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1
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Bagheri-Yarmand R, Grubbs EG, Hofmann MC. Thyroid C-Cell Biology and Oncogenic Transformation. Recent Results Cancer Res 2025; 223:51-91. [PMID: 40102254 DOI: 10.1007/978-3-031-80396-3_3] [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] [Indexed: 03/20/2025]
Abstract
The thyroid parafollicular cell, or commonly named "C-cell," functions in serum calcium homeostasis. Elevations in serum calcium trigger release of calcitonin from the C-cell, which in turn functions to inhibit absorption of calcium by the intestine, resorption of bone by the osteoclast, and reabsorption of calcium by renal tubular cells. Oncogenic transformation of the thyroid C-cell is thought to progress through a hyperplastic process prior to malignancy with increasing levels of serum calcitonin serving as a biomarker for tumor burden. The discovery that Multiple Endocrine Neoplasia, type 2 is caused by activating mutations of the RET gene serves to highlight the RET-RAS-MAPK signaling pathway in both initiation and progression of medullary thyroid carcinoma. Thyroid C-cells are known to express RET at high levels relative to most cell types, therefore aberrant activation of this receptor is targeted primarily to the C-cell, providing one possible cause of tissue-specific oncogenesis. The role of RET signaling in normal C-cell function is unknown though calcitonin gene transcription appears to be sensitive to RET activation. Beyond RET the modeling of oncogenesis in animals and screening of human tumors for candidate gene mutations has uncovered mutation of RAS family members and inactivation of RB1 regulatory pathway as potential mediators of C-cell transformation. More recently, the integration of multiple biological layers of omics studies has uncovered new pathways of oncogenesis. A growing understanding of how RET interacts with these pathways, both in normal C-cell function and during oncogenic transformation, will help in the development of novel molecular targeted therapies.
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Affiliation(s)
- Rozita Bagheri-Yarmand
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Elizabeth G Grubbs
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Marie-Claude Hofmann
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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2
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Papachristos AJ, Serrao-Brown H, Gill AJ, Clifton-Bligh R, Sidhu SB. Medullary Thyroid Cancer: Molecular Drivers and Immune Cellular Milieu of the Tumour Microenvironment-Implications for Systemic Treatment. Cancers (Basel) 2024; 16:2296. [PMID: 39001359 PMCID: PMC11240419 DOI: 10.3390/cancers16132296] [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: 05/12/2024] [Revised: 06/16/2024] [Accepted: 06/20/2024] [Indexed: 07/16/2024] Open
Abstract
In this review, we explore the underlying molecular biology of medullary thyroid carcinoma (MTC) and its interplay with the host immune system. MTC is consistently driven by a small number of specific pathogenic variants, beyond which few additional genetic events are required for tumorigenesis. This explains the exceedingly low tumour mutational burden seen in most MTC, in contrast to other cancers. However, because of the low tumour mutational burden (TMB), there is a correspondingly low level of tumour-associated neoantigens that are presented to the host immune system. This reduces tumour visibility and vigour of the anti-tumour immune response and suggests the efficacy of immunotherapy in MTC is likely to be poor, acknowledging this inference is largely based on the extrapolation of data from other tumour types. The dominance of specific RET (REarranged during Transfection) pathogenic variants in MTC tumorigenesis rationalizes the observed efficacy of the targeted RET-specific tyrosine kinase inhibitors (TKIs) in comparison to multi-kinase inhibitors (MKIs). Therapeutic durability of pathway inhibitors is an ongoing research focus. It may be limited by the selection pressure TKI treatment creates, promoting survival of resistant tumour cell clones that can escape pathway inhibition through binding-site mutations, activation of alternate pathways, and modulation of the cellular and cytokine milieu of the tumour microenvironment (TME).
