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Iliev P, McCutcheon C, Admas TH, Reithmeier A, Lopez McDonald M, van Outryve A, Hanke D, Brown JI, Haraldsson M, Toillon RA, Frank DA, Page BDG. Challenging the "Undruggable"─Targeting STAT3 but Identifying Potent TrkA-Targeted Inhibitors. J Med Chem 2025; 68:9501-9524. [PMID: 40245441 DOI: 10.1021/acs.jmedchem.5c00214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/19/2025]
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a promising yet challenging anticancer drug target due to its complex signaling and limited "druggability". To this end, we herein highlight a target engagement-focused screening and optimization pipeline pursuing the discovery of novel STAT3 inhibitors. From a STAT3 differential scanning fluorimetry high-throughput screen, we identified compounds that appeared to stabilize STAT3 toward thermal aggregation and moderately inhibited cellular STAT3 activity. Subsequent evaluation using complementary and orthogonal assays revealed their high affinity for tropomyosin receptor kinase A (TrkA). Applying a similar target engagement-inspired approach, we refined inhibitor binding and selectivity toward TrkA, showing efficacy in cellular TrkA cancer models. Top compound, PI-15, demonstrated successful target engagement in a cellular thermal shift assay and potently inhibited TrkA activity in cancer cells. These approaches highlight the importance of prioritizing rigorous target engagement validation early in the drug discovery pipeline, resulting in promising new inhibitors.
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Affiliation(s)
- Petar Iliev
- Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver V6T 1Z3, Canada
| | - Conall McCutcheon
- Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver V6T 1Z3, Canada
| | - Tizita H Admas
- Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver V6T 1Z3, Canada
| | - Anja Reithmeier
- Chemical Biology Consortium Sweden, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-171 77, Sweden
| | - Melanie Lopez McDonald
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, United States
| | - Alexandre van Outryve
- CNRS, Inserm, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, Univ. Lille, Lille F-59000, France
| | - Danielle Hanke
- Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver V6T 1Z3, Canada
| | - Jennifer I Brown
- Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver V6T 1Z3, Canada
| | - Martin Haraldsson
- Chemical Biology Consortium Sweden, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-171 77, Sweden
| | - Robert-Alain Toillon
- CNRS, Inserm, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, Univ. Lille, Lille F-59000, France
| | - David A Frank
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, United States
| | - Brent D G Page
- Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver V6T 1Z3, Canada
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Panchal I, Tripathi RKP, Yadav MR, Valera M, Parmar K. Design, Synthesis, Biological and in silico Evaluation of Novel Indazole-pyridine Hybrids for the Treatment of Breast Cancer. Curr Comput Aided Drug Des 2025; 21:211-225. [PMID: 39108123 DOI: 10.2174/0115734099308839240724100224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 06/12/2024] [Accepted: 06/13/2024] [Indexed: 01/03/2025]
Abstract
INTRODUCTION The prevalence of breast cancer presents a substantial global health concern, underscoring the ongoing need for the development of inventive therapeutic remedies. METHODS In this investigation, an array of novel indazole-pyridine hybrids (5a-h) have been designed and synthesized to assess their potential as candidates for treating breast cancer. Subsequently, we have conducted biological evaluations to determine their cytotoxic effects on the human MCF-7 breast cancer cell line. Furthermore, in silico analysis was conducted to estimate the inhibition potential of the compounds against TrkA (Tropomyosin receptor kinase A), a specific molecular target associated with breast cancer, through molecular docking. In silico physicochemical and pharmacokinetic predictions were made to assess the compounds' drug-like properties. RESULTS Compound 5a emerged as the most active compound among the others with GI50 < 10 μg/ml. Besides, compound 5a showed high binding energy (BE -10.7 kcal/mol) against TrkA and was stabilized within the TrkA binding pocket through hydrophobic, H-bonding, and van der Waals interactions. In silico physicochemical and pharmacokinetic prediction studies indicated that compound 5a obeyed both Lipinski's and Veber's rule and displayed a versatile pharmacokinetic profile, implying compound 5a to appear as a viable candidate and that it could be further refined to develop therapeutic agents for potentially treating breast cancer. CONCLUSION This study offers a promising direction for the advancement of innovative breast cancer treatments, highlighting the effectiveness of indazole-pyridine hybrids as potential anticancer agents. Further optimization and preclinical development are necessary to advance these compounds to clinical trials.
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Affiliation(s)
- Ishan Panchal
- Department of Pharmaceutical Chemistry, Parul Institute of Pharmacy, Parul University, Vadodara, Gujarat, 391760, India
- Department of Pharmaceutical Chemistry, Arihant School of Pharmacy and Bio-Research Institute, Gandhinagar, Gujarat, 382421, India
| | - Rati Kailash Prasad Tripathi
- Department of Pharmaceutical Sciences, Sushruta School of Medical and Paramedical Sciences, Assam University (A Central University), Silchar, Assam, 788011, India
| | - Mange Ram Yadav
- Director (R & D), Research and Development Cell, Parul University, Vadodara, Gujarat, 391760, India
| | - Meet Valera
- Department of Pharmaceutical Chemistry, Parul Institute of Pharmacy, Parul University, Vadodara, Gujarat, 391760, India
| | - Kinjal Parmar
- Department of Quality Assurance, Parul Institute of Pharmacy & Research, Parul University, Vadodara, Gujarat, 391760, India
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Kashyap D, Salman H. Targeting Interleukin-13 Receptor α2 and EphA2 in Aggressive Breast Cancer Subtypes with Special References to Chimeric Antigen Receptor T-Cell Therapy. Int J Mol Sci 2024; 25:3780. [PMID: 38612592 PMCID: PMC11011362 DOI: 10.3390/ijms25073780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 03/24/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Breast cancer (BCA) remains the leading cause of cancer-related mortality among women worldwide. This review delves into the therapeutic challenges of BCA, emphasizing the roles of interleukin-13 receptor α2 (IL-13Rα2) and erythropoietin-producing hepatocellular receptor A2 (EphA2) in tumor progression and resistance. Highlighting their overexpression in BCA, particularly in aggressive subtypes, such as Her-2-enriched and triple-negative breast cancer (TNBC), we discuss the potential of these receptors as targets for chimeric antigen receptor T-cell (CAR-T) therapies. We examine the structural and functional roles of IL-13Rα2 and EphA2, their pathological significance in BCA, and the promising therapeutic avenues their targeting presents. With an in-depth analysis of current immunotherapeutic strategies, including the limitations of existing treatments and the potential of dual antigen-targeting CAR T-cell therapies, this review aims to summarize potential future novel, more effective therapeutic interventions for BCA. Through a thorough examination of preclinical and clinical studies, it underlines the urgent need for targeted therapies in combating the high mortality rates associated with Her-2-enriched and TNBC subtypes and discusses the potential role of IL-13Rα2 and EphA2 as promising candidates for the development of CAR T-cell therapies.
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Affiliation(s)
| | - Huda Salman
- Brown Center for Immunotherapy, Melvin and Bren Simon Comprehensive Cancer Center, Division of Hematology and Oncology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA;
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Cicero J, Trouvilliez S, Palma M, Ternier G, Decoster L, Happernegg E, Barois N, Van Outryve A, Dehouck L, Bourette RP, Adriaenssens E, Lagadec C, Tarhan CM, Collard D, Souguir Z, Vandenhaute E, Maubon G, Sipieter F, Borghi N, Shimizu F, Kanda T, Giacobini P, Gosselet F, Maubon N, Le Bourhis X, Van Seuningen I, Mysiorek C, Toillon RA. ProNGF promotes brain metastasis through TrkA/EphA2 induced Src activation in triple negative breast cancer cells. Exp Hematol Oncol 2023; 12:104. [PMID: 38072918 PMCID: PMC10710730 DOI: 10.1186/s40164-023-00463-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 11/29/2023] [Indexed: 10/16/2024] Open
Abstract
BACKGROUND Triple-Negative Breast Cancer is particularly aggressive, and its metastasis to the brain has a significant psychological impact on patients' quality of life, in addition to reducing survival. The development of brain metastases is particularly harmful in triple-negative breast cancer (TNBC). To date, the mechanisms that induce brain metastasis in TNBC are poorly understood. METHODS Using a human blood-brain barrier (BBB) in vitro model, an in vitro 3D organotypic extracellular matrix, an ex vivo mouse brain slices co-culture and in an in vivo xenograft experiment, key step of brain metastasis were recapitulated to study TNBC behaviors. RESULTS In this study, we demonstrated for the first time the involvement of the precursor of Nerve Growth Factor (proNGF) in the development of brain metastasis. More importantly, our results showed that proNGF acts through TrkA independent of its phosphorylation to induce brain metastasis in TNBC. In addition, we found that proNGF induces BBB transmigration through the TrkA/EphA2 signaling complex. More importantly, our results showed that combinatorial inhibition of TrkA and EphA2 decreased TBNC brain metastasis in a preclinical model. CONCLUSIONS These disruptive findings provide new insights into the mechanisms underlying brain metastasis with proNGF as a driver of brain metastasis of TNBC and identify TrkA/EphA2 complex as a potential therapeutic target.
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Affiliation(s)
- Julien Cicero
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
- Laboratoire de La Barrière Hémato-Encéphalique (LBHE), University of Artois, UR 2465, F-62300, Lens, France
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France
| | - Sarah Trouvilliez
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France
| | - Martine Palma
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France
| | - Gaetan Ternier
- UMR-S1172, University of Lille, Inserm, CHU Lille, Équipe Développement et Plasticité du cerveau neuroendocrine, Lille Neuroscience et Cognition, 1 Place de Verdun, 59000, Lille Cedex, France
| | - Laurine Decoster
- UMR-S1172, University of Lille, Inserm, CHU Lille, Équipe Développement et Plasticité du cerveau neuroendocrine, Lille Neuroscience et Cognition, 1 Place de Verdun, 59000, Lille Cedex, France
| | - Eloise Happernegg
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
- Laboratoire de La Barrière Hémato-Encéphalique (LBHE), University of Artois, UR 2465, F-62300, Lens, France
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France
| | - Nicolas Barois
- University of Lille, CNRS, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, 59000, Lille, Inserm, France
| | - Alexandre Van Outryve
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France
- UMR 8520 -IEMN - Institut d'Electronique de Microélectronique et de Nanotechnologie, University of Lille, CNRS, Centrale Lille, Junia, University Polytechnique Hauts-de-France, 59000, Lille, France
| | - Lucie Dehouck
- Laboratoire de La Barrière Hémato-Encéphalique (LBHE), University of Artois, UR 2465, F-62300, Lens, France
| | - Roland P Bourette
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
| | - Eric Adriaenssens
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
| | - Chann Lagadec
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France
| | - Cagatay Mehmet Tarhan
- UMR 8520 -IEMN - Institut d'Electronique de Microélectronique et de Nanotechnologie, University of Lille, CNRS, Centrale Lille, Junia, University Polytechnique Hauts-de-France, 59000, Lille, France
- LIMMS/CNRS-IIS IRL2820, The University of Tokyo, Tokyo, Japan
| | - Dominique Collard
- LIMMS/CNRS-IIS IRL2820, The University of Tokyo, Tokyo, Japan
- CNRS, IIS, University of Lille SMMiL-E Project, 59000, Lille, COL, France
| | | | | | | | - François Sipieter
- Université Paris Cité, Centre National de La Recherche Scientifique (CNRS), Institut Jacques Monod, 15 rue Hélène Brion, 75013, Paris, France
| | - Nicolas Borghi
- Université Paris Cité, Centre National de La Recherche Scientifique (CNRS), Institut Jacques Monod, 15 rue Hélène Brion, 75013, Paris, France
| | - Fumitaka Shimizu
- Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Takashi Kanda
- Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Paolo Giacobini
- UMR-S1172, University of Lille, Inserm, CHU Lille, Équipe Développement et Plasticité du cerveau neuroendocrine, Lille Neuroscience et Cognition, 1 Place de Verdun, 59000, Lille Cedex, France
| | - Fabien Gosselet
- Laboratoire de La Barrière Hémato-Encéphalique (LBHE), University of Artois, UR 2465, F-62300, Lens, France
| | | | - Xuefen Le Bourhis
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
| | - Isabelle Van Seuningen
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
| | - Caroline Mysiorek
- Laboratoire de La Barrière Hémato-Encéphalique (LBHE), University of Artois, UR 2465, F-62300, Lens, France
| | - Robert-Alain Toillon
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France.
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France.
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Morisse M, Bourhis T, Lévêque R, Guilbert M, Cicero J, Palma M, Chevalier D, le Bourhis X, Toillon RA, Mouawad F. Influence of EGF and pro-NGF on EGFR/SORTILIN interaction and clinical impact in head and neck squamous cell carcinoma. Front Oncol 2023; 13:661775. [PMID: 37576898 PMCID: PMC10416107 DOI: 10.3389/fonc.2023.661775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 07/12/2023] [Indexed: 08/15/2023] Open
Abstract
Head and Neck Squamous Cell Carcinoma (HNSCC) remains a cancer with a poor prognosis, with a 5-year survival rate of less than 50%. Although epidermal growth factor receptor (EGFR) is almost always overexpressed, targeted anti-EGFR therapies have modest efficacy and are mainly used in palliative care. Growth factors such as Nerve Growth Factor (NGF) and its precursor proNGF have been shown in our laboratory to play a role in tumor growth and aggressiveness. Interestingly, an interaction between Sortilin, a proNGF receptor, and EGFR has been observed. This interaction appears to interfere with the pro-oncogenic signaling of EGF and modulate the membrane expression of EGFR. The aim of this study was to characterize this interaction biologically, to assess its impact on clinical prognosis and to analyze its role in the cellular trafficking of EGFR. Using immunohistochemical staining on tumor sections from patients treated at our university center and PLA (Proximity Ligation Assay) labeling, we showed that Sortilin expression is significantly associated with reduced 5-year survival. However, when Sortilin was associated with EGFR, this association was not found. Using the Cal-27 and Cal-33 cancer cell lines, we observed that proNGF reduces the effects of EGF on cell growth by inducing the internalization of its receptor. These results therefore suggest a regulatory role for Sortilin in the degradation or renewal of EGFR on the membrane. It would be interesting in future work to show the intracellular fate of EGFR and the role of (pro)neurotrophins in these mechanisms.
