patients with FGFR3 molecular alterations Full article

(This article belongs to the Special Issue FGF/FGFR Signaling Pathway in Development and Human Diseases)

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14 pages, 3127 KiB

Open AccessArticle

PTX3 Modulates Neovascularization and Immune Inflammatory Infiltrate in a Murine Model of Fibrosarcoma

by Tiziana Annese, Roberto Ronca, Roberto Tamma, Arianna Giacomini, Simona Ruggieri, Elisabetta Grillo, Marco Presta and Domenico Ribatti

Int. J. Mol. Sci. 2019, 20(18), 4599; https://doi.org/10.3390/ijms20184599 - 17 Sep 2019

Cited by 15 | Viewed by 2593

Abstract

Fibrosarcoma is an aggressive subtype of soft tissue sarcoma categorized in infantile/congenital-type and adult-type. Fibrosarcoma cells and its surrounding immune inflammatory infiltrates overexpress or induce the expression of fibroblast growth factor-2 (FGF-2) that have a crucial role in tumor progression and angiogenesis. The inflammation-associated long pentraxin 3 (PTX3) was found to reduce FGF-2-mediated angiogenesis, but its role on fibrosarcoma immune inflammatory infiltrate is still unknown. In this study, we have evaluated the PTX3 activity on immune infiltrating mast cells, macrophages and T-lymphocytes by immunohistochemistry on murine MC-TGS17-51 fibrosarcoma cells and on transgenic TgN(Tie2-hPTX3) mouse. In these fibrosarcoma models we found a reduced neovascularization and a significant decrease of inflammatory infiltrate. Indeed, we show that PTX3 reduces the level of complement 3 (C3) deposition reducing fibrosarcoma progression. In conclusion, we hypothesize that targeting fibrosarcoma microenvironment by FGF/FGFR inhibitors may improve treatment outcome. Full article

(This article belongs to the Special Issue FGF/FGFR Signaling Pathway in Development and Human Diseases)

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Review

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18 pages, 544 KiB

Open AccessReview

FGFR Fusions in Cancer: From Diagnostic Approaches to Therapeutic Intervention

by Antonella De Luca, Riziero Esposito Abate, Anna Maria Rachiglio, Monica Rosaria Maiello, Claudia Esposito, Clorinda Schettino, Francesco Izzo, Guglielmo Nasti and Nicola Normanno

Int. J. Mol. Sci. 2020, 21(18), 6856; https://doi.org/10.3390/ijms21186856 - 18 Sep 2020

Cited by 83 | Viewed by 6737

Abstract

Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors involved in many biological processes. Deregulated FGFR signaling plays an important role in tumor development and progression in different cancer types. FGFR genomic alterations, including FGFR gene fusions that originate by chromosomal rearrangements, represent a promising therapeutic target. Next-generation-sequencing (NGS) approaches have significantly improved the discovery of FGFR gene fusions and their detection in clinical samples. A variety of FGFR inhibitors have been developed, and several studies are trying to evaluate the efficacy of these agents in molecularly selected patients carrying FGFR genomic alterations. In this review, we describe the most frequent FGFR aberrations in human cancer. We also discuss the different approaches employed for the detection of FGFR fusions and the potential role of these genomic alterations as prognostic/predictive biomarkers. Full article

(This article belongs to the Special Issue FGF/FGFR Signaling Pathway in Development and Human Diseases)

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14 pages, 1586 KiB

Open AccessReview

The Emerging Role of the FGF/FGFR Pathway in Gastrointestinal Stromal Tumor

by Annalisa Astolfi, Maria Abbondanza Pantaleo, Valentina Indio, Milena Urbini and Margherita Nannini

Int. J. Mol. Sci. 2020, 21(9), 3313; https://doi.org/10.3390/ijms21093313 - 7 May 2020

Cited by 23 | Viewed by 7323

Abstract

Gastrointestinal stromal tumors (GIST) are rare neoplasms of mesenchymal origin arising in the gastrointestinal tract. The vast majority are characterized by mutually exclusive activating mutations in KIT or Platelet-derived growth factor alpha (PDGFRA) receptors, or less frequently by succinate dehydrogenase complex (SDH) or NF1 inactivation, with very rare cases harboring mutant BRAF or RAS alleles. Approximately 5% of GISTs lack any of such mutations and are called quadruple wild-type (WT) GISTs. Recently, deregulated Fibroblast Growth Factor (FGF)/FGF-receptor (FGFR) signaling emerged as a relevant pathway driving oncogenic activity in different molecular subgroups of GISTs. This review summarizes all the current evidences supporting the key role of the FGF/FGFR pathway activation in GISTs, whereby either activating mutations, oncogenic gene fusions, or autocrine/paracrine signaling have been detected in quadruple WT, SDH-deficient, or KIT-mutant GISTs. Full article

(This article belongs to the Special Issue FGF/FGFR Signaling Pathway in Development and Human Diseases)

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16 pages, 1103 KiB

Open AccessReview

The Fibroblast Growth Factor Receptors in Breast Cancer: from Oncogenesis to Better Treatments

by Navid Sobhani, Chunmei Fan, Pedro O. Flores-Villanueva, Daniele Generali and Yong Li

Int. J. Mol. Sci. 2020, 21(6), 2011; https://doi.org/10.3390/ijms21062011 - 16 Mar 2020

Cited by 42 | Viewed by 5643

Abstract

Breast cancer (BC) is the most frequent form of malignancy and second only to lung cancer as cause of deaths in women. Notwithstanding many progresses made in the field, metastatic BC has a very poor prognosis. As therapies are becoming more personalized to meet the needs of patients, a better knowledge of the molecular biology leading to the disease unfolds the possibility to project more precise compounds or antibodies targeting definite alteration at the molecular level and functioning on such cancer-causing molecules expressed in cancer cells of patients, or present as antigens on the surface of cancer cell membranes. Fibroblast growth factor receptor (FGFR) is one of such druggable targets, activated by its own ligands -namely the Fibroblast Growth Factors (FGFs). This pathway provides a vast range of interesting molecular targets pursued at different levels of clinical investigation. Herein we provide an update on the knowledge of genetic alterations of the receptors in breast cancer, their role in tumorigenesis and the most recent drugs against this particular receptor for the treatment of the disease. Full article

(This article belongs to the Special Issue FGF/FGFR Signaling Pathway in Development and Human Diseases)

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