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Affiliation(s)
- Alexander J Papachristos
- Northern Clinical School, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
- Endocrine Surgical Unit, Royal North Shore Hospital, Sydney, NSW 2065, Australia
| | - Hazel Serrao-Brown
- Endocrine Surgical Unit, Royal North Shore Hospital, Sydney, NSW 2065, Australia
| | - Anthony J Gill
- Northern Clinical School, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
- NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW 2065, Australia
- Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW 2065, Australia
| | - Roderick Clifton-Bligh
- Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW 2065, Australia
- Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW 2065, Australia
| | - Stanley B Sidhu
- Northern Clinical School, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
- Endocrine Surgical Unit, Royal North Shore Hospital, Sydney, NSW 2065, Australia
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3
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Karna B, Pellegata NS, Mohr H. Animal and Cell Culture Models of PPGLs - Achievements and Limitations. Horm Metab Res 2024; 56:51-64. [PMID: 38171372 DOI: 10.1055/a-2204-4549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Research on rare tumors heavily relies on suitable models for basic and translational research. Paragangliomas (PPGL) are rare neuroendocrine tumors (NET), developing from adrenal (pheochromocytoma, PCC) or extra-adrenal (PGL) chromaffin cells, with an annual incidence of 2-8 cases per million. While most PPGL cases exhibit slow growth and are primarily treated with surgery, limited systemic treatment options are available for unresectable or metastatic tumors. Scarcity of appropriate models has hindered PPGL research, preventing the translation of omics knowledge into drug and therapy development. Human PPGL cell lines are not available, and few animal models accurately replicate the disease's genetic and phenotypic characteristics. This review provides an overview of laboratory models for PPGLs, spanning cellular, tissue, organ, and organism levels. We discuss their features, advantages, and potential contributions to diagnostics and therapeutics. Interestingly, it appears that in the PPGL field, disease models already successfully implemented in other cancers have not been fully explored.
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Affiliation(s)
- Bhargavi Karna
- Institute for Diabetes and Cancer, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany
| | - Natalia Simona Pellegata
- Institute for Diabetes and Cancer, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany
- Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
| | - Hermine Mohr
- Institute for Diabetes and Cancer, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany
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4
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Garton DR, Turconi G, Iivanainen V, Andressoo JO. Opposing Spatially Segregated Function of Endogenous GDNF-RET Signaling in Cocaine Addiction. Biomolecules 2023; 13:biom13050761. [PMID: 37238631 DOI: 10.3390/biom13050761] [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: 03/14/2023] [Revised: 04/23/2023] [Accepted: 04/24/2023] [Indexed: 05/28/2023] Open
Abstract
Cocaine addiction is a serious condition with potentially lethal complications and no current pharmacological approaches towards treatment. Perturbations of the mesolimbic dopamine system are crucial to the establishment of cocaine-induced conditioned place preference and reward. As a potent neurotrophic factor modulating the function of dopamine neurons, glial cell line-derived neurotrophic factor (GDNF) acting through its receptor RET on dopamine neurons may provide a novel therapeutic avenue towards psychostimulant addiction. However, current knowledge on endogenous GDNF and RET function after the onset of addiction is scarce. Here, we utilized a conditional knockout approach to reduce the expression of the GDNF receptor tyrosine kinase RET from dopamine neurons in the ventral tegmental area (VTA) after the onset of cocaine-induced conditioned place preference. Similarly, after establishing cocaine-induced conditioned place preference, we studied the effect of conditionally reducing GDNF in the ventral striatum nucleus accumbens (NAc), the target of mesolimbic dopaminergic innervation. We find that the reduction of RET within the VTA hastens cocaine-induced conditioned place preference extinction and reduces reinstatement, while the reduction of GDNF within the NAc does the opposite: prolongs cocaine-induced conditioned place preference and increases preference during reinstatement. In addition, the brain-derived neurotrophic factor (BDNF) was increased and key dopamine-related genes were reduced in the GDNF cKO mutant animals after cocaine administration. Thus, RET antagonism in the VTA coupled with intact or enhanced accumbal GDNF function may provide a new approach towards cocaine addiction treatment.