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Affiliation(s)
- Martin Morisse
- Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital Center (CHU) de Lille, University of Lille, Lille, France
- Univ. Lille, Inserm, University Hospital Center (CHU) Lille, UMR9020-U1277 - CANTHER – Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
| | - Thomas Bourhis
- Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital Center (CHU) de Lille, University of Lille, Lille, France
- Univ. Lille, Inserm, University Hospital Center (CHU) Lille, UMR9020-U1277 - CANTHER – Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
| | - Romain Lévêque
- Univ. Lille, Inserm, University Hospital Center (CHU) Lille, UMR9020-U1277 - CANTHER – Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
| | - Mathieu Guilbert
- Univ. Lille, Inserm, University Hospital Center (CHU) Lille, UMR9020-U1277 - CANTHER – Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
| | - Julien Cicero
- Univ. Lille, Inserm, University Hospital Center (CHU) Lille, UMR9020-U1277 - CANTHER – Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
| | - Martine Palma
- Univ. Lille, Inserm, University Hospital Center (CHU) Lille, UMR9020-U1277 - CANTHER – Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
| | - Dominique Chevalier
- Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital Center (CHU) de Lille, University of Lille, Lille, France
- Univ. Lille, Inserm, University Hospital Center (CHU) Lille, UMR9020-U1277 - CANTHER – Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
| | - Xuefen le Bourhis
- Univ. Lille, Inserm, University Hospital Center (CHU) Lille, UMR9020-U1277 - CANTHER – Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
| | - Robert-Alain Toillon
- Univ. Lille, Inserm, University Hospital Center (CHU) Lille, UMR9020-U1277 - CANTHER – Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
| | - Francois Mouawad
- Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital Center (CHU) de Lille, University of Lille, Lille, France
- Univ. Lille, Inserm, University Hospital Center (CHU) Lille, UMR9020-U1277 - CANTHER – Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
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Pourzand P, Tabasi F, Fayazbakhsh F, Sarhadi S, Bahari G, Mohammadi M, Jomepour S, Nafeli M, Mosayebi F, Heravi M, Taheri M, Hashemi M, Ghavami S. The Reticulon-4 3-bp Deletion/Insertion Polymorphism Is Associated with Structural mRNA Changes and the Risk of Breast Cancer: A Population-Based Case-Control Study with Bioinformatics Analysis. Life (Basel) 2023; 13:1549. [PMID: 37511924 PMCID: PMC10381770 DOI: 10.3390/life13071549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/08/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Breast cancer (BC) is a complex disease caused by molecular events that disrupt cellular survival and death. Discovering novel biomarkers is still required to better understand and treat BC. The reticulon-4 (RTN4) gene, encoding Nogo proteins, plays a critical role in apoptosis and cancer development, with genetic variations affecting its function. We investigated the rs34917480 in RTN4 and its association with BC risk in an Iranian population sample. We also predicted the rs34917480 effect on RTN4 mRNA structure and explored the RTN4's protein-protein interaction network (PPIN) and related pathways. In this case-control study, 437 women (212 BC and 225 healthy) were recruited. The rs34917480 was genotyped using AS-PCR, mRNA secondary structure was predicted with RNAfold, and PPIN was constructed using the STRING database. Our findings revealed that this variant was associated with a decreased risk of BC in heterozygous (p = 0.012), dominant (p = 0.015), over-dominant (p = 0.017), and allelic (p = 0.035) models. Our prediction model showed that this variant could modify RTN4's mRNA thermodynamics and potentially its translation. RTN4's PPIN also revealed a strong association with apoptosis regulation and key signaling pathways highly implicated in BC. Consequently, our findings, for the first time, demonstrate that rs34917480 could be a protective factor against BC in our cohort, probably via preceding mechanisms.
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Affiliation(s)
- Pouria Pourzand
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran
| | - Farhad Tabasi
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 1411713116, Iran
| | - Fariba Fayazbakhsh
- School of Medicine, Zahedan University of Medical Science, Zahedan 9816743463, Iran
| | - Shamim Sarhadi
- Faculty of Advanced Medical Sciences, Department of Medical Biotechnology, Tabriz University of Medical Sciences, Tabriz 5166616471, Iran
| | - Gholamreza Bahari
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran
- Children and Adolescent Health Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran
| | - Mohsen Mohammadi
- School of Medicine, Zahedan University of Medical Science, Zahedan 9816743463, Iran
| | - Sahar Jomepour
- Department of Cardiology, Cardiovascular Research Center, School of Medicine, Hormozgan University of Medical Science, Bandar Abbas 7916613885, Iran
| | - Mohammad Nafeli
- School of Medicine, Zahedan University of Medical Science, Zahedan 9816743463, Iran
| | - Fatemeh Mosayebi
- Tehran Heart Center, Tehran University of Medical Science, Tehran 1416634793, Iran
| | - Mehrdad Heravi
- School of Medicine, Zahedan University of Medical Science, Zahedan 9816743463, Iran
| | - Mohsen Taheri
- Genetics of Non-Communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran
- Department of Genetics, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran
| | - Mohammad Hashemi
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran
- Genetics of Non-Communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran
| | - Saeid Ghavami
- Research Institute of Oncology and Hematology, Cancer Care Manitoba-University of Manitoba, Winnipeg, MB R3E 0V9, Canada
- Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
- Faculty of Medicine in Zabrze, University of Technology in Katowice, 41-800 Zabrze, Poland
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
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ProNGF Expression and Targeting in Glioblastoma Multiforme. Int J Mol Sci 2023; 24:ijms24021616. [PMID: 36675126 PMCID: PMC9863529 DOI: 10.3390/ijms24021616] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 01/03/2023] [Accepted: 01/06/2023] [Indexed: 01/14/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most lethal adult brain cancer. Temozolomide (TMZ), the standard chemotherapeutic drug used in GBM, has limited benefit and alternate therapies are needed to improve GBM treatment. Nerve growth factor (NGF) and its precursor proNGF are increasingly recognized as stimulators of human tumor progression. The expression and stimulatory effect of NGF on GBM cell growth has previously been reported, but the status of proNGF in GBM is unreported. In this study, we have investigated proNGF expression and biological activity in GBM. A clinical cohort of GBM (n = 72) and low-grade glioma (n = 20) was analyzed by immunohistochemistry for proNGF and digital quantification. ProNGF expression was significantly increased in GBM compared to low grade gliomas and proNGF was also detected in patient plasma samples. ProNGF was also detected in most GBM cell lines by Western blotting. Although anti-proNGF blocking antibodies inhibited cell growth in GBM cells with methylated MGMT gene promoter, targeting proNGF could not potentiate the efficacy of TMZ. In subcutaneous xenograft of human GBM cells, anti-proNGF antibodies slightly reduced tumor volume but had no impact on TMZ efficacy. In conclusion, this data reveals that proNGF is overexpressed in GBM and can stimulate cancer cell growth. The potential of proNGF as a clinical biomarker and therapeutic target warrants further investigations.
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8
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Expression and Signaling Pathways of Nerve Growth Factor (NGF) and Pro-NGF in Breast Cancer: A Systematic Review. Curr Oncol 2022; 29:8103-8120. [PMID: 36354700 PMCID: PMC9689427 DOI: 10.3390/curroncol29110640] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/19/2022] [Accepted: 10/25/2022] [Indexed: 11/07/2022] Open
Abstract
Breast cancer represents the most common type of cancer and is the leading cause of death due to cancer among women. Thus, the prevention and early diagnosis of breast cancer is of primary urgency, as well as the development of new treatments able to improve its prognosis. Nerve Growth Factor (NGF) is a neurotrophic factor involved in the regulation of neuronal functions through the binding of the Tropomyosin receptor kinase A (TrkA) and the Nerve Growth Factor receptor or Pan-Neurotrophin Receptor 75 (NGFR/p75NTR). In addition, its precursor (pro-NGF) can extert biological activity by forming a trimeric complex with NGFR/p75NTR and sortilin, or by binding to TrkA receptors with low affinity. Several examples of in vitro and in vivo evidence show that NGF is both synthesized and released by breast cancer cells, and has mitogen, antiapoptotic and angiogenic effects on these cells through the activation of different signaling cascades that involve TrkA and NGFR/p75NTR receptors. Conversely, pro-NGF signaling has been related to breast cancer invasion and metastasis. Other studies suggested that NGF and its receptors could represent a good diagnostic and prognostic tool, as well as promising therapeutic targets for breast cancer. In this paper, we comprehensively summarize and systematically review the current experimental evidence on this topic. INPLASY ID: INPLASY2022100017.
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9
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Wang C, Shen Y, Ni J, Hu W, Yang Y. Effect of chronic stress on tumorigenesis and development. Cell Mol Life Sci 2022; 79:485. [PMID: 35974132 PMCID: PMC11071880 DOI: 10.1007/s00018-022-04455-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 06/22/2022] [Accepted: 06/27/2022] [Indexed: 11/03/2022]
Abstract
Chronic stress activates the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis to aggravates tumorigenesis and development. Although the importance of SNS and HPA in maintaining homeostasis has already attracted much attention, there is still a lot remained unknown about the molecular mechanisms by which chronic stress influence the occurrence and development of tumor. While some researches have already concluded the mechanisms underlying the effect of chronic stress on tumor, complicated processes of tumor progression resulted in effects of chronic stress on various stages of tumor remains elusive. In this reviews we concluded recent research progresses of chronic stress and its effects on premalignancy, tumorigenesis and tumor development, we comprehensively summarized the molecular mechanisms in between. And we highlight the available treatments and potential therapies for stressed patients with tumor.
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Affiliation(s)
- Chen Wang
- State Key Laboratory of Natural Medicines, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, No. 639 Long Mian Avenue, Jiangning District, Nanjing, 211198, Jiangsu, People's Republic of China
| | - Yumeng Shen
- State Key Laboratory of Natural Medicines, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, No. 639 Long Mian Avenue, Jiangning District, Nanjing, 211198, Jiangsu, People's Republic of China
| | - Jiaping Ni
- State Key Laboratory of Natural Medicines, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, No. 639 Long Mian Avenue, Jiangning District, Nanjing, 211198, Jiangsu, People's Republic of China
| | - Weiwei Hu
- State Key Laboratory of Natural Medicines, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, No. 639 Long Mian Avenue, Jiangning District, Nanjing, 211198, Jiangsu, People's Republic of China.
- Lingang Laboratory, Shanghai, 200032, People's Republic of China.
| | - Yong Yang
- State Key Laboratory of Natural Medicines, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, No. 639 Long Mian Avenue, Jiangning District, Nanjing, 211198, Jiangsu, People's Republic of China.
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10
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Mitok KA, Keller MP, Attie AD. Sorting through the extensive and confusing roles of sortilin in metabolic disease. J Lipid Res 2022; 63:100243. [PMID: 35724703 PMCID: PMC9356209 DOI: 10.1016/j.jlr.2022.100243] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 06/10/2022] [Accepted: 06/13/2022] [Indexed: 01/06/2023] Open
Abstract
Sortilin is a post-Golgi trafficking receptor homologous to the yeast vacuolar protein sorting receptor 10 (VPS10). The VPS10 motif on sortilin is a 10-bladed β-propeller structure capable of binding more than 50 proteins, covering a wide range of biological functions including lipid and lipoprotein metabolism, neuronal growth and death, inflammation, and lysosomal degradation. Sortilin has a complex cellular trafficking itinerary, where it functions as a receptor in the trans-Golgi network, endosomes, secretory vesicles, multivesicular bodies, and at the cell surface. In addition, sortilin is associated with hypercholesterolemia, Alzheimer's disease, prion diseases, Parkinson's disease, and inflammation syndromes. The 1p13.3 locus containing SORT1, the gene encoding sortilin, carries the strongest association with LDL-C of all loci in human genome-wide association studies. However, the mechanism by which sortilin influences LDL-C is unclear. Here, we review the role sortilin plays in cardiovascular and metabolic diseases and describe in detail the large and often contradictory literature on the role of sortilin in the regulation of LDL-C levels.
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Affiliation(s)
- Kelly A Mitok
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA
| | - Mark P Keller
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA
| | - Alan D Attie
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
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11
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Stravodimou A, Voutsadakis IA. Neurotrophic receptor tyrosine kinase family members in secretory and non-secretory breast carcinomas. World J Clin Oncol 2022; 13:135-146. [PMID: 35316931 PMCID: PMC8894271 DOI: 10.5306/wjco.v13.i2.135] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 07/11/2021] [Accepted: 01/14/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Breast cancer is the most common female cancer and a major cause of morbidity and mortality. Progress in breast cancer therapeutics has been attained with the introduction of targeted therapies for specific sub-sets. However, other subsets lack targeted interventions and thus there is persisting need for identification and characterization of molecular targets in order to advance breast cancer therapeutics.
AIM To analyze the role of lesions in neurotrophic receptor tyrosine kinase (NTRK) genes in breast cancers.
METHODS Analysis of publicly available genomic breast cancer datasets was performed for identification and characterization of cases with fusions and other molecular abnormalities involving NTRK1, NTRK2 and NTRK3 genes.
RESULTS NTRK fusions are present in a small number of breast cancers at the extensive GENIE project data set which contains more than 10000 breast cancers. These cases are not identified as secretory in the database, suggesting that the histologic characterization is not always evident. In the breast cancer The Cancer Genome Atlas (TCGA) cohort the more common molecular lesion in NTRK genes is amplification of NTRK1 observed in 7.9% of breast cancers.
CONCLUSION Neurotrophin receptors molecular lesions other than fusions are observed more often than fusions. However, currently available NTRK inhibitors are effective mainly for fusion lesions. Amplifications of NTRK1, being more frequent in breast cancers, could be a viable therapeutic target if inhibitors efficacious for them become available.
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Affiliation(s)
| | - Ioannis A Voutsadakis
- Department of Medical Oncology, Sault Area Hospital, Sault Ste Marie P6B0A8, Ontario, Canada
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12
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Sánchez ML, Coveñas R. The Neurotensinergic System: A Target for Cancer Treatment. Curr Med Chem 2021; 29:3231-3260. [PMID: 34711154 DOI: 10.2174/0929867328666211027124328] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/19/2021] [Accepted: 08/26/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The scientific interest regarding the involvement of peptides in cancer has increased in the last years. In tumor cells the overexpression of peptides and their receptors is known and new therapeutic targets for the treatment of cancer have been suggested. The overexpression of the neurotensinergic system has been associated with poor prognosis, tumor size, higher tumor aggressiveness, increased relapse risk and worse sensitivity to chemotherapy agents. OBJECTIVE The aim of this review is to update the findings regarding the involvement of the neurotensinergic system in cancer to suggest anticancer therapeutic strategies targeting this system. The neurotensin (NT) precursor, NT and its receptors (NTR) and the involvement of the neurotensinergic system in lung, breast, prostate, gastric, colon, liver and pancreatic cancers, glioblastoma, neuroendocrine tumors and B-cell leukemia will be mentioned and discussed as well as the signaling pathways mediated by NT. Some research lines to be developed in the future will be suggested such as: molecules regulating the expression of the NT precursor, influence of the diet in the development of tumors, molecules and signaling pathways activated by NT and antitumor therapeutic strategies targeting the neurotensinergic system. CONCLUSION NT, via the NTR, exerts oncogenic (tumor cell proliferation, invasion, migration, angiogenesis) and antiapoptotic effects, whereas NTR antagonists inhibit these effects. NTR expression can be used as a diagnostic tool/therapeutic target and the administration of NTR antagonists as antitumor drugs could be a therapeutic strategy to treat tumors overexpressing NTR.