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Affiliation(s)
- Daniel R Garton
- Department of Pharmacology, Faculty of Medicine, Helsinki Institute of Life Science, University of Helsinki, 00290 Helsinki, Finland
| | - Giorgio Turconi
- Department of Pharmacology, Faculty of Medicine, Helsinki Institute of Life Science, University of Helsinki, 00290 Helsinki, Finland
| | - Vilma Iivanainen
- Department of Pharmacology, Faculty of Medicine, Helsinki Institute of Life Science, University of Helsinki, 00290 Helsinki, Finland
| | - Jaan-Olle Andressoo
- Department of Pharmacology, Faculty of Medicine, Helsinki Institute of Life Science, University of Helsinki, 00290 Helsinki, Finland
- Division of Neurogeriatrics, Department of Neurobiology, Care Science and Society (NVS), Karolinska Institutet, 17177 Stockholm, Sweden
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5
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Preclinical Models of Neuroendocrine Neoplasia. Cancers (Basel) 2022; 14:cancers14225646. [PMID: 36428741 PMCID: PMC9688518 DOI: 10.3390/cancers14225646] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/15/2022] [Accepted: 11/15/2022] [Indexed: 11/18/2022] Open
Abstract
Neuroendocrine neoplasia (NENs) are a complex and heterogeneous group of cancers that can arise from neuroendocrine tissues throughout the body and differentiate them from other tumors. Their low incidence and high diversity make many of them orphan conditions characterized by a low incidence and few dedicated clinical trials. Study of the molecular and genetic nature of these diseases is limited in comparison to more common cancers and more dependent on preclinical models, including both in vitro models (such as cell lines and 3D models) and in vivo models (such as patient derived xenografts (PDXs) and genetically-engineered mouse models (GEMMs)). While preclinical models do not fully recapitulate the nature of these cancers in patients, they are useful tools in investigation of the basic biology and early-stage investigation for evaluation of treatments for these cancers. We review available preclinical models for each type of NEN and discuss their history as well as their current use and translation.
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6
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Gonzalez Malagon SG, Liu KJ. Linking neural crest development to neuroblastoma pathology. Development 2022; 149:276149. [DOI: 10.1242/dev.200331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
ABSTRACT
Although rare, childhood (paediatric) cancers are a major cause of death in young children. Unlike many adult cancers, paediatric cancers, such as neuroblastoma (NB), are developmental diseases that rarely show genetic predispositions. NB is the most common extracranial solid tumour in children, accounting for ∼15% of paediatric cancer deaths. This heterogeneous cancer arises from undifferentiated neural crest-derived progenitor cells. As neural crest cells are multipotent and migratory, they are often considered the embryonic paradigm of cancer stem cells. However, very little is known about the events that trigger tumour initiation and progression. Here, we discuss recent insights into sympathoadrenal lineage specification, as well as genetic factors associated with NB. With this in mind, we consider the molecular underpinnings of NB in the context of developmental trajectories of the neural crest lineage. This allows us to compare distinct subtypes of the disease and gene-function interactions during sensitive phases of neural crest development.
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Affiliation(s)
- Sandra Guadalupe Gonzalez Malagon
- Biomedical Research Institute, Foundation for Research and Technology, University of Ioannina Campus 1 , 45115 Ioannina , Greece
- School of Health Sciences and Institute of Biosciences, University Research Centre, University of Ioannina 2 Department of Biological Applications and Technology , , 45110 Ioannina , Greece
| | - Karen J. Liu
- Centre for Craniofacial and Regenerative Biology, King's College London 3 , London SE1 9RT , UK
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7
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Eckardt L, Prange-Barczynska M, Hodson EJ, Fielding JW, Cheng X, Lima JDCC, Kurlekar S, Douglas G, Ratcliffe PJ, Bishop T. Developmental role of PHD2 in the pathogenesis of pseudohypoxic pheochromocytoma. Endocr Relat Cancer 2021; 28:757-772. [PMID: 34658364 PMCID: PMC8558849 DOI: 10.1530/erc-21-0211] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 09/20/2021] [Indexed: 01/03/2023]
Abstract
Despite a general role for the HIF hydroxylase system in cellular oxygen sensing and tumour hypoxia, cancer-associated mutations of genes in this pathway, including PHD2, PHD1, EPAS1 (encoding HIF-2α) are highly tissue-restricted, being observed in pseudohypoxic pheochromocytoma and paraganglioma (PPGL) but rarely, if ever, in other tumours. In an effort to understand that paradox and gain insights into the pathogenesis of pseudohypoxic PPGL, we constructed mice in which the principal HIF prolyl hydroxylase, Phd2, is inactivated in the adrenal medulla using TH-restricted Cre recombinase. Investigation of these animals revealed a gene expression pattern closely mimicking that of pseudohypoxic PPGL. Spatially resolved analyses demonstrated a binary distribution of two contrasting patterns of gene expression among adrenal medullary cells. Phd2 inactivation resulted in a marked shift in this distribution towards a Pnmt-/Hif-2α+/Rgs5+ population. This was associated with morphological abnormalities of adrenal development, including ectopic TH+ cells within the adrenal cortex and external to the adrenal gland. These changes were ablated by combined inactivation of Phd2 with Hif-2α, but not Hif-1α. However, they could not be reproduced by inactivation of Phd2 in adult life, suggesting that they arise from dysregulation of this pathway during adrenal development. Together with the clinical observation that pseudohypoxic PPGL manifests remarkably high heritability, our findings suggest that this type of tumour likely arises from dysregulation of a tissue-restricted action of the PHD2/HIF-2α pathway affecting adrenal development in early life and provides a model for the study of the relevant processes.