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Affiliation(s)
- Manuel Lisardo Sánchez
- University of Salamanca, Laboratory of Neuroanatomy of the Peptidergic Systems (Lab. 14), Institute of Neurosciences of Castilla y León (INCYL), Salamanca. Spain
| | - Rafael Coveñas
- University of Salamanca, Laboratory of Neuroanatomy of the Peptidergic Systems (Lab. 14), Institute of Neurosciences of Castilla y León (INCYL), Salamanca. Spain
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13
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Toth AE, Helms HC, Harazin A, Johnsen KB, Goldeman C, Burkhart A, Thomsen MS, Kempen PJ, Klepe A, Lipka DV, Møller PL, Andresen TL, Nyegaard M, Moos T, Brodin B, Nielsen MS. Sortilin regulates blood-brain barrier integrity. FEBS J 2021; 289:1062-1079. [PMID: 34626084 DOI: 10.1111/febs.16225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 09/09/2021] [Accepted: 10/07/2021] [Indexed: 01/09/2023]
Abstract
Brain homeostasis depends on the existence of the blood-brain barrier (BBB). Despite decades of research, the factors and signalling pathways for modulating and maintaining BBB integrity are not fully elucidated. Here, we characterise the expression and function of the multifunctional receptor, sortilin, in the cells of the BBB, in vivo and in vitro. We show that sortilin acts as an important regulatory protein of the BBB's tightness. In rats lacking sortilin, the BBB was leaky, which correlated well with relocated distribution of the localisation of zonula occludens-1, VE-cadherin and β-catenin junctional proteins. Furthermore, the absence of sortilin in brain endothelial cells resulted in decreased phosphorylation of Akt signalling protein and increased the level of phospho-ERK1/2. As a putative result of MAPK/ERK pathway activity, the junctions between the brain endothelial cells were disintegrated and the integrity of the BBB became compromised. The identified barrier differences between wild-type and Sort1-/- brain endothelial cells can pave the way for a better understanding of sortilin's role in the healthy and diseased BBB.
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Affiliation(s)
- Andrea E Toth
- Department of Biomedicine, Faculty of Health, Aarhus University, Denmark.,Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Copenhagen, Denmark
| | - Hans C Helms
- Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Copenhagen, Denmark.,Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Andras Harazin
- Department of Biomedicine, Faculty of Health, Aarhus University, Denmark
| | - Kasper B Johnsen
- Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Copenhagen, Denmark.,Department of Health Technology, Section for Biotherapeutic Engineering and Drug Targeting, Technical University of Denmark, Lyngby, Denmark
| | - Charlotte Goldeman
- Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Copenhagen, Denmark.,Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Annette Burkhart
- Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Copenhagen, Denmark.,Laboratory of Neurobiology, Biomedicine Group, Department of Health Science and Technology, Aalborg University, Denmark
| | - Maj S Thomsen
- Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Copenhagen, Denmark.,Laboratory of Neurobiology, Biomedicine Group, Department of Health Science and Technology, Aalborg University, Denmark
| | - Paul J Kempen
- Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Copenhagen, Denmark.,Department of Health Technology, Section for Biotherapeutic Engineering and Drug Targeting, Technical University of Denmark, Lyngby, Denmark
| | - Adrián Klepe
- Department of Biomedicine, Faculty of Health, Aarhus University, Denmark
| | - Dora V Lipka
- Department of Biomedicine, Faculty of Health, Aarhus University, Denmark
| | - Peter L Møller
- Department of Biomedicine, Faculty of Health, Aarhus University, Denmark
| | - Thomas L Andresen
- Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Copenhagen, Denmark.,Department of Health Technology, Section for Biotherapeutic Engineering and Drug Targeting, Technical University of Denmark, Lyngby, Denmark
| | - Mette Nyegaard
- Department of Biomedicine, Faculty of Health, Aarhus University, Denmark
| | - Torben Moos
- Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Copenhagen, Denmark.,Laboratory of Neurobiology, Biomedicine Group, Department of Health Science and Technology, Aalborg University, Denmark
| | - Birger Brodin
- Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Copenhagen, Denmark.,Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Morten S Nielsen
- Department of Biomedicine, Faculty of Health, Aarhus University, Denmark.,Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery, Copenhagen, Denmark
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14
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Regua AT, Aguayo NR, Jalboush SA, Doheny DL, Manore SG, Zhu D, Wong GL, Arrigo A, Wagner CJ, Yu Y, Thomas A, Chan MD, Ruiz J, Jin G, Strowd R, Sun P, Lin J, Lo HW. TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers. Cancers (Basel) 2021; 13:2340. [PMID: 34066153 PMCID: PMC8150921 DOI: 10.3390/cancers13102340] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/05/2021] [Accepted: 05/07/2021] [Indexed: 01/15/2023] Open
Abstract
JAK2-STAT3 and TrkA signaling pathways have been separately implicated in aggressive breast cancers; however, whether they are co-activated or undergo functional interaction has not been thoroughly investigated. Herein we report, for the first time that STAT3 and TrkA are significantly co-overexpressed and co-activated in triple-negative breast cancer (TNBC) and HER2-enriched breast cancer, as shown by immunohistochemical staining and data mining. Through immunofluorescence staining-confocal microscopy and immunoprecipitation-Western blotting, we found that TrkA and STAT3 co-localize and physically interact in the cytoplasm, and the interaction is dependent on STAT3-Y705 phosphorylation. TrkA-STAT3 interaction leads to STAT3 phosphorylation at Y705 by TrkA in breast cancer cells and cell-free kinase assays, indicating that STAT3 is a novel substrate of TrkA. β-NGF-mediated TrkA activation induces TrkA-STAT3 interaction, STAT3 nuclear transport and transcriptional activity, and the expression of STAT3 target genes, SOX2 and MYC. The co-activation of both pathways promotes breast cancer stem cells. Finally, we found that TNBC and HER2-enriched breast cancer with JAK2-STAT3 and TrkA co-activation are positively associated with poor overall metastasis-free and organ-specific metastasis-free survival. Collectively, our study uncovered that TrkA is a novel activating kinase of STAT3, and their co-activation enhances gene transcription and promotes breast cancer stem cells in TNBC and HER2-enriched breast cancer.
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Affiliation(s)
- Angelina T. Regua
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (A.T.R.); (N.R.A.); (S.A.J.); (D.L.D.); (S.G.M.); (D.Z.); (G.L.W.); (A.A.); (C.J.W.); (Y.Y.); (G.J.); (P.S.)
| | - Noah R. Aguayo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (A.T.R.); (N.R.A.); (S.A.J.); (D.L.D.); (S.G.M.); (D.Z.); (G.L.W.); (A.A.); (C.J.W.); (Y.Y.); (G.J.); (P.S.)
| | - Sara Abu Jalboush
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (A.T.R.); (N.R.A.); (S.A.J.); (D.L.D.); (S.G.M.); (D.Z.); (G.L.W.); (A.A.); (C.J.W.); (Y.Y.); (G.J.); (P.S.)
| | - Daniel L. Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (A.T.R.); (N.R.A.); (S.A.J.); (D.L.D.); (S.G.M.); (D.Z.); (G.L.W.); (A.A.); (C.J.W.); (Y.Y.); (G.J.); (P.S.)
| | - Sara G. Manore
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (A.T.R.); (N.R.A.); (S.A.J.); (D.L.D.); (S.G.M.); (D.Z.); (G.L.W.); (A.A.); (C.J.W.); (Y.Y.); (G.J.); (P.S.)
| | - Dongqin Zhu
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (A.T.R.); (N.R.A.); (S.A.J.); (D.L.D.); (S.G.M.); (D.Z.); (G.L.W.); (A.A.); (C.J.W.); (Y.Y.); (G.J.); (P.S.)
| | - Grace L. Wong
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (A.T.R.); (N.R.A.); (S.A.J.); (D.L.D.); (S.G.M.); (D.Z.); (G.L.W.); (A.A.); (C.J.W.); (Y.Y.); (G.J.); (P.S.)
| | - Austin Arrigo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (A.T.R.); (N.R.A.); (S.A.J.); (D.L.D.); (S.G.M.); (D.Z.); (G.L.W.); (A.A.); (C.J.W.); (Y.Y.); (G.J.); (P.S.)
| | - Calvin J. Wagner
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (A.T.R.); (N.R.A.); (S.A.J.); (D.L.D.); (S.G.M.); (D.Z.); (G.L.W.); (A.A.); (C.J.W.); (Y.Y.); (G.J.); (P.S.)
| | - Yang Yu
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (A.T.R.); (N.R.A.); (S.A.J.); (D.L.D.); (S.G.M.); (D.Z.); (G.L.W.); (A.A.); (C.J.W.); (Y.Y.); (G.J.); (P.S.)
| | - Alexandra Thomas
- Department of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (A.T.); (J.R.)
- Breast Cancer Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (M.D.C.); (R.S.)
| | - Michael D. Chan
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (M.D.C.); (R.S.)
- Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Jimmy Ruiz
- Department of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (A.T.); (J.R.)
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (M.D.C.); (R.S.)
| | - Guangxu Jin
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (A.T.R.); (N.R.A.); (S.A.J.); (D.L.D.); (S.G.M.); (D.Z.); (G.L.W.); (A.A.); (C.J.W.); (Y.Y.); (G.J.); (P.S.)
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (M.D.C.); (R.S.)
| | - Roy Strowd
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (M.D.C.); (R.S.)
- Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Peiqing Sun
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (A.T.R.); (N.R.A.); (S.A.J.); (D.L.D.); (S.G.M.); (D.Z.); (G.L.W.); (A.A.); (C.J.W.); (Y.Y.); (G.J.); (P.S.)
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (M.D.C.); (R.S.)
| | - Jiayuh Lin
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (A.T.R.); (N.R.A.); (S.A.J.); (D.L.D.); (S.G.M.); (D.Z.); (G.L.W.); (A.A.); (C.J.W.); (Y.Y.); (G.J.); (P.S.)
- Breast Cancer Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (M.D.C.); (R.S.)
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15
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Zhao P, Jiang D, Huang Y, Chen C. EphA2: A promising therapeutic target in breast cancer. J Genet Genomics 2021; 48:261-267. [PMID: 33962882 DOI: 10.1016/j.jgg.2021.02.011] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/24/2021] [Accepted: 02/28/2021] [Indexed: 10/21/2022]
Abstract
Ephrin type-A receptor 2 (EphA2), a receptor tyrosine kinase, is overexpressed in human breast cancers often linked to poor patient prognosis. Accumulating evidence demonstrates that EphA2 plays important roles in several critical processes associated with malignant breast progression, such as proliferation, survival, migration, invasion, drug resistance, metastasis, and angiogenesis. As its inhibition through multiple approaches can inhibit the growth of breast cancer and restore drug sensitivity, EphA2 has become a promising therapeutic target for breast cancer treatment. Here, we summarize the expression, functions, mechanisms of action, and regulation of EphA2 in breast cancer. We also list the potential therapeutic strategies targeting EphA2. Furthermore, we discuss the future directions of studying EphA2 in breast cancer.
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Affiliation(s)
- Ping Zhao
- Department of the First Breast Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, China
| | - Dewei Jiang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
| | - Yunchao Huang
- Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, China.
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China; KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China.
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16
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Ghaemimanesh F, Mehravar M, Milani S, Poursani EM, Saliminejad K. The multifaceted role of sortilin/neurotensin receptor 3 in human cancer development. J Cell Physiol 2021; 236:6271-6281. [PMID: 33634506 DOI: 10.1002/jcp.30344] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 01/20/2021] [Accepted: 02/12/2021] [Indexed: 12/16/2022]
Abstract
Sortilin (also known as neurotensin receptor 3) is a multitasking protein implicated in numerous pathophysiological processes, including cancer development, cardiovascular impairment, Alzheimer-type dementia, and depression. Although the definitive role of sortilin in human solid and hematological malignancies has been evidenced, few articles reviewed the task. The aim of the current review is to unravel the mechanisms by which sortilin controls oncogenicity and cancer progression; and also to summarize and discuss the original data obtained from international research laboratories on this topic. Questions on how sortilin is involving in the impairment of cell junctions, in exosomes composition and release, as well as in the regulation of epidermal growth factor receptor trafficking are also responded. In addition, we provide a special focus on the regulatory role of sortilin in signal transduction by either neurotrophins or neurotensin in normal and malignant cells. The relevance of sortilin with normal and cancer stem cells is also discussed. The last section provides a general overview of sortilin applications as a diagnostic and prognostic biomarker in the context of cancer detection. Finally, we comment on the future research aspects in which the field of cancer diagnosis, prognosis, and therapy might be developed.
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Affiliation(s)
- Fatemeh Ghaemimanesh
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Majid Mehravar
- Department of Anatomy and Developmental Biology, Development and Stem Cells Program, Biomedicine Discovery Institute, Monash University, Melbourne, Australia
| | - Saeideh Milani
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Ensieh M Poursani
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Kioomars Saliminejad
- Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
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17
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Al-Yozbaki M, Acha-Sagredo A, George A, Liloglou T, Wilson CM. Balancing neurotrophin pathway and sortilin function: Its role in human disease. Biochim Biophys Acta Rev Cancer 2020; 1874:188429. [DOI: 10.1016/j.bbcan.2020.188429] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 08/12/2020] [Accepted: 09/02/2020] [Indexed: 01/03/2023]
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18
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The neurotrophic tyrosine kinase receptor 1 (TrkA) is overexpressed in oesophageal squamous cell carcinoma. Pathology 2020; 53:470-477. [PMID: 33143904 DOI: 10.1016/j.pathol.2020.08.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 08/20/2020] [Accepted: 08/26/2020] [Indexed: 01/31/2023]
Abstract
Nerve growth factor (NGF) and its receptors, the neurotrophic receptor tyrosine kinase 1 (NTRK1/TrkA) and the common neurotrophin receptor (NGFR/p75NTR), are increasingly implicated in cancer progression, but their clinicopathological significance in oesophageal cancer is unclear. In this study, the expression of NGF, NTRK1 and NGFR were analysed by immunohistochemistry in a cohort of 303 oesophageal cancers versus 137 normal adjacent oesophageal tissues. Immunostaining was digitally quantified and compared to clinicopathological parameters. NGF and NGFR staining were found in epithelial cells and at similar levels between oesophageal cancers and normal oesophageal tissue. NGFR staining was slightly increased with grade (p=0.0389). Interestingly, NTRK1 staining was markedly higher in oesophageal squamous cell carcinoma (OR 2.31, 95%CI 1.13-4.38, p<0.0001) and significantly lower in adenocarcinoma (OR 0.50, 95%CI 0.44-0.63, p<0.0001) compared to normal oesophageal tissue. In addition, NTRK1 staining was decreased in grade 2 and grade 3 (OR 0.51, 95%CI 0.21-1.40, p<0.0001) compared to grade 1, suggesting a preferential involvement of this receptor in the more differentiated forms of oesophageal carcinomas. Together, these data point to NTRK1 as a biomarker and a candidate therapeutic target in oesophageal squamous cell carcinoma.