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Affiliation(s)
- Luise Eckardt
- Target Discovery Institute, University of Oxford, Oxford, UK
- Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany
| | - Maria Prange-Barczynska
- Target Discovery Institute, University of Oxford, Oxford, UK
- Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK
| | - Emma J Hodson
- The Francis Crick Institute, London, UK
- The Department of Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, UK
| | - James W Fielding
- Target Discovery Institute, University of Oxford, Oxford, UK
- Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK
| | - Xiaotong Cheng
- Target Discovery Institute, University of Oxford, Oxford, UK
- Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK
| | | | - Samvid Kurlekar
- Target Discovery Institute, University of Oxford, Oxford, UK
| | - Gillian Douglas
- BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Peter J Ratcliffe
- Target Discovery Institute, University of Oxford, Oxford, UK
- Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK
- The Francis Crick Institute, London, UK
- Correspondence should be addressed to P J Ratcliffe or T Bishop: or
| | - Tammie Bishop
- Target Discovery Institute, University of Oxford, Oxford, UK
- Correspondence should be addressed to P J Ratcliffe or T Bishop: or
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8
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Cardoso F, Klein Wolterink RGJ, Godinho-Silva C, Domingues RG, Ribeiro H, da Silva JA, Mahú I, Domingos AI, Veiga-Fernandes H. Neuro-mesenchymal units control ILC2 and obesity via a brain-adipose circuit. Nature 2021; 597:410-414. [PMID: 34408322 PMCID: PMC7614847 DOI: 10.1038/s41586-021-03830-7] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 07/16/2021] [Indexed: 12/12/2022]
Abstract
Signals from sympathetic neurons and immune cells regulate adipocytes and thereby contribute to fat tissue biology. Interactions between the nervous and immune systems have recently emerged as important regulators of host defence and inflammation1-4. Nevertheless, it is unclear whether neuronal and immune cells co-operate in brain-body axes to orchestrate metabolism and obesity. Here we describe a neuro-mesenchymal unit that controls group 2 innate lymphoid cells (ILC2s), adipose tissue physiology, metabolism and obesity via a brain-adipose circuit. We found that sympathetic nerve terminals act on neighbouring adipose mesenchymal cells via the β2-adrenergic receptor to control the expression of glial-derived neurotrophic factor (GDNF) and the activity of ILC2s in gonadal fat. Accordingly, ILC2-autonomous manipulation of the GDNF receptor machinery led to alterations in ILC2 function, energy expenditure, insulin resistance and propensity to obesity. Retrograde tracing and chemical, surgical and chemogenetic manipulations identified a sympathetic aorticorenal circuit that modulates ILC2s in gonadal fat and connects to higher-order brain areas, including the paraventricular nucleus of the hypothalamus. Our results identify a neuro-mesenchymal unit that translates cues from long-range neuronal circuitry into adipose-resident ILC2 function, thereby shaping host metabolism and obesity.