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Garrido MP, Salvatierra R, Valenzuela-Valderrama M, Vallejos C, Bruneau N, Hernández A, Vega M, Selman A, Quest AFG, Romero C. Metformin Reduces NGF-Induced Tumour Promoter Effects in Epithelial Ovarian Cancer Cells. Pharmaceuticals (Basel) 2020; 13:E315. [PMID: 33081077 PMCID: PMC7602813 DOI: 10.3390/ph13100315] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 09/22/2020] [Accepted: 09/24/2020] [Indexed: 12/13/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is a lethal gynaecological neoplasm characterized by rapid growth and angiogenesis. Nerve growth factor (NGF) and its high affinity receptor tropomyosin receptor kinase A (TRKA) contribute to EOC progression by increasing the expression of c-MYC, survivin and vascular endothelial growth factor (VEGF) along with a decrease in microRNAs (miR) 23b and 145. We previously reported that metformin prevents NGF-induced proliferation and angiogenic potential of EOC cells. In this study, we sought to obtain a better understanding of the mechanism(s) by which metformin blocks these NGF-induced effects in EOC cells. Human ovarian surface epithelial (HOSE) and EOC (A2780/SKOV3) cells were stimulated with NGF and/or metformin to assess the expression of c-MYC, β-catenin, survivin and VEGF and the abundance of the tumor suppressor miRs 23b and 145. Metformin decreased the NGF-induced transcriptional activity of MYC and β-catenin/T-cell factor/lymphoid enhancer-binding factor (TCF-Lef), as well as the expression of c-MYC, survivin and VEGF in EOC cells, while it increased miR-23b and miR-145 levels. The preliminary analysis of ovarian biopsies from women users or non-users of metformin was consistent with these in vitro results. Our observations shed light on the mechanisms by which metformin may suppress tumour growth in EOC and suggest that metformin should be considered as a possible complementary therapy in EOC treatment.
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Affiliation(s)
- Maritza P. Garrido
- Laboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile; (M.P.G.); (R.S.); (C.V.); (N.B.); (A.H.); (M.V.)
- Departamento de Obstetricia y Ginecología, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile;
| | - Renato Salvatierra
- Laboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile; (M.P.G.); (R.S.); (C.V.); (N.B.); (A.H.); (M.V.)
| | - Manuel Valenzuela-Valderrama
- Laboratorio de Microbiología Celular, Instituto de Investigación e Innovación en Salud, Facultad de Ciencias de la Salud, Universidad Central de Chile, Santiago 8320000, Chile;
| | - Christopher Vallejos
- Laboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile; (M.P.G.); (R.S.); (C.V.); (N.B.); (A.H.); (M.V.)
| | - Nicole Bruneau
- Laboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile; (M.P.G.); (R.S.); (C.V.); (N.B.); (A.H.); (M.V.)
| | - Andrea Hernández
- Laboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile; (M.P.G.); (R.S.); (C.V.); (N.B.); (A.H.); (M.V.)
| | - Margarita Vega
- Laboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile; (M.P.G.); (R.S.); (C.V.); (N.B.); (A.H.); (M.V.)
- Departamento de Obstetricia y Ginecología, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile;
| | - Alberto Selman
- Departamento de Obstetricia y Ginecología, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile;
- Instituto Nacional del Cáncer, Santiago 8380455, Chile
| | - Andrew F. G. Quest
- Laboratorio de Comunicaciones Celulares, Centro de estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas (ICBM), Facultad De Medicina, Universidad de Chile, Santiago 8380453, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Santiago 8380000, Chile
| | - Carmen Romero
- Laboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile; (M.P.G.); (R.S.); (C.V.); (N.B.); (A.H.); (M.V.)
- Departamento de Obstetricia y Ginecología, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile;
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20
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McCullough D, Atofanei C, Knight E, Trim SA, Trim CM. Kinome scale profiling of venom effects on cancer cells reveals potential new venom activities. Toxicon 2020; 185:129-146. [PMID: 32682827 DOI: 10.1016/j.toxicon.2020.07.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 07/07/2020] [Accepted: 07/12/2020] [Indexed: 02/07/2023]
Abstract
The search for novel and relevant cancer therapeutics is continuous and ongoing. Cancer adaptations, resulting in therapeutic treatment failures, fuel this continuous necessity for new drugs to novel targets. Recently, researchers have started to investigate the effect of venoms and venom components on different types of cancer, investigating their mechanisms of action. Receptor tyrosine kinases (RTKs) comprise a family of highly conserved and functionally important druggable targets for cancer therapy. This research exploits the novelty of complex venom mixtures to affect phosphorylation of the epidermal growth factor receptor (EGFR) and related RTK family members, dually identifying new activities and unexplored avenues for future cancer and venom research. Six whole venoms from diverse species taxa, were evaluated for their ability to illicit changes in the phosphorylated expression of a panel of 49 commonly expressed RTKs. The triple negative breast cancer cell line MDA-MB-468 was treated with optimised venom doses, pre-determined by SDS PAGE and Western blot analysis. The phosphorylated expression levels of 49 RTKs in response to the venoms were assessed with the use of Human Phospho-RTK Arrays and analysed using ImageLab 5.2.1 analysis software (BioRad). Inhibition of EGFR phosphorylation occurred with treatment of venom from Acanthoscurria geniculata (Theraphosidae), Heterometrus swammerdami (Scorpionidae), Crotalus durissus vegrandis (Crotalidae) and Naja naja (Elapidae). Western green mamba Dendroaspis viridis venom increased EGFR phosphorylation. Eph, HGFR and HER were the most affected receptor families by venoms. Whilst the importance of these changes in terms of effect on MDA-MB-468 cells' long-term viability and functionality are still unclear, the findings present exciting opportunities for further investigation as potential drug targets in cancer and as tools to understand better how these pathways interact.
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Affiliation(s)
- Danielle McCullough
- School of Human and Life Sciences, Canterbury Christ Church University, Canterbury, CT1 1QU, UK
| | - Cristina Atofanei
- School of Human and Life Sciences, Canterbury Christ Church University, Canterbury, CT1 1QU, UK
| | - Emily Knight
- School of Human and Life Sciences, Canterbury Christ Church University, Canterbury, CT1 1QU, UK; Life Sciences Industry Liaison laboratory, Canterbury Christ Church University, Discovery Park, Sandwich, Kent, CT13 9FF, UK
| | - Steven A Trim
- Venomtech Ltd., Discovery Park, Sandwich, Kent, CT13 9FF, UK
| | - Carol M Trim
- School of Human and Life Sciences, Canterbury Christ Church University, Canterbury, CT1 1QU, UK.
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The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer. Biomolecules 2020; 10:biom10091329. [PMID: 32957504 PMCID: PMC7564775 DOI: 10.3390/biom10091329] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/13/2020] [Accepted: 09/15/2020] [Indexed: 12/21/2022] Open
Abstract
The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive ductal carcinomas (IDC), 158 invasive lobular carcinomas (ILC) and 50 ductal carcinomas in situ (DCIS). TrkA was expressed in cancer epithelial and myoepithelial cells, with higher levels of TrkA positively associated with IDC (39% of cases) (p < 0.0001). Interestingly, TrkA was significantly increased in tumours expressing the human epidermal growth factor receptor-2 (HER2), with expression in 49% of HER2-positive compared to 25% of HER2-negative tumours (p = 0.0027). A panel of breast cancer cells were used to confirm TrkA protein expression, demonstrating higher levels of TrkA (total and phosphorylated) in HER2-positive cell lines. Functional investigations using four different HER2-positive breast cancer cell lines indicated that the Trk tyrosine kinase inhibitor GNF-5837 reduced cell viability, through decreased phospho-TrkA (Tyr490) and downstream AKT (Ser473) activation, but did not display synergy with Herceptin. Overall, these data highlight a relationship between the tyrosine kinase receptors TrkA and HER2 and suggest the potential of TrkA as a novel or adjunct target for HER2-positive breast tumours.
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Faulkner S, Griffin N, Rowe CW, Jobling P, Lombard JM, Oliveira SM, Walker MM, Hondermarck H. Nerve growth factor and its receptor tyrosine kinase TrkA are overexpressed in cervical squamous cell carcinoma. FASEB Bioadv 2020; 2:398-408. [PMID: 32676580 PMCID: PMC7354692 DOI: 10.1096/fba.2020-00016] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 04/02/2020] [Accepted: 05/21/2020] [Indexed: 01/05/2023] Open
Abstract
Nerve growth factor (NGF) and its receptors are increasingly implicated in cancer progression, but their expression in cervical cancer is unclear. The objective of this study was to define the protein expression of NGF, its precursor (proNGF), as well as their receptors, the tyrosine kinase receptor TrkA, the common neurotrophin receptor p75NTR and the pro-neurotrophin receptor sortilin in cervical cancer. Immunohistochemistry was performed in a cohort of cervical cancers (n = 287), including the two major subtypes of the disease: squamous cell carcinomas (SCC) and adenocarcinomas (AC). Normal cervical tissues (n = 28) were also analyzed. Protein expression was determined by computer-based digital quantification of staining intensity and comparative statistical analyses were made with clinicopathological parameters including histological subtype, age, grade, tumor size, lymph node invasion, and stage. The expression of NGF, proNGF, TrkA, p75NTR, and sortilin was higher in cervical cancer compared to normal cervical tissues. NGF and TrkA were found overexpressed in SCC compared to AC (P = .0006 and P < .0001, respectively). The expression of NGF (P = .0053), proNGF (P = .0022), and p75NTR (P = .0002), but not that of TrkA or sortilin, was associated with increasing grade in SCC. In addition, nerve infiltration into the tumor microenvironment was assessed using the pan-neuronal marker PGP9.5. Infiltrating nerves were detected in 27% of cervical tumors and expressed TrkA. Functional investigations using the HELA cervical cancer cell line indicated that the Trk tyrosine kinase inhibitor GNF-5837 reduced cell viability through decreased ERK1/2 activation. Together, these data reveal the overexpression of NGF and TrkA in cervical SCC, suggesting a potential therapeutic value of targeting the NGF-TrkA signaling pathway in this subtype of cervical cancer.
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Affiliation(s)
- Sam Faulkner
- School of Biomedical Sciences and PharmacyFaculty of Health and MedicineUniversity of NewcastleCallaghanNSWAustralia
- Hunter Medical Research InstituteUniversity of NewcastleNew LambtonNSWAustralia
| | - Nathan Griffin
- School of Biomedical Sciences and PharmacyFaculty of Health and MedicineUniversity of NewcastleCallaghanNSWAustralia
- Hunter Medical Research InstituteUniversity of NewcastleNew LambtonNSWAustralia
| | - Christopher W. Rowe
- Hunter Medical Research InstituteUniversity of NewcastleNew LambtonNSWAustralia
- School of Medicine and Public HealthFaculty of Health and MedicineUniversity of NewcastleCallaghanNSWAustralia
| | - Phillip Jobling
- School of Biomedical Sciences and PharmacyFaculty of Health and MedicineUniversity of NewcastleCallaghanNSWAustralia
- Hunter Medical Research InstituteUniversity of NewcastleNew LambtonNSWAustralia
| | - Janine M. Lombard
- School of Medicine and Public HealthFaculty of Health and MedicineUniversity of NewcastleCallaghanNSWAustralia
- Department of Medical OncologyCalvary Mater NewcastleWaratahNSWAustralia
| | - Sonia M. Oliveira
- Hunter Medical Research InstituteUniversity of NewcastleNew LambtonNSWAustralia
| | - Marjorie M. Walker
- Hunter Medical Research InstituteUniversity of NewcastleNew LambtonNSWAustralia
- School of Medicine and Public HealthFaculty of Health and MedicineUniversity of NewcastleCallaghanNSWAustralia
| | - Hubert Hondermarck
- School of Biomedical Sciences and PharmacyFaculty of Health and MedicineUniversity of NewcastleCallaghanNSWAustralia
- Hunter Medical Research InstituteUniversity of NewcastleNew LambtonNSWAustralia
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23
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Rogez B, Pascal Q, Bobillier A, Machuron F, Toillon RA, Tierny D, Chopin V, Le Bourhis X. Expression and Prognostic Significance of Neurotrophins and Their Receptors in Canine Mammary Tumors. Vet Pathol 2020; 57:507-519. [PMID: 32351171 DOI: 10.1177/0300985820921813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Accumulating data highlight the role of neurotrophins and their receptors in human breast cancer. This family includes nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), both synthetized as proneurotrophins (proNGF and proBDNF). (pro)NGF and (pro)BDNF initiate their biological effects by binding to both their specific receptors TrkA and TrkB, respectively, and the common receptor p75NTR. Currently, no data are available about their expression and potential role in canine mammary tumors. The aim of this study was to investigate expression of proNGF and BDNF as well as their receptors TrkA, TrkB, and p75NTR in canine mammary carcinomas, and to correlate them with clinicopathological parameters (grade, histological type, lymph node status, recurrence, and distant metastasis) and survival. Immunohistochemistry was performed on serial sections of 96 canine mammary carcinomas with antibodies against proNGF, BDNF, TrkA, TrkB, and p75NTR. Of the 96 carcinomas, proNGF expression was detected in 71 (74%), BDNF in 79 (82%), TrkA in 94 (98%), TrkB in 35 (37%), and p75NTR in 44 (46%). No association was observed between proNGF, BDNF, or TrkA expression and either clinicopathological parameters or survival. TrkB and p75NTR expression were associated with favorable clinicopathological parameters as well as better overall survival.
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Affiliation(s)
- Bernadette Rogez
- University of Lille, INSERM U908 "Cell Plasticity and Cancer," Villeneuve d'Ascq, France.,OCR (Oncovet Clinical Research), Parc Eurasanté, Loos, France
| | - Quentin Pascal
- OCR (Oncovet Clinical Research), Parc Eurasanté, Loos, France
| | | | | | - Robert-Alain Toillon
- University of Lille, INSERM U908 "Cell Plasticity and Cancer," Villeneuve d'Ascq, France
| | | | - Valérie Chopin
- University of Lille, INSERM U908 "Cell Plasticity and Cancer," Villeneuve d'Ascq, France.,University of Picardie Jules Verne, Amiens, France.,Contributed equally to this work
| | - Xuefen Le Bourhis
- University of Lille, INSERM U908 "Cell Plasticity and Cancer," Villeneuve d'Ascq, France.,Contributed equally to this work
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24
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Dileepan M, Ge XN, Bastan I, Greenberg YG, Liang Y, Sriramarao P, Rao SP. Regulation of Eosinophil Recruitment and Allergic Airway Inflammation by Tropomyosin Receptor Kinase A. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2020; 204:682-693. [PMID: 31871023 PMCID: PMC7058110 DOI: 10.4049/jimmunol.1900786] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 11/24/2019] [Indexed: 12/13/2022]
Abstract
Eosinophilia is a hallmark of allergic airway inflammation (AAI). Identifying key molecules and specific signaling pathways that regulate eosinophilic inflammation is critical for development of novel therapeutics. Tropomycin receptor kinase A (TrkA) is the high-affinity receptor for nerve growth factor. AAI is associated with increased expression of TrkA by eosinophils; however, the functional role of TrkA in regulating eosinophil recruitment and contributing to AAI is poorly understood. This study identifies, to our knowledge, a novel mechanism of eotaxin-mediated activation of TrkA and its role in regulating eosinophil recruitment by using a chemical-genetic approach to specifically inhibit TrkA kinase activity with 1-NM-PP1 in TrkAF592A-knock-in (TrkA-KI) eosinophils. Blockade of TrkA by 1-NM-PP1 enhanced eosinophil spreading on VCAM-1 but inhibited eotaxin-1 (CCL11)-mediated eosinophil migration, calcium flux, cell polarization, and ERK1/2 activation, suggesting that TrkA is an important player in the signaling pathway activated by eotaxin-1 during eosinophil migration. Further, blockade of matrix metalloprotease with BB-94 inhibited eotaxin-1-induced TrkA activation and eosinophil migration, additively with 1-NM-PP1, indicating a role for matrix metalloproteases in TrkA activation. TrkA inhibition in Alternaria alternata-challenged TrkA-KI mice markedly inhibited eosinophilia and attenuated various features of AAI. These findings are indicative of a distinctive eotaxin-mediated TrkA-dependent signaling pathway, which, in addition to other TrkA-activating mediators, contributes to eosinophil recruitment during AAI and suggests that targeting the TrkA signaling pathway to inhibit eosinophil recruitment may serve as a therapeutic strategy for management of eosinophilic inflammation in allergic airway disease, including asthma.
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Affiliation(s)
- Mythili Dileepan
- Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN
| | | | | | - Yana G. Greenberg
- Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN
| | - Yuying Liang
- Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN
| | - P. Sriramarao
- Corresponding authors: P. Srirama Rao (), University of Minnesota, 1971 Commonwealth Avenue, St. Paul, MN 55108, Phone: 612-626-6989; Yuying Liang (), University of Minnesota, 1988 Fitch Ave., 295 AS/VM Bldg, St. Paul, MN 55108, Phone: 612-625-3376
| | - Savita P. Rao
- Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN
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25
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Triaca V, Carito V, Fico E, Rosso P, Fiore M, Ralli M, Lambiase A, Greco A, Tirassa P. Cancer stem cells-driven tumor growth and immune escape: the Janus face of neurotrophins. Aging (Albany NY) 2019; 11:11770-11792. [PMID: 31812953 PMCID: PMC6932930 DOI: 10.18632/aging.102499] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 11/17/2019] [Indexed: 05/12/2023]
Abstract
Cancer Stem Cells (CSCs) are self-renewing cancer cells responsible for expansion of the malignant mass in a dynamic process shaping the tumor microenvironment. CSCs may hijack the host immune surveillance resulting in typically aggressive tumors with poor prognosis.In this review, we focus on neurotrophic control of cellular substrates and molecular mechanisms involved in CSC-driven tumor growth as well as in host immune surveillance. Neurotrophins have been demonstrated to be key tumor promoting signaling platforms. Particularly, Nerve Growth Factor (NGF) and its specific receptor Tropomyosin related kinase A (TrkA) have been implicated in initiation and progression of many aggressive cancers. On the other hand, an active NGF pathway has been recently proven to be critical to oncogenic inflammation control and in promoting immune response against cancer, pinpointing possible pro-tumoral effects of NGF/TrkA-inhibitory therapy.A better understanding of the molecular mechanisms involved in the control of tumor growth/immunoediting is essential to identify new predictive and prognostic intervention and to design more effective therapies. Fine and timely modulation of CSCs-driven tumor growth and of peripheral lymph nodes activation by the immune system will possibly open the way to precision medicine in neurotrophic therapy and improve patient's prognosis in both TrkA- dependent and independent cancers.
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Affiliation(s)
- Viviana Triaca
- Institute of Biochemistry and Cell Biology, National Research Council (CNR), International Campus A. Buzzati-Traverso, Monterotondo Scalo, Rome, Italy
| | - Valentina Carito
- Institute of Biochemistry and Cell Biology, National Research Council (CNR), at Department of Sense Organs, University of Rome La Sapienza, Rome, Italy
| | - Elena Fico
- Institute of Biochemistry and Cell Biology, National Research Council (CNR), at Department of Sense Organs, University of Rome La Sapienza, Rome, Italy
| | - Pamela Rosso
- Institute of Biochemistry and Cell Biology, National Research Council (CNR), at Department of Sense Organs, University of Rome La Sapienza, Rome, Italy
| | - Marco Fiore
- Institute of Biochemistry and Cell Biology, National Research Council (CNR), at Department of Sense Organs, University of Rome La Sapienza, Rome, Italy
| | - Massimo Ralli
- Department of Sense Organs, University of Rome La Sapienza, Rome, Italy
| | | | - Antonio Greco
- Department of Sense Organs, University of Rome La Sapienza, Rome, Italy
| | - Paola Tirassa
- Institute of Biochemistry and Cell Biology, National Research Council (CNR), at Department of Sense Organs, University of Rome La Sapienza, Rome, Italy
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26
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Rowe CW, Faulkner S, Paul JW, Tolosa JM, Gedye C, Bendinelli C, Wynne K, McGrath S, Attia J, Smith R, Hondermarck H. The precursor for nerve growth factor (proNGF) is not a serum or biopsy-rinse biomarker for thyroid cancer diagnosis. BMC Endocr Disord 2019; 19:128. [PMID: 31775768 PMCID: PMC6882079 DOI: 10.1186/s12902-019-0457-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 11/13/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Nerves and neurotrophic growth factors are emerging promoters of cancer growth. The precursor for Nerve Growth Factor (proNGF) is overexpressed in thyroid cancer, but its potential role as a clinical biomarker has not been reported. Here we have examined the value of proNGF as a serum and biopsy-rinse biomarker for thyroid cancer diagnosis. METHODS Patients presenting for thyroid surgery or biopsy were enrolled in separate cohorts examining serum (n = 204, including 46 cases of thyroid cancer) and biopsy-rinse specimens (n = 188, including 26 cases of thyroid cancer). ProNGF levels in clinical samples were analysed by ELISA. Univariate and multivariate statistical analyses were used to compare proNGF levels with malignancy status and clinicopathological parameters. RESULTS ProNGF was not detected in the majority of serum samples (176/204, 86%) and the detection of proNGF was not associated with thyroid cancer diagnosis. In the few cases where proNGF was detected in the serum, thyroidectomy did not affect proNGF concentration, demonstrating that the thyroid was not the source of serum proNGF. Intriguingly, an association between hyperthyroidism and serum proNGF was observed (OR 3.3, 95% CI 1.6-8.7 p = 0.02). In biopsy-rinse, proNGF was detected in 73/188 (39%) cases, with no association between proNGF and thyroid cancer. However, a significant positive association between follicular lesions and biopsy-rinse proNGF was found (OR 3.3, 95% CI 1.2-8.7, p = 0.02). CONCLUSIONS ProNGF levels in serum and biopsy-rinse are not increased in thyroid cancer and therefore proNGF is not a clinical biomarker for this condition.
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Affiliation(s)
- Christopher W Rowe
- School of Medicine and Public Health, University of Newcastle, Newcastle, Australia.
- Department of Endocrinology, John Hunter Hospital, Locked Bag 1 HMRC, Newcastle, 2310, Australia.
- Hunter Medical Research Institute, New Lambton Heights, Australia.
| | - Sam Faulkner
- Hunter Medical Research Institute, New Lambton Heights, Australia
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia
| | - Jonathan W Paul
- School of Medicine and Public Health, University of Newcastle, Newcastle, Australia
- Hunter Medical Research Institute, New Lambton Heights, Australia
| | - Jorge M Tolosa
- School of Medicine and Public Health, University of Newcastle, Newcastle, Australia
- Hunter Medical Research Institute, New Lambton Heights, Australia
| | - Craig Gedye
- Hunter Medical Research Institute, New Lambton Heights, Australia
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia
- Department of Surgery, John Hunter Hospital, Newcastle, Australia
| | - Cino Bendinelli
- School of Medicine and Public Health, University of Newcastle, Newcastle, Australia
- Department of Medical Oncology, Calvary Mater Newcastle, Waratah, Australia
| | - Katie Wynne
- School of Medicine and Public Health, University of Newcastle, Newcastle, Australia
- Department of Endocrinology, John Hunter Hospital, Locked Bag 1 HMRC, Newcastle, 2310, Australia
- Hunter Medical Research Institute, New Lambton Heights, Australia
| | - Shaun McGrath
- School of Medicine and Public Health, University of Newcastle, Newcastle, Australia
- Department of Endocrinology, John Hunter Hospital, Locked Bag 1 HMRC, Newcastle, 2310, Australia
| | - John Attia
- School of Medicine and Public Health, University of Newcastle, Newcastle, Australia
- Hunter Medical Research Institute, New Lambton Heights, Australia
- Clinical Research Design, IT, and Statistical Support Unit, Hunter Medical Research Institute, Newcastle, Australia
| | - Roger Smith
- School of Medicine and Public Health, University of Newcastle, Newcastle, Australia
- Department of Endocrinology, John Hunter Hospital, Locked Bag 1 HMRC, Newcastle, 2310, Australia
- Hunter Medical Research Institute, New Lambton Heights, Australia
| | - Hubert Hondermarck
- Hunter Medical Research Institute, New Lambton Heights, Australia
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia
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Rowe CW, Dill T, Faulkner S, Gedye C, Paul JW, Tolosa JM, Jones M, King S, Smith R, Hondermarck H. The Precursor for Nerve Growth Factor (proNGF) in Thyroid Cancer Lymph Node Metastases: Correlation with Primary Tumour and Pathological Variables. Int J Mol Sci 2019; 20:ijms20235924. [PMID: 31775361 PMCID: PMC6929117 DOI: 10.3390/ijms20235924] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 11/21/2019] [Accepted: 11/24/2019] [Indexed: 01/14/2023] Open
Abstract
Metastases in thyroid cancer are associated with aggressive disease and increased patient morbidity, but the factors driving metastatic progression are unclear. The precursor for nerve growth factor (proNGF) is increased in primary thyroid cancers, but its expression or significance in metastases is not known. In this study, we analysed the expression of proNGF in a retrospective cohort of thyroid cancer lymph node metastases (n = 56), linked with corresponding primary tumours, by automated immunohistochemistry and digital quantification. Potential associations of proNGF immunostaining with clinical and pathological parameters were investigated. ProNGF staining intensity (defined by the median h-score) was significantly higher in lymph node metastases (h-score 94, interquartile range (IQR) 50-147) than in corresponding primary tumours (57, IQR 42-84) (p = 0.002). There was a correlation between proNGF expression in primary tumours and corresponding metastases, where there was a 0.68 (95% CI 0 to 1.2) increase in metastatic tumour h-score for each unit increase in the primary tumour h-score. However, larger tumours (both primary and metastatic) had lower proNGF expression. In a multivariate model, proNGF expression in nodal metastases was negatively correlated with lateral neck disease and being male. In conclusion, ProNGF is expressed in locoregional metastases of thyroid cancer and is higher in lymph node metastases than in primary tumours, but is not associated with high-risk clinical features.
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Affiliation(s)
- Christopher W. Rowe
- School of Medicine and Public Health, University of Newcastle, Callaghan 2308, Australia
- Department of Endocrinology, John Hunter Hospital, Newcastle 2310, Australia
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights 2310, Australia
| | - Tony Dill
- Department of Anatomical Pathology, NSW Health Pathology (Hunter), Newcastle 2310, Australia
| | - Sam Faulkner
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights 2310, Australia
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan 2308, Australia
| | - Craig Gedye
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan 2308, Australia
- Department of Medical Oncology, Calvary Mater Newcastle, Waratah 2298, Australia
| | - Jonathan W. Paul
- School of Medicine and Public Health, University of Newcastle, Callaghan 2308, Australia
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights 2310, Australia
| | - Jorge M. Tolosa
- School of Medicine and Public Health, University of Newcastle, Callaghan 2308, Australia
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights 2310, Australia
| | - Mark Jones
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights 2310, Australia
| | - Simon King
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights 2310, Australia
- Department of Anatomical Pathology, NSW Health Pathology (Hunter), Newcastle 2310, Australia
| | - Roger Smith
- School of Medicine and Public Health, University of Newcastle, Callaghan 2308, Australia
- Department of Endocrinology, John Hunter Hospital, Newcastle 2310, Australia
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights 2310, Australia
| | - Hubert Hondermarck
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights 2310, Australia
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan 2308, Australia
- Correspondence:
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Different responses of PC12 cells to different pro-nerve growth factor protein variants. Neurochem Int 2019; 129:104498. [PMID: 31278975 DOI: 10.1016/j.neuint.2019.104498] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 05/24/2019] [Accepted: 07/01/2019] [Indexed: 01/20/2023]
Abstract
The present work aimed to explore the innovative hypothesis that different transcript/protein variants of a pro-neurotrophin may generate different biological outcomes in a cellular system. Nerve growth factor (NGF) is important in the development and progression of neurodegenerative and cancer conditions. Mature NGF (mNGF) originates from a precursor, proNGF, produced in mouse in two major variants, proNGF-A and proNGF-B. Different receptors bind mNGF and proNGF, generating neurotrophic or neurotoxic outcomes. It is known that dysregulation in the proNGF/mNGF ratio and in NGF-receptors expression affects brain homeostasis. To date, however, the specific roles of the two major proNGF variants remain unexplored. Here we attempted a first characterization of the possible differential effects of proNGF-A and proNGF-B on viability, differentiation and endogenous ngf gene expression in the PC12 cell line. We also investigated the differential involvement of NGF receptors in the actions of proNGF. We found that native mouse mNGF, proNGF-A and proNGF-B elicited different effects on PC12 cell survival and differentiation. Only mNGF and proNGF-A promoted neurotrophic responses when all NGF receptors are exposed at the cell surface. Tropomyosine receptor kinase A (TrkA) blockade inhibited cell differentiation, regardless of which NGF was added to culture media. Only proNGF-A exerted a pro-survival effect when TrkA was inhibited. Conversely, proNGF-B exerted differentiative effects when the p75 neurotrophin receptor (p75NTR) was antagonized. Stimulation with NGF variants differentially regulated the autocrine production of distinct proNgf mRNA. Overall, our findings suggest that mNGF and proNGF-A may elicit similar neurotrophic effects, not necessarily linked to activation of the same NGF-receptor, while the action of proNGF-B may be determined by the NGF-receptors balance. Thus, the proposed involvement of proNGF/NGF on the development and progression of neurodegenerative and tumor conditions may depend on the NGF-receptors balance, on specific NGF trancript expression and on the proNGF protein variant ratio.
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Xu J, Song J, Yang X, Guo J, Wang T, Zhuo W. ProNGF siRNA inhibits cell proliferation and invasion of pancreatic cancer cells and promotes anoikis. Biomed Pharmacother 2019; 111:1066-1073. [PMID: 30841420 DOI: 10.1016/j.biopha.2019.01.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 12/21/2018] [Accepted: 01/01/2019] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Precursor of nerve growth factor (proNGF) was previously considered biologically inactive; however, it has recently been identified as having important roles in the pathology of cancer development. AIM This study aimed to explore the therapeutic effects of proNGF siRNA on the proliferation, invasion, and anoikis of pancreatic cancer cells and determine the functions of proNGF. METHODS Pancreatic ductal adenocarcinoma (PDAC) and paired paracancerous tissue samples were collected from 60 patients for evaluation of proNGF expression by immunohistochemistry staining, qPCR, and western blotting. PDAC cell proliferation, migration, apoptosis, and anoikis following proNGF siRNA knockdown were investigated in two pancreatic cancer cell lines, Panc-1 and Bxpc-3, using BrdU incorporation assays, EdU staining, Ki-67 immunofluorescence (IF) staining, wound-healing assays, transwell invasion assays, and EthD-1 IF staining. Autophagy-related proteins were also measured by western blotting. RESULTS Levels of proNGF protein were higher in pancreatic cancer tissues and cells lines than those in paracancerous tissues and normal pancreatic duct epithelial cells, respectively. In vitro, ProNGF knockdown by siRNA led to significantly reduced cell proliferation, remarkably inhibited wound-healing, and reduced the number of invaded PDAC cells in migration and transwell assays. Treatment with proNGF siRNA also downregulated ATG5 and Beclin 1 protein levels, increased those of P62, and increased EthD-1 staining in PDAC cells. CONCLUSION ProNGF expression is elevated in PDAC tissues and cell lines, and proNGF siRNA can inhibit cell proliferation, migration, and invasion, and promote anoikis of pancreatic cancer cells, in which decreased proNGF may participate.