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Affiliation(s)
- Filipa Cardoso
- Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal
- Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | | | | | - Rita G Domingues
- Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal
- Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research (MCCIR), Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Hélder Ribeiro
- Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | | | - Inês Mahú
- Max Planck Institute for Metabolism Research, Köln, Germany
| | - Ana I Domingos
- Department of Physiology, Anatomy & Genetics, Oxford University, Oxford, UK
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9
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Siaw JT, Gabre JL, Uçkun E, Vigny M, Zhang W, Van den Eynden J, Hallberg B, Palmer RH, Guan J. Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells. Cancers (Basel) 2021; 13:cancers13081909. [PMID: 33921066 PMCID: PMC8071449 DOI: 10.3390/cancers13081909] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/21/2021] [Accepted: 04/12/2021] [Indexed: 12/18/2022] Open
Abstract
Aberrant activation of anaplastic lymphoma kinase (ALK) drives neuroblastoma (NB). Previous work identified the RET receptor tyrosine kinase (RTK) as a downstream target of ALK activity in NB models. We show here that ALK activation in response to ALKAL2 ligand results in the rapid phosphorylation of RET in NB cells, providing additional insight into the contribution of RET to the ALK-driven gene signature in NB. To further address the role of RET in NB, RET knockout (KO) SK-N-AS cells were generated by CRISPR/Cas9 genome engineering. Gene expression analysis of RET KO NB cells identified a reprogramming of NB cells to a mesenchymal (MES) phenotype that was characterized by increased migration and upregulation of the AXL and MNNG HOS transforming gene (MET) RTKs, as well as integrins and extracellular matrix components. Strikingly, the upregulation of AXL in the absence of RET reflects the development timeline observed in the neural crest as progenitor cells undergo differentiation during embryonic development. Together, these findings suggest that a MES phenotype is promoted in mesenchymal NB cells in the absence of RET, reflective of a less differentiated developmental status.
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Affiliation(s)
- Joachim T. Siaw
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, Sweden; (J.T.S.); (J.L.G.); (E.U.); (B.H.); (R.H.P.)
| | - Jonatan L. Gabre
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, Sweden; (J.T.S.); (J.L.G.); (E.U.); (B.H.); (R.H.P.)
- Anatomy and Embryology Unit, Department of Human Structure and Repair, Ghent University, 9000 Ghent, Belgium;
| | - Ezgi Uçkun
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, Sweden; (J.T.S.); (J.L.G.); (E.U.); (B.H.); (R.H.P.)
| | - Marc Vigny
- Université Pierre et Marie Curie, UPMC, INSERM UMRS-839, 75005 Paris, France;
| | - Wancun Zhang
- Department of Pediatric Oncology Surgery, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, China;
| | - Jimmy Van den Eynden
- Anatomy and Embryology Unit, Department of Human Structure and Repair, Ghent University, 9000 Ghent, Belgium;
| | - Bengt Hallberg
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, Sweden; (J.T.S.); (J.L.G.); (E.U.); (B.H.); (R.H.P.)
| | - Ruth H. Palmer
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, Sweden; (J.T.S.); (J.L.G.); (E.U.); (B.H.); (R.H.P.)
| | - Jikui Guan
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530 Gothenburg, Sweden; (J.T.S.); (J.L.G.); (E.U.); (B.H.); (R.H.P.)
- Department of Pediatric Oncology Surgery, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou 450018, China;
- Correspondence:
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10
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Conway JA, Ince S, Black S, Kramer ER. GDNF/RET signaling in dopamine neurons in vivo. Cell Tissue Res 2020; 382:135-146. [PMID: 32870383 DOI: 10.1007/s00441-020-03268-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 07/24/2020] [Indexed: 12/15/2022]
Abstract
The glial cell line-derived neurotrophic factor (GDNF) and its canonical receptor Ret can signal both in tandem and separately to exert many vital functions in the midbrain dopamine system. It is known that Ret has effects on maintenance, physiology, protection and regeneration in the midbrain dopamine system, with the physiological functions of GDNF still somewhat unclear. Notwithstanding, Ret ligands, such as GDNF, are considered as promising candidates for neuroprotection and/or regeneration in Parkinson's disease, although data from clinical trials are so far inconclusive. In this review, we discuss the current knowledge of GDNF/Ret signaling in the dopamine system in vivo as well as crosstalk with pathology-associated proteins and their signaling in mammals.
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Affiliation(s)
- James A Conway
- Peninsula Medical School, Institute of Translational and Stratified Medicine, Faculty of Health, University of Plymouth, Plymouth, UK
| | - Selvi Ince
- Peninsula Medical School, Institute of Translational and Stratified Medicine, Faculty of Health, University of Plymouth, Plymouth, UK
| | | | - Edgar R Kramer
- Peninsula Medical School, Institute of Translational and Stratified Medicine, Faculty of Health, University of Plymouth, Plymouth, UK.