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Affiliation(s)
- Jianbiao Xu
- Second Department of General Surgery, The First People's Hospital of Yunnan Province, Kunming 650032, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, China
| | - Jianlin Song
- Second Department of General Surgery, The First People's Hospital of Yunnan Province, Kunming 650032, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, China
| | - Xiaochun Yang
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, China; Department of Ophthalmology, The First People's Hospital of Yunnan Province, Kunming 650032, China.
| | - Jianhui Guo
- Second Department of General Surgery, The First People's Hospital of Yunnan Province, Kunming 650032, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, China.
| | - Tongmin Wang
- Second Department of General Surgery, The First People's Hospital of Yunnan Province, Kunming 650032, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, China
| | - Weidong Zhuo
- Second Department of General Surgery, The First People's Hospital of Yunnan Province, Kunming 650032, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, China
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ProNGF increases breast tumor aggressiveness through functional association of TrkA with EphA2. Cancer Lett 2019; 449:196-206. [PMID: 30771434 DOI: 10.1016/j.canlet.2019.02.019] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 02/07/2019] [Accepted: 02/10/2019] [Indexed: 12/19/2022]
Abstract
ProNGF expression has been linked to several types of cancers including breast cancer, and we have previously shown that proNGF stimulates breast cancer invasion in an autocrine manner through membrane receptors sortilin and TrkA. However, little is known regarding TrkA-associated protein partners upon proNGF stimulation. By proteomic analysis and proximity ligation assays, we found that proNGF binding to sortilin induced sequential formation of the functional sortilin/TrkA/EphA2 complex, leading to TrkA-phosphorylation dependent Akt activation and EphA2-dependent Src activation. EphA2 inhibition using siRNA approach abolished proNGF-stimulated clonogenic growth of breast cancer cell lines. Combinatorial targeting of TrkA and EphA2 dramatically reduced colony formation in vitro, primary tumor growth and metastatic dissemination towards the brain in vivo. Finally, proximity ligation assay in breast tumor samples revealed that increased TrkA/EphA2 proximity ligation assay signals were correlated with a decrease of overall survival in patients. All together, these data point out the importance of TrkA/EphA2 functional association in proNGF-induced tumor promoting effects, and provide a rationale to target proNGF/TrkA/EphA2 axis by alternative methods other than the simple use of tyrosine kinase inhibitors in breast cancer.
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31
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Targeting neurotrophin signaling in cancer: The renaissance. Pharmacol Res 2018; 135:12-17. [DOI: 10.1016/j.phrs.2018.07.019] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 07/17/2018] [Accepted: 07/17/2018] [Indexed: 01/15/2023]
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32
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Elshaer SL, El-Remessy AB. Deletion of p75 NTR prevents vaso-obliteration and retinal neovascularization via activation of Trk- A receptor in ischemic retinopathy model. Sci Rep 2018; 8:12490. [PMID: 30131506 PMCID: PMC6104090 DOI: 10.1038/s41598-018-30029-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 07/23/2018] [Indexed: 02/07/2023] Open
Abstract
Ischemic retinopathy is characterized by ischemia followed by retinal neovascularization (RNV) resulting in visual impairment. Given the role of neuron-secreted growth factors in regulating angiogenesis, we examined how genetic deletion of the neurotrophin receptor; p75NTR can overcome retinal ischemia using oxygen-induced retinopathy (OIR) mouse model. Wildtype (WT) or p75NTR-/- mice pups were subjected to hyperoxia (70% O2, p7-p12) then returned to normal air (relative hypoxia, p12-p17). Vascular alterations were assessed at p12 and p17 time-points. Deletion of p75NTR prevented hyperoxia-associated central vascular cell death (p12) and hypoxia-associated RNV and enhanced central vascular repair (p17). Decreased expression of apoptotic markers; preserved Akt survival signal decreased proNGF were also observed at p12. During hypoxia, deletion of p75NTR maintained VEGF and VEGFR2 activation and restored NGF/proNGF and BDNF/proBDNF levels. Deletion of p75NTR coincided with significant increases in expression and activation of NGF survival receptor, TrkA at basal and hyperoxic condition. Pharmacological inhibition of TrkA using compound K-252a (0.5 μg 1 μl-1/eye) resulted in 2-fold increase in pathological RNV and 1.34-fold increase in central vascular cell death in p75NTR-/- pups. In conclusion, deletion of p75NTR protected against retinal ischemia and prevented RNV, in part, through restoring neurotrophic support and activating TrkA receptor.
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Affiliation(s)
- Sally L Elshaer
- Augusta Biomedical Research Corporation, Augusta, GA, 30912, USA
- Charlie Norwood VA Medical Center, Augusta, GA, 30912, USA
- Ophthalmology Department, Hamilton Eye Institute, University of Tennessee Health Sciences Center, Memphis, TN, 38163, USA
| | - Azza B El-Remessy
- Augusta Biomedical Research Corporation, Augusta, GA, 30912, USA.
- Charlie Norwood VA Medical Center, Augusta, GA, 30912, USA.
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33
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The neurotrophic tyrosine kinase receptor TrkA and its ligand NGF are increased in squamous cell carcinomas of the lung. Sci Rep 2018; 8:8135. [PMID: 29802376 PMCID: PMC5970205 DOI: 10.1038/s41598-018-26408-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 05/10/2018] [Indexed: 02/06/2023] Open
Abstract
The neurotrophic tyrosine kinase receptor TrkA (NTRK1) and its ligand nerve growth factor (NGF) are emerging promoters of tumor progression. In lung cancer, drugs targeting TrkA are in clinical trials, but the clinicopathological significance of TrkA and NGF, as well as that of the precursor proNGF, the neurotrophin co-receptor p75NTR and the proneurotrophin co-receptor sortilin, remains unclear. In the present study, analysis of these proteins was conducted by immunohistochemistry and digital quantification in a series of 204 lung cancers of different histological subtypes versus 121 normal lung tissues. TrkA immunoreactivity was increased in squamous cell carcinoma compared with benign and other malignant lung cancer histological subtypes (p < 0.0001). NGF and proNGF were also increased in squamous cell carcinoma, as well as in adenocarcinoma (p < 0.0001). In contrast, p75NTR was increased across all lung cancer histological subtypes compared to normal lung (p < 0.0001). Sortilin was higher in adenocarcinoma and small cell carcinoma (p < 0.0001). Nerves in the tumor microenvironment were negative for TrkA, NGF, proNGF, p75NTR and sortilin. In conclusion, these data suggest a preferential therapeutic value of targeting the NGF-TrkA axis in squamous cell carcinomas of the lung.
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34
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De la Cruz-Morcillo MA, Berger J, Sánchez-Prieto R, Saada S, Naves T, Guillaudeau A, Perraud A, Sindou P, Lacroix A, Descazeaud A, Lalloué F, Jauberteau MO. p75 neurotrophin receptor and pro-BDNF promote cell survival and migration in clear cell renal cell carcinoma. Oncotarget 2018; 7:34480-97. [PMID: 27120782 PMCID: PMC5085170 DOI: 10.18632/oncotarget.8911] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 04/10/2016] [Indexed: 12/13/2022] Open
Abstract
p75NTR, a member of TNF receptor family, is the low affinity receptor common to several mature neurotrophins and the high affinity receptor for pro-neurotrophins. Brain-Derived Neurotrophic Factor (BDNF), a member of neurotrophin family has been described to play an important role in development and progression of several cancers, through its binding to a high affinity tyrosine kinase receptor B (TrkB) and/or p75NTR. However, the functions of these two receptors in renal cell carcinoma (RCC) have never been investigated. An overexpression of p75NTR, pro-BDNF, and to a lesser extent for TrkB and sortilin, was detected by immunohistochemistry in a cohort of 83 clear cell RCC tumors. p75NTR, mainly expressed in tumor tissues, was significantly associated with higher Fuhrman grade in multivariate analysis. In two derived-RCC lines, 786-O and ACHN cells, we demonstrated that pro-BDNF induced cell survival and migration, through p75NTR as provided by p75NTR RNA silencing or blocking anti-p75NTR antibody. This mechanism is independent of TrkB activation as demonstrated by k252a, a tyrosine kinase inhibitor for Trk neurotrophin receptors. Taken together, these data highlight for the first time an important role for p75NTR in renal cancer and indicate a putative novel target therapy in RCC.
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Affiliation(s)
- Miguel A De la Cruz-Morcillo
- Limoges University, Equipe Accueil 3842, Cellular Homeostasis and Diseases, Faculty of Medicine, 87025 Limoges, Cedex, France
| | - Julien Berger
- Limoges University, Equipe Accueil 3842, Cellular Homeostasis and Diseases, Faculty of Medicine, 87025 Limoges, Cedex, France.,Department of Urology, University Hospital Limoges, 87042 Limoges, Cedex, France
| | - Ricardo Sánchez-Prieto
- PCTCLM/CRIB Unidad de Medicina Molecular Laboratorio de Oncología/Unidad de Biomedicina UCLM-CSIC, Universidad de Castilla la Mancha, 02006 Albacete, Spain
| | - Sofiane Saada
- Limoges University, Equipe Accueil 3842, Cellular Homeostasis and Diseases, Faculty of Medicine, 87025 Limoges, Cedex, France
| | - Thomas Naves
- Limoges University, Equipe Accueil 3842, Cellular Homeostasis and Diseases, Faculty of Medicine, 87025 Limoges, Cedex, France
| | | | - Aurélie Perraud
- Limoges University, Equipe Accueil 3842, Cellular Homeostasis and Diseases, Faculty of Medicine, 87025 Limoges, Cedex, France
| | - Philippe Sindou
- Limoges University, Equipe Accueil 3842, Cellular Homeostasis and Diseases, Faculty of Medicine, 87025 Limoges, Cedex, France
| | - Aurélie Lacroix
- Limoges University, Equipe Accueil 3842, Cellular Homeostasis and Diseases, Faculty of Medicine, 87025 Limoges, Cedex, France
| | - Aurélien Descazeaud
- Limoges University, Equipe Accueil 3842, Cellular Homeostasis and Diseases, Faculty of Medicine, 87025 Limoges, Cedex, France.,Department of Urology, University Hospital Limoges, 87042 Limoges, Cedex, France
| | - Fabrice Lalloué
- Limoges University, Equipe Accueil 3842, Cellular Homeostasis and Diseases, Faculty of Medicine, 87025 Limoges, Cedex, France
| | - Marie-Odile Jauberteau
- Limoges University, Equipe Accueil 3842, Cellular Homeostasis and Diseases, Faculty of Medicine, 87025 Limoges, Cedex, France
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35
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Kim JT, Napier DL, Weiss HL, Lee EY, Townsend CM, Evers BM. Neurotensin Receptor 3/Sortilin Contributes to Tumorigenesis of Neuroendocrine Tumors Through Augmentation of Cell Adhesion and Migration. Neoplasia 2017; 20:175-181. [PMID: 29272741 PMCID: PMC5884004 DOI: 10.1016/j.neo.2017.11.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 11/21/2017] [Accepted: 11/21/2017] [Indexed: 01/15/2023] Open
Abstract
Neurotensin (NTS), a 13–amino acid peptide which is distributed predominantly along gastrointestinal tract, has multiple physiologic and pathologic functions, and its effects are mediated by three distinct NTS receptors (NTSRs). Overexpression and activation of NTS signaling components, especially NTS and/or NTSR1, are closely linked with cancer progression and metastasis in various types of cancers including neuroendocrine tumors (NETs). Although deregulation of NTSR3/sortilin has been implicated in a variety of human diseases, the expression and role of NTSR3/sortilin in NETs have not been elucidated. In this study, we investigated the expression and oncogenic effect of NTSR3/sortilin in NETs. Increased protein levels of NTSR3/sortilin were noted in the majority of human clinical NETs (n = 21) by immunohistochemical analyses compared with normal tissues (n = 12). Expression of NTS and NTSR3/sortilin was also noted in all tested NET cell lines. In addition, small interfering RNA–mediated knockdown of NTSR3/sortilin decreased cell number without alteration of cell cycle progression and apoptosis induction in NET cell lines BON and QGP-1. Moreover, silencing of NTSR3/sortilin significantly suppressed cell adhesion and cell migration with inhibition of focal adhesion kinase and Src phosphorylation in the NET cells. Our results demonstrate increased expression of NTSR3/sortilin in NET patient tissues and a critical role of NTSR3/sortilin on NET cell adhesion and migration suggesting that NTSR3/sortilin contributes to NET tumorigenesis.
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Affiliation(s)
- Ji Tae Kim
- Markey Cancer Center, University of Kentucky, Lexington, KY
| | - Dana L Napier
- Markey Cancer Center, University of Kentucky, Lexington, KY
| | - Heidi L Weiss
- Markey Cancer Center, University of Kentucky, Lexington, KY; Department of Surgery, University of Kentucky, Lexington, KY
| | - Eun Y Lee
- Department of Pathology, University of Kentucky, Lexington, KY
| | | | - B Mark Evers
- Markey Cancer Center, University of Kentucky, Lexington, KY; Department of Surgery, University of Kentucky, Lexington, KY.
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Faulkner S, Roselli S, Demont Y, Pundavela J, Choquet G, Leissner P, Oldmeadow C, Attia J, Walker MM, Hondermarck H. ProNGF is a potential diagnostic biomarker for thyroid cancer. Oncotarget 2017; 7:28488-97. [PMID: 27074571 PMCID: PMC5053740 DOI: 10.18632/oncotarget.8652] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 03/28/2016] [Indexed: 11/25/2022] Open
Abstract
The precursor for nerve growth factor (proNGF) is expressed in some cancers but its clinicopathological significance is unclear. The present study aimed to define the clinicopathological significance of proNGF in thyroid cancer. ProNGF expression was analysed by immunohistochemistry in two cohorts of cancer versus benign tumors (adenoma) and normal thyroid tissues. In the first cohort (40 thyroid cancers, 40 thyroid adenomas and 80 normal thyroid tissues), proNGF was found overexpressed in cancers compared to adenomas and normal samples (p<0.0001). The area under the receiver-operating characteristic (ROC) curve was 0.84 (95% CI 0.75-0.93, p<0.0001) for cancers versus adenomas, and 0.99 (95% CI 0.98-1.00, p<0.0001) for cancers versus normal tissues. ProNGF overexpression was confirmed in a second cohort (127 cancers of various histological types and 55 normal thyroid tissues) and using a different antibody (p<0.0001). ProNGF staining intensity was highest in papillary carcinomas compared to other histological types (p<0.0001) and there was no significant association with age, gender, tumor size, stage and lymph node status. In conclusion, proNGF is increased in thyroid cancer and should be considered as a new potential diagnostic biomarker.