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11
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Nakatani T, Iwasaki M, Yamamichi A, Yoshioka Y, Uesaka T, Bitoh Y, Maeda K, Fukumoto T, Takemoto T, Enomoto H. Point mutagenesis in mouse reveals contrasting pathogenetic effects between MEN2B‐ and Hirschsprung disease‐associated missense mutations of the
RET
gene. Dev Growth Differ 2020; 62:214-222. [DOI: 10.1111/dgd.12664] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 03/28/2020] [Indexed: 01/06/2023]
Affiliation(s)
- Taichi Nakatani
- Division for Neural Differentiation and Regeneration Department of Physiology and Cell Biology Kobe University Graduate School of Medicine Kobe Japan
- Division of Pediatric Surgery Department of Surgery Kobe University Graduate School of Medicine Kobe Japan
| | - Mitsuhiro Iwasaki
- Division for Neural Differentiation and Regeneration Department of Physiology and Cell Biology Kobe University Graduate School of Medicine Kobe Japan
| | - Atsuhiro Yamamichi
- Division for Neural Differentiation and Regeneration Department of Physiology and Cell Biology Kobe University Graduate School of Medicine Kobe Japan
| | - Yuta Yoshioka
- Division for Neural Differentiation and Regeneration Department of Physiology and Cell Biology Kobe University Graduate School of Medicine Kobe Japan
| | - Toshihiro Uesaka
- Division for Neural Differentiation and Regeneration Department of Physiology and Cell Biology Kobe University Graduate School of Medicine Kobe Japan
| | - Yuko Bitoh
- Division of Pediatric Surgery Department of Surgery Kobe University Graduate School of Medicine Kobe Japan
| | - Kosaku Maeda
- Department of Surgery Hyogo Prefectural Kobe Children's Hospital Kobe Japan
| | - Takumi Fukumoto
- Division of Hepato‐Biliary‐Pancreatic surgery Department of Physiology and Cell Biology Kobe University Graduate School of Medicine Kobe Japan
| | - Tatsuya Takemoto
- Institute of Advanced Medical Sciences Tokushima University Tokushima Japan
| | - Hideki Enomoto
- Division for Neural Differentiation and Regeneration Department of Physiology and Cell Biology Kobe University Graduate School of Medicine Kobe Japan
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12
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Turconi G, Kopra J, Võikar V, Kulesskaya N, Vilenius C, Piepponen TP, Andressoo JO. Chronic 2-Fold Elevation of Endogenous GDNF Levels Is Safe and Enhances Motor and Dopaminergic Function in Aged Mice. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2020; 17:831-842. [PMID: 32368564 PMCID: PMC7191127 DOI: 10.1016/j.omtm.2020.04.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 04/02/2020] [Indexed: 02/08/2023]
Abstract
Glial cell line-derived neurotrophic factor (GDNF) supports function and survival of dopamine neurons that degenerate in Parkinson’s disease (PD). Ectopic delivery of GDNF in clinical trials to treat PD is safe but lacks significant therapeutic effect. In pre-clinical models, ectopic GDNF is effective but causes adverse effects, including downregulation of tyrosine hydroxylase, only a transient boost in dopamine metabolism, aberrant neuronal sprouting, and hyperactivity. Hindering development of GDNF mimetic increased signaling via GDNF receptor RET by activating mutations results in cancer. Safe and effective mode of action must be defined first in animal models to develop successful GDNF-based therapies. Previously we showed that about a 2-fold increase in endogenous GDNF expression is safe and results in increased motor and dopaminergic function and protection in a PD model in young animals. Recently, similar results were reported using a novel Gdnf mRNA-targeting strategy. Next, it is important to establish the safety of a long-term increase in endogenous GDNF expression. We report behavioral, dopamine system, and cancer analysis of five cohorts of aged mice with a 2-fold increase in endogenous GDNF. We found a sustained increase in dopamine levels, improvement in motor learning, and no side effects or cancer. These results support the rationale for further development of endogenous GDNF-based treatments and GDNF mimetic.
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Affiliation(s)
- Giorgio Turconi
- Department of Pharmacology, Faculty of Medicine and Helsinki Institute of Life Science, Haartmaninkatu 8, University of Helsinki, Helsinki 00014, Finland
| | - Jaakko Kopra
- Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikinkaari 5E, University of Helsinki, Helsinki 00014, Finland
| | - Vootele Võikar
- Neuroscience Center/Laboratory Animal Center, Mustialankatu 1, University of Helsinki, Helsinki 00014, Finland
| | - Natalia Kulesskaya
- Neuroscience Center/Laboratory Animal Center, Mustialankatu 1, University of Helsinki, Helsinki 00014, Finland
| | - Carolina Vilenius
- Institute of Biotechnology, Viikinkaari 5D, University of Helsinki, Helsinki 00014, Finland
| | - T Petteri Piepponen
- Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, Viikinkaari 5E, University of Helsinki, Helsinki 00014, Finland
| | - Jaan-Olle Andressoo
- Department of Pharmacology, Faculty of Medicine and Helsinki Institute of Life Science, Haartmaninkatu 8, University of Helsinki, Helsinki 00014, Finland.,Institute of Biotechnology, Viikinkaari 5D, University of Helsinki, Helsinki 00014, Finland.,Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Stockholm 141 83, Sweden
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13
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Kovac M, Woolley C, Ribi S, Blattmann C, Roth E, Morini M, Kovacova M, Ameline B, Kulozik A, Bielack S, Hartmann W, Ballinger ML, Thomas DM, Tomlinson I, Nathrath M, Heinimann K, Baumhoer D. Germline RET variants underlie a subset of paediatric osteosarcoma. J Med Genet 2020; 58:20-24. [PMID: 32179705 DOI: 10.1136/jmedgenet-2019-106734] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 02/12/2020] [Accepted: 02/14/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Although considerable effort has been put into decoding of the osteosarcoma genome, very little is known about germline mutations that underlie this primary malignant tumour of bone. METHODS AND RESULTS We followed here a coincidental finding in a multiple endocrine neoplasia family in which a 32-year-old patient carrying a germline pathogenic RET mutation developed an osteosarcoma 2 years after the resection of a medullary thyroid carcinoma. Sequencing analysis of additional 336 patients with osteosarcoma led to the identification of germline activating mutations in the RET proto-oncogene in three cases and somatic amplifications of the gene locus in five matched tumours (4%, n=5/124 tumours). Functional analysis of the pathogenic variants together with an integrative analysis of osteosarcoma genomes confirmed that the mutant RET proteins couple functional kinase activity to dysfunctional ligand binding. RET mutations further co-operated with alterations in TP53 and RB1, suggesting that osteosarcoma pathogenesis bears reminiscence to the stepwise model of medullary thyroid carcinoma. CONCLUSIONS After Li-Fraumeni-predisposing mutations in TP53, RET becomes the second most mutated cancer-predisposing gene in the germline of patients with osteosarcoma. Hence, early identification of RET mutation carriers can help to identify at-risk family members and carry out preventive measures.
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Affiliation(s)
- Michal Kovac
- Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Connor Woolley
- Cancer Genetics and Evolution Laboratory, Edinburgh Cancer Research Centre, Edinburgh, UK.,Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Sebastian Ribi
- Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Claudia Blattmann
- Pediatrics 5 (Oncology, Hematology, Immunology), Klinikum Stuttgart Olgahospital, Stuttgart, Germany.,Department of Pediatric Hematology, Oncology, Immunology and Pulmology, University of Heidelberg, Heidelberg, Germany
| | - Eva Roth
- Department of Pediatric Hematology, Oncology, Immunology and Pulmology, University of Heidelberg, Heidelberg, Germany
| | - Marco Morini
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Monika Kovacova
- Institute of Mathematics and Physics, Faculty of Mechanical Engineering, Slovak University of Technology, Bratislava, Slovakia
| | - Baptiste Ameline
- Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Andreas Kulozik
- Department of Pediatric Hematology, Oncology, Immunology and Pulmology, University of Heidelberg, Heidelberg, Germany
| | - Stefan Bielack
- Pediatrics 5 (Oncology, Hematology, Immunology), Klinikum Stuttgart Olgahospital, Stuttgart, Germany
| | - Wolfgang Hartmann
- Gerhard Domagk Institute of Pathology, University Hospital Münster, Münster, Germany
| | - Mandy L Ballinger
- Genomic Cancer Medicine Laboratory, The Kinghorn Cancer Center and Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
| | - David M Thomas
- Genomic Cancer Medicine Laboratory, The Kinghorn Cancer Center and Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
| | - Ian Tomlinson