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Affiliation(s)
- Sam Faulkner
- School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan NSW 2308, Australia.,Hunter Medical Research Institute, University of Newcastle, New Lambton NSW 2305, Australia
| | - Severine Roselli
- School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan NSW 2308, Australia.,Hunter Medical Research Institute, University of Newcastle, New Lambton NSW 2305, Australia
| | - Yohann Demont
- Inserm U908, Growth Factor Signaling and Functional Proteomics of Breast Cancer, University of Lille, 59655 Villeneuve d'Ascq, France.,Present address: INSERM U1138 team 11, Centre de Recherche des Cordeliers, 75006 Paris, France
| | - Jay Pundavela
- School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan NSW 2308, Australia.,Hunter Medical Research Institute, University of Newcastle, New Lambton NSW 2305, Australia
| | - Genevieve Choquet
- Medical Diagnostic Discovery Department, bioMérieux, 69280 Marcy l'Etoile, France
| | - Philippe Leissner
- Medical Diagnostic Discovery Department, bioMérieux, 69280 Marcy l'Etoile, France
| | - Christopher Oldmeadow
- School of Mathematical and Physical Sciences, Faculty of Science and Information Technology, University of Newcastle, Callaghan NSW 2308, Australia
| | - John Attia
- Hunter Medical Research Institute, University of Newcastle, New Lambton NSW 2305, Australia.,School of Public Health & Medicine, Faculty of Health and Medicine, University of Newcastle, Callaghan NSW 2308, Australia
| | - Marjorie M Walker
- Hunter Medical Research Institute, University of Newcastle, New Lambton NSW 2305, Australia.,School of Public Health & Medicine, Faculty of Health and Medicine, University of Newcastle, Callaghan NSW 2308, Australia
| | - Hubert Hondermarck
- School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan NSW 2308, Australia.,Hunter Medical Research Institute, University of Newcastle, New Lambton NSW 2305, Australia
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37
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Faulkner S, Jobling P, Rowe CW, Rodrigues Oliveira SM, Roselli S, Thorne RF, Oldmeadow C, Attia J, Jiang CC, Zhang XD, Walker MM, Hondermarck H. Neurotrophin Receptors TrkA, p75 NTR, and Sortilin Are Increased and Targetable in Thyroid Cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 188:229-241. [PMID: 29037860 DOI: 10.1016/j.ajpath.2017.09.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 08/14/2017] [Accepted: 09/21/2017] [Indexed: 12/21/2022]
Abstract
Neurotrophin receptors are emerging targets in oncology, but their clinicopathologic significance in thyroid cancer is unclear. In this study, the neurotrophin tyrosine receptor kinase TrkA (also called NTRK1), the common neurotrophin receptor p75NTR, and the proneurotrophin receptor sortilin were analyzed with immunohistochemistry in a cohort of thyroid cancers (n = 128) and compared with adenomas and normal thyroid tissues (n = 62). TrkA was detected in 20% of thyroid cancers, compared with none of the benign samples (P = 0.0007). TrkA expression was independent of histologic subtypes but associated with lymph node metastasis (P = 0.0148), suggesting the involvement of TrkA in tumor invasiveness. Nerves in the tumor microenvironment were positive for TrkA. p75NTR was overexpressed in anaplastic thyroid cancers compared with papillary and follicular subtypes (P < 0.0001). Sortilin was overexpressed in thyroid cancers compared with benign thyroid tissues (P < 0.0001). Neurotrophin receptor expression was confirmed in a panel of thyroid cancer cell lines at the mRNA and protein levels. Functional investigations using the anaplastic thyroid cancer cell line CAL-62 found that siRNA against TrkA, p75NTR, and sortilin decreased cell survival and cell migration through decreased SRC and ERK activation. Together, these data reveal TrkA, p75NTR, and sortilin as potential therapeutic targets in thyroid cancer.
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Affiliation(s)
- Sam Faulkner
- School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia
| | - Philip Jobling
- School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia
| | - Christopher W Rowe
- Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia; School of Medicine & Public Health, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia; Department of Endocrinology, John Hunter Hospital, Callaghan, New South Wales, Australia
| | - S M Rodrigues Oliveira
- School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia
| | - Severine Roselli
- School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia
| | - Rick F Thorne
- Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia
| | - Christopher Oldmeadow
- Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia; School of Mathematical and Physical Sciences, Faculty of Science and Information Technology, University of Newcastle, Callaghan, New South Wales, Australia
| | - John Attia
- Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia; School of Medicine & Public Health, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia
| | - Chen Chen Jiang
- Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia; School of Medicine & Public Health, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia
| | - Xu Dong Zhang
- School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia
| | - Marjorie M Walker
- Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia; School of Medicine & Public Health, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia; Department of Anatomical Pathology, John Hunter Hospital, Callaghan, New South Wales, Australia
| | - Hubert Hondermarck
- School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia; Hunter Medical Research Institute, University of Newcastle, Callaghan, New South Wales, Australia.
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Zhu MC, Xiong P, Li GL, Zhu M. Could lung cancer exosomes induce apoptosis of natural killer cells through the p75NTR–proNGF–sortilin axis? Med Hypotheses 2017; 108:151-153. [DOI: 10.1016/j.mehy.2017.09.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 09/04/2017] [Indexed: 01/08/2023]
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Chen CC, Chiou SH, Yang CL, Chow KC, Lin TY, Chang HW, You WC, Huang HW, Chen CM, Chen NC, Chou FP, Chou MC. Secreted gelsolin desensitizes and induces apoptosis of infiltrated lymphocytes in prostate cancer. Oncotarget 2017; 8:77152-77167. [PMID: 29100377 PMCID: PMC5652770 DOI: 10.18632/oncotarget.20414] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 06/12/2017] [Indexed: 12/16/2022] Open
Abstract
Loss of immunosurveillance is a major cause of cancer progression. Here, we demonstrate that gelsolin, a constituent of ejaculate, induces apoptosis of activated lymphocytes in prostate cancer. Gelsolin was highly expressed in prostate cancer cells, and was associated with tumor progression, recurrence, metastasis, and poor prognosis. In vitro, secreted gelsolin inactivated CD4+ T cells by binding to CD37, and induced apoptosis of activated CD8+ T lymphocytes by binding to Fas ligand during cell contact dependent on major histocompatibility complex I. Moreover, secreted gelsolin bound to sortilin, which in turn bound to Wiskott-Aldrich syndrome protein family member 3, thereby enhancing the endocytosis and intracellular transport of essential lipids needed to facilitate tumor growth and expansion. Under normal conditions, gelsolin is a seemingly harmless protein that prevents immune responses in female recipients. In disease states, however, this protein can inhibit immunosurveillance and promote cancer progression.
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Affiliation(s)
- Chun-Chi Chen
- Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan.,Section of Urology, Departments of Surgery, Changhua Christian Hospital, Chang-Hua, Taiwan
| | - Shiow-Her Chiou
- Graduate Institute of Microbiology and Public Health, National Chung Hsing University, Taichung, Taiwan
| | - Cheng-Lin Yang
- Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Kuan-Chih Chow
- Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Tze-Yi Lin
- Department of Pathology, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Hui-Wen Chang
- Department of Pathology, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Weir-Chiang You
- Department of Radiation Oncology, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Hisu-Wen Huang
- Endemic Species Research Institute, Council of Agriculture, Executive Yuan, Chi-Chi, Taiwan
| | - Chien-Min Chen
- Endemic Species Research Institute, Council of Agriculture, Executive Yuan, Chi-Chi, Taiwan
| | - Nien-Cheng Chen
- Institute of Biochemistry, Microbiology and Immunology, Chung-Shan Medical University, Taichung, Taiwan
| | - Fen-Pi Chou
- Institute of Biochemistry, Microbiology and Immunology, Chung-Shan Medical University, Taichung, Taiwan
| | - Ming-Chih Chou
- Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan.,Department of Family and Community Medicine, Chung-Shan Medical University Hospital, Chung-Shan Medical University, Taichung, Taiwan
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40
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Noh SJ, Kim KM, Jang KY. Individual and co-expression patterns of nerve growth factor and heme oxygenase-1 predict shorter survival of gastric carcinoma patients. Diagn Pathol 2017; 12:48. [PMID: 28679437 PMCID: PMC5498870 DOI: 10.1186/s13000-017-0644-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Accepted: 06/30/2017] [Indexed: 02/09/2023] Open
Abstract
BACKGROUND Nerve growth factor (NGF) is a neurotrophic factor which regulates cell development and proliferation. Recently, it has been suggested that NGF induces heme oxygenase-1 (HO1) expression, and that both NGF and HO1 are involved in the progression of malignant human tumors. However, exact roles of NGF and HO1 in tumorigenesis remain controversial. Therefore, we investigated the expression and correlation of NGF and HO1 in human gastric carcinoma tissues. METHODS We examined immunohistochemical expression of NGF and HO1 in 167 gastric carcinomas and compared with various prognostic clinicopathological factors. RESULTS The expression of NGF and HO1 was positive in 40% (67/167) and 51% (85/167) of cases, respectively, and their expression was significantly correlated with each other (p < 0.001). Individual expression patterns of NGF and HO1, and co-expression pattern of these two molecules were significantly associated with shorter survival by univariate analysis. HO1 expression (overall survival; p < 0.001, relapse-free survival; p = 0.002) and co-expression pattern of NGF and HO1 (overall survival; p = 0.002, relapse-free survival; p = 0.003) were independent poor prognostic indicators of gastric carcinoma patients by multivariate analysis. CONCLUSIONS These results demonstrate that the individual and co-expression patterns of NGF and HO1 might be used as prognostic indicators for gastric carcinoma patients.
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Affiliation(s)
- Sang Jae Noh
- Department of Forensic Medicine, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, 20, Geonji-ro, Deokjin-gu, Jeonju, Jeonbuk, 54907, Republic of Korea
| | - Kyoung Min Kim
- Department of Pathology, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, 20, Geonji-ro, Deokjin-gu, Jeonju, Jeonbuk, 54907, Republic of Korea
| | - Kyu Yun Jang
- Department of Pathology, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, 20, Geonji-ro, Deokjin-gu, Jeonju, Jeonbuk, 54907, Republic of Korea.
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41
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Shargh VH, Hondermarck H, Liang M. Gelatin-albumin hybrid nanoparticles as matrix metalloproteinases-degradable delivery systems for breast cancer therapy. Nanomedicine (Lond) 2017; 12:977-989. [PMID: 28440712 DOI: 10.2217/nnm-2016-0419] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIM To develop matrix metalloproteinase-responsive gelatin-albumin hybrid nanoparticles encapsulating a selective tropomyosin receptor kinase A (TrkA) inhibitor GNF-5837 (Gel-Alb-GNF HNPs) and to demonstrate their anticancer effects in breast cancer. METHODS Gel-Alb-GNF HNPs were prepared using a pH-controlled complexation process from cationic gelatin, dextran sulfate and albumin-bound GNF-5837. The anticancer activities of Gel-Alb-GNF HNPs were tested in a panel of subtype-specific breast cancer cell lines. RESULTS Gel-Alb-GNF HNPs (∼130 nm) displayed excellent stability and matrix metalloproteinase-triggered drug release. Compared with GNF-5837 alone, Gel-Alb-GNF HNPs not only significantly enhanced the antiproliferative and anti-invasive effects but also restored the apoptosis of cancer cells. CONCLUSION Gel-Alb-GNF HNPs may be adaptable for stand-alone therapies or used in combination with traditional chemotherapies for breast cancer treatment.
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Affiliation(s)
- Vahid Heravi Shargh
- School of Biomedical Sciences & Pharmacy, Faculty of Health & Medicine, University of Newcastle, Callaghan, NSW 2308, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Hubert Hondermarck
- School of Biomedical Sciences & Pharmacy, Faculty of Health & Medicine, University of Newcastle, Callaghan, NSW 2308, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Mingtao Liang
- School of Biomedical Sciences & Pharmacy, Faculty of Health & Medicine, University of Newcastle, Callaghan, NSW 2308, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
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Abstract
In the last few years, exciting properties have emerged regarding the activation, signaling, mechanisms of action, and therapeutic targeting of the two types of neurotrophin receptors: the p75NTR with its intracellular and extracellular peptides, the Trks, their precursors and their complexes. This review summarizes these new developments, with particular focus on neurodegenerative diseases. Based on the evolving knowledge, innovative concepts have been formulated regarding the pathogenesis of these diseases, especially the Alzheimer's and two other, the Parkinson's and Huntington's diseases. The medical progresses include original procedures of diagnosis, started from studies in mice and now investigated for human application, based on innovative classes of receptor agonists and blockers. In parallel, comprehensive studies have been and are being carried out for the development of drugs. The relevance of these studies is based on the limitations of the therapies employed until recently, especially for the treatment of Alzheimer's patients. Starting from well known drugs, previously employed for non-neurodegenerative diseases, the ongoing progress has lead to the development of small molecules that cross rapidly the blood-brain barrier. Among these molecules the most promising are specific blockers of the p75NTR receptor. Additional drugs, that activate Trk receptors, were shown effective against synaptic loss and memory deficits. In the near future such approaches, coordinated with treatments with monoclonal antibodies and with developments in the microRNA field, are expected to improve the therapy of neurodegenerative diseases, and may be relevant also for other human disease conditions.
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Affiliation(s)
- Jacopo Meldolesi
- Department of Neuroscience, Vita-Salute San Raffaele University and Scientific Institute San Raffaele, via Olgettina 58, 20132 Milan, Italy.
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ProNGF, but Not NGF, Switches from Neurotrophic to Apoptotic Activity in Response to Reductions in TrkA Receptor Levels. Int J Mol Sci 2017; 18:ijms18030599. [PMID: 28282920 PMCID: PMC5372615 DOI: 10.3390/ijms18030599] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 03/03/2017] [Accepted: 03/07/2017] [Indexed: 12/13/2022] Open
Abstract
Nerve growth factor (NGF) promotes the survival and differentiation of neurons. NGF is initially synthesized as a precursor, proNGF, which is the predominant form in the central nervous system. NGF and proNGF bind to TrkA/p75NTR to mediate cell survival and to sortilin/p75NTR to promote apoptosis. The ratio of TrkA to p75NTR affects whether proNGF and mature NGF signal cell survival or apoptosis. The purpose of this study was to determine whether the loss of TrkA influences p75NTR or sortilin expression levels, and to establish whether proNGF and mature NGF have a similar ability to switch between cell survival and cell death. We systematically altered TrkA receptor levels by priming cells with NGF, using small interfering RNA, and using the mutagenized PC12nnr5 cell line. We found that both NGF and proNGF can support cell survival in cells expressing TrkA, even in the presence of p75NTR and sortilin. However, when TrkA is reduced, proNGF signals cell death, while NGF exhibits no activity. In the absence of TrkA, proNGF-induced cell death occurs, even when p75NTR and sortilin levels are reduced. These results show that proNGF can switch between neurotrophic and apoptotic activity in response to changes in TrkA receptor levels, whereas mature NGF cannot. These results also support the model that proNGF is neurotrophic under normal circumstances, but that a loss in TrkA in the presence of p75NTR and sortilin, as occurs in neurodegenerative disease or injury, shifts proNGF, but not NGF, signalling from cell survival to cell death.