- Cancer Genetics and Evolution Laboratory, Edinburgh Cancer Research Centre, Edinburgh, UK.,Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Michaela Nathrath
- Department of Pediatric Hematology and Oncology, Klinikum Kassel, Kassel, Germany.,Department of Pediatrics, Technical University Munich, Munich, Germany
| | - Karl Heinimann
- Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Daniel Baumhoer
- Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
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14
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Chang X, Li Z, Ma X, Cui Y, Chen S, Tong A. A Novel Phenotype of Germline Pathogenic Variants in MAX: Concurrence of Pheochromocytoma and Ganglioneuroma in a Chinese Family and Literature Review. Front Endocrinol (Lausanne) 2020; 11:558. [PMID: 32973681 PMCID: PMC7472796 DOI: 10.3389/fendo.2020.00558] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 07/07/2020] [Indexed: 12/28/2022] Open
Abstract
Background:MYC associated factor X (MAX) is a tumor suppressor gene and has been identified as one of the pathogenic genes of hereditary pheochromocytoma (PCC). To date, there have been no reports of ganglioneuroma (GN) with MAX variants. Case Presentation: The proband was a 45-years-old Chinese female with paroxysmal hypertension and palpitations who had undergone adrenalectomy for PCC 14 years ago. Her plasma free normetanephrine and 24-h urinary norepinephrine excretion were significantly increased, and abdominal computed tomography (CT) revealed an irregular mass in the left adrenal region, suggesting a recurrence of PCC. The mass was surgically removed and pathologically diagnosed as PCC with lymph node metastasis. The proband's son suffered from paroxysmal hypertension and palpitations. His plasma free metanephrine levels were normal. CT revealed a mass in the right adrenal. The tumor was surgically removed, and the pathological diagnosis was GN. Genetic testing of peripheral blood DNA revealed that the proband and her son had germline pathogenic MAX variant c.C97T, p.Arg33Ter, while proband's parents did not have MAX variants. Tumor DNA sequencing showed the same MAX variant (c.C97T, p.Arg33Ter) in PCC of the proband and GN of her son, both with retention of heterozygosity. Immunohistochemistry demonstrated loss of MAX protein expression in most tumor cells in PCC of the proband and some Schwannian cells in GN of the proband's son. Conclusion: We report a family with a new clinical phenotype of germline pathogenic variants in MAX who developed both PCC and GN. Germline pathogenic variants in MAX may contribute to the development of GN. Our findings suggest that it is not just paternally inherited MAX variants that can cause tumors.
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Affiliation(s)
- Xiaoyan Chang
- Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Zelin Li
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission of the People's Republic of China, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
- Department of Endocrinology, Hebei General Hospital, Hebei Medical University, Shijiazhuang, China
| | - Xiaosen Ma
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission of the People's Republic of China, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Yunying Cui
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission of the People's Republic of China, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Shuchun Chen
- Department of Endocrinology, Hebei General Hospital, Hebei Medical University, Shijiazhuang, China
| | - Anli Tong
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission of the People's Republic of China, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
- *Correspondence: Anli Tong
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15
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Development of the urogenital system is regulated via the 3'UTR of GDNF. Sci Rep 2019; 9:5302. [PMID: 30923332 PMCID: PMC6438985 DOI: 10.1038/s41598-019-40457-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 02/13/2019] [Indexed: 12/30/2022] Open
Abstract
Mechanisms controlling ureter lenght and the position of the kidney are poorly understood. Glial cell-line derived neurotrophic factor (GDNF) induced RET signaling is critical for ureteric bud outgrowth, but the function of endogenous GDNF in further renal differentiation and urogenital system development remains discursive. Here we analyzed mice where 3′ untranslated region (UTR) of GDNF is replaced with sequence less responsive to microRNA-mediated regulation, leading to increased GDNF expression specifically in cells naturally transcribing Gdnf. We demonstrate that increased Gdnf leads to short ureters in kidneys located in an abnormally caudal position thus resembling human pelvic kidneys. High GDNF levels expand collecting ductal progenitors at the expense of ureteric trunk elongation and result in expanded tip and short trunk