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44
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Albumin hybrid nanoparticles loaded with tyrosine kinase A inhibitor GNF-5837 for targeted inhibition of breast cancer cell growth and invasion. Int J Pharm 2016; 515:527-534. [DOI: 10.1016/j.ijpharm.2016.10.057] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 09/17/2016] [Accepted: 10/24/2016] [Indexed: 01/18/2023]
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Nerve growth factor regulates CD133 function to promote tumor cell migration and invasion via activating ERK1/2 signaling in pancreatic cancer. Pancreatology 2016; 16:1005-1014. [PMID: 27654574 DOI: 10.1016/j.pan.2016.09.005] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 08/07/2016] [Accepted: 09/12/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Perineural invasion (PNI) is extremely high frequency among the various metastatic routes in pancreatic cancer. Nerve growth factor, secreted by astroglial cells, exerts effects on tumor invasion in some cancer cells, but its function on migration and invasion in pancreatic cancer is still unclear. In the present study, we determined the effects of NGF on modulating tumor cell metastatic potential and invasion activity and explored its mechanisms in pancreatic cancer. METHODS NGF and CD133 expression were detected in tumor tissues using immunohistochemical analysis and Western blotting analysis. The effects of NGF on the regulation of CD133 expression and the promotion of cancer migration and invasion were investigated using wound healing and matrigel transwell assay. A related mechanism that NGF regulates CD133's function via activating ERK1/2 signaling also was observed. RESULTS NGF/CD133 is overexpressed in human pancreatic cancer and promotes the migration and invasion of human pancreatic cancer cells through the activation of the ERK/CD133 signaling cascade. NGF/ERK signaling modulates the cancer cell EMT process, migration and invasion through the regulation of CD133 expression and its subcellular localization. CONCLUSIONS NGF/CD133 signaling initiated the migration and invasion of pancreatic cancer cells. NGF/CD133 might be an effective and potent therapeutic target for pancreatic cancer metastasis, particularly in PNI.
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Demir IE, Tieftrunk E, Schorn S, Friess H, Ceyhan GO. Nerve growth factor & TrkA as novel therapeutic targets in cancer. Biochim Biophys Acta Rev Cancer 2016; 1866:37-50. [PMID: 27264679 DOI: 10.1016/j.bbcan.2016.05.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 05/24/2016] [Accepted: 05/28/2016] [Indexed: 12/11/2022]
Abstract
In the past 20years, nerve growth factor (NGF) and its receptors TrkA & p75NTR were recognized to be overexpressed in the overwhelming majority of human solid cancers. Recent studies discovered the presence of overactive TrkA signaling due to TrkA rearrangements or TrkA fusion products in frequent cancers like colorectal cancer, thyroid cancer, or acute myeloid leukemia. Thus, targeting TrkA/NGF via selective small-molecule-inhibitors or antibodies has gained enormous attention in the drug discovery sector. Clinical studies on the anti-cancer impact of NGF-blocking antibodies are likely to be accelerated after the recent removal of clinical holds on these agents by regulatory authorities. Based on these current developments, the present review provides not only a broad overview of the biological effects of NGF-TrkA-p75NTR on cancer cells and their microenvironment, but also explains why NGF and its receptors are going to evoke major interest as promising therapeutic anti-cancer targets in the coming decade.
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Affiliation(s)
- Ihsan Ekin Demir
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
| | - Elke Tieftrunk
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany
| | - Stephan Schorn
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany
| | - Helmut Friess
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany
| | - Güralp O Ceyhan
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany
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Chopin V, Lagadec C, Toillon RA, Le Bourhis X. Neurotrophin signaling in cancer stem cells. Cell Mol Life Sci 2016; 73:1859-70. [PMID: 26883804 PMCID: PMC11108437 DOI: 10.1007/s00018-016-2156-7] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 01/06/2016] [Accepted: 02/04/2016] [Indexed: 12/26/2022]
Abstract
Cancer stem cells (CSCs), are thought to be at the origin of tumor development and resistance to therapies. Thus, a better understanding of the molecular mechanisms involved in the control of CSC stemness is essential to the design of more effective therapies for cancer patients. Cancer cell stemness and the subsequent expansion of CSCs are regulated by micro-environmental signals including neurotrophins. Over the years, the roles of neurotrophins in tumor development have been well established and regularly reviewed. Especially, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are reported to stimulate tumor cell proliferation, survival, migration and/or invasion, and favors tumor angiogenesis. More recently, neurotrophins have been reported to regulate CSCs. This review briefly presents neurotrophins and their receptors, summarizes their roles in different cancers, and discusses the emerging evidence of neurotrophins-induced enrichment of CSCs as well as the involved signaling pathways.
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Affiliation(s)
- Valérie Chopin
- CPAC, Cell Plasticity and Cancer, Univ. Lille, INSERM U908, F-59 000, Villeneuve d'Ascq, France
- University of Picardie Jules Verne, 80000, Amiens, France
| | - Chann Lagadec
- CPAC, Cell Plasticity and Cancer, Univ. Lille, INSERM U908, F-59 000, Villeneuve d'Ascq, France
| | - Robert-Alain Toillon
- CPAC, Cell Plasticity and Cancer, Univ. Lille, INSERM U908, F-59 000, Villeneuve d'Ascq, France
| | - Xuefen Le Bourhis
- CPAC, Cell Plasticity and Cancer, Univ. Lille, INSERM U908, F-59 000, Villeneuve d'Ascq, France.
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Yao P, Ding Y, Wang Z, Ma J, Hong T, Zhu Y, Li H, Pan S. Impacts of anti-nerve growth factor antibody on pain-related behaviors and expressions of opioid receptor in spinal dorsal horn and dorsal root ganglia of rats with cancer-induced bone pain. Mol Pain 2016; 12:12/0/1744806916644928. [PMID: 27118770 PMCID: PMC4955994 DOI: 10.1177/1744806916644928] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 03/20/2016] [Indexed: 11/15/2022] Open
Abstract
Objective To investigate the impacts of anti-nerve growth factor antibody on pain-related behaviors and expressions of μ-opioid receptor in spinal dorsal horn and dorsal root ganglia of rats with cancer-induced bone pain. Methods The rats were randomly grouped and then injected with 10 μl of phosphate buffer saline or Walker256 tumor cells into the upper segment of left tibia. Thirteen days after the injection, the intrathecal catheterization was performed, followed by the injection of saline, anti-nerve growth factor, nerve growth factor, and naloxone twice a day. The pain ethological changes were measured at the set time points; the expression changes of μ-opioid receptor protein and mRNA in spinal dorsal horn and dorsal root ganglia were detected on the 18th day. Results After the tumor cells were injected into the tibia, hyperalgesia appeared and the expression of μ-opioid receptor protein and mRNA in spinal dorsal horn and dorsal root ganglia was increased, compared with the sham group; after intrathecally injected anti-nerve growth factor, the significant antinociceptive effects appeared, and the μ-opioid receptor expression was increased, compared with the cancer pain group; the μ-opioid receptor expressions in the other groups showed no statistical significance. The naloxone pretreatment could mostly inverse the antinociception effects of anti-nerve growth factor. Conclusions Anti-nerve growth factor could reduce hyperalgesia in the cancer-induced bone pain rats, and the antinociceptive effects were related with the upregulation of μ-opioid receptor.
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Affiliation(s)
- Peng Yao
- Department of Pain Management, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yuanyuan Ding
- Department of Pain Management, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhibin Wang
- Department of Pain Management, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jiaming Ma
- Department of Pain Management, Shengjing Hospital of China Medical University, Shenyang, China
| | - Tao Hong
- Department of Pain Management, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yongqiang Zhu
- Department of Pain Management, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hongxi Li
- Department of Pain Management, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shinong Pan
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
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Aubert L, Guilbert M, Corbet C, Génot E, Adriaenssens E, Chassat T, Bertucci F, Daubon T, Magné N, Le Bourhis X, Toillon RA. NGF-induced TrkA/CD44 association is involved in tumor aggressiveness and resistance to lestaurtinib. Oncotarget 2016; 6:9807-19. [PMID: 25840418 PMCID: PMC4496399 DOI: 10.18632/oncotarget.3227] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 01/27/2015] [Indexed: 11/25/2022] Open
Abstract
There is accumulating evidence that TrkA and its ligand Nerve Growth Factor (NGF) are involved in cancer development. Staurosporine derivatives such as K252a and lestaurtinib have been developed to block TrkA kinase signaling, but no clinical trial has fully demonstrated their therapeutic efficacy. Therapeutic failures are likely due to the existence of intrinsic signaling pathways in cancer cells that impede or bypass the effects of TrkA tyrosine kinase inhibitors. To verify this hypothesis, we combined different approaches including mass spectrometry proteomics, co-immunoprecipitation and proximity ligation assays. We found that NGF treatment induced CD44 binding to TrkA at the plasma membrane and subsequent activation of the p115RhoGEF/RhoA/ROCK1 pathway to stimulate breast cancer cell invasion. The NGF-induced CD44 signaling was independent of TrkA kinase activity. Moreover, both TrkA tyrosine kinase inhibition with lestaurtinib and CD44 silencing with siRNA inhibited cell growth in vitro as well as tumor development in mouse xenograft model; combined treatment significantly enhanced the antineoplastic effects of either treatment alone. Altogether, our results demonstrate that NGF-induced tyrosine kinase independent TrkA signaling through CD44 was sufficient to maintain tumor aggressiveness. Our findings provide an alternative mechanism of cancer resistance to lestaurtinib and indicate that dual inhibition of CD44 and TrkA tyrosine kinase activity may represent a novel therapeutic strategy.
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Affiliation(s)
- Léo Aubert
- INSERM U908, 59655 Villeneuve d'Ascq, France.,University Lille 1, 59655 Villeneuve d'Ascq, France.,SIRIC OncoLille, 59000 Lille, France
| | - Matthieu Guilbert
- INSERM U908, 59655 Villeneuve d'Ascq, France.,University Lille 1, 59655 Villeneuve d'Ascq, France.,SIRIC OncoLille, 59000 Lille, France
| | - Cyril Corbet
- INSERM U908, 59655 Villeneuve d'Ascq, France.,University Lille 1, 59655 Villeneuve d'Ascq, France.,SIRIC OncoLille, 59000 Lille, France
| | | | - Eric Adriaenssens
- INSERM U908, 59655 Villeneuve d'Ascq, France.,University Lille 1, 59655 Villeneuve d'Ascq, France.,CNRS UMR 8161, 59000 Lille, France
| | | | | | | | - Nicolas Magné
- Radiobiologie Cellulaire et Moléculaire, EMR3738 - Equipe 4, Faculté de Médecine Lyon-Sud, 69000 Lyon, France.,Département de Radiothérapie, Institut de Cancérologie Lucien Neuwirth, 42270 Saint Priest en Jarez, France
| | - Xuefen Le Bourhis
- INSERM U908, 59655 Villeneuve d'Ascq, France.,University Lille 1, 59655 Villeneuve d'Ascq, France.,SIRIC OncoLille, 59000 Lille, France
| | - Robert-Alain Toillon
- INSERM U908, 59655 Villeneuve d'Ascq, France.,University Lille 1, 59655 Villeneuve d'Ascq, France.,SIRIC OncoLille, 59000 Lille, France
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50
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Roselli S, Pundavela J, Demont Y, Faulkner S, Keene S, Attia J, Jiang CC, Zhang XD, Walker MM, Hondermarck H. Sortilin is associated with breast cancer aggressiveness and contributes to tumor cell adhesion and invasion. Oncotarget 2016; 6:10473-86. [PMID: 25871389 PMCID: PMC4496368 DOI: 10.18632/oncotarget.3401] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Accepted: 02/16/2015] [Indexed: 11/25/2022] Open
Abstract
The neuronal membrane protein sortilin has been reported in a few cancer cell lines, but its expression and impact in human tumors is unclear. In this study, sortilin was analyzed by immunohistochemistry in a series of 318 clinically annotated breast cancers and 53 normal breast tissues. Sortilin was detected in epithelial cells, with increased levels in cancers, as compared to normal tissues (p = 0.0088). It was found in 79% of invasive ductal carcinomas and 54% of invasive lobular carcinomas (p < 0.0001). There was an association between sortilin expression and lymph node involvement (p = 0.0093), suggesting a relationship with metastatic potential. In cell culture, sortilin levels were higher in cancer cell lines compared to non-tumorigenic breast epithelial cells and siRNA knockdown of sortilin inhibited cancer cell adhesion, while proliferation and apoptosis were not affected. Breast cancer cell migration and invasion were also inhibited by sortilin knockdown, with a decrease in focal adhesion kinase and SRC phosphorylation. In conclusion, sortilin participates in breast tumor aggressiveness and may constitute a new therapeutic target against tumor cell invasion.
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Affiliation(s)
- Séverine Roselli
- School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan NSW 2308, Australia.,Hunter Medical Research Institute, University of Newcastle, New Lambton NSW 2305, Australia
| | - Jay Pundavela
- School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan NSW 2308, Australia.,Hunter Medical Research Institute, University of Newcastle, New Lambton NSW 2305, Australia
| | - Yohann Demont
- INSERM U908, IFR-147, Universite Lille 1, Villeneuve d'Ascq 59655, France.,INSERM U1138, Equipe 11, Centre de Recherche des Cordeliers, Paris 75006, France
| | - Sam Faulkner
- School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan NSW 2308, Australia.,Hunter Medical Research Institute, University of Newcastle, New Lambton NSW 2305, Australia
| | - Sheridan Keene
- School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan NSW 2308, Australia.,Hunter Medical Research Institute, University of Newcastle, New Lambton NSW 2305, Australia
| | - John Attia
- Hunter Medical Research Institute, University of Newcastle, New Lambton NSW 2305, Australia.,School of Public Health & Medicine, Faculty of Health and Medicine, University of Newcastle, Callaghan NSW 2308, Australia
| | - Chen Chen Jiang
- School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan NSW 2308, Australia.,Hunter Medical Research Institute, University of Newcastle, New Lambton NSW 2305, Australia
| | - Xu Dong Zhang
- School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan NSW 2308, Australia.,Hunter Medical Research Institute, University of Newcastle, New Lambton NSW 2305, Australia
| | - Marjorie M Walker
- Hunter Medical Research Institute, University of Newcastle, New Lambton NSW 2305, Australia.,School of Public Health & Medicine, Faculty of Health and Medicine, University of Newcastle, Callaghan NSW 2308, Australia
| | - Hubert Hondermarck
- School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan NSW 2308, Australia.,Hunter Medical Research Institute, University of Newcastle, New Lambton NSW 2305, Australia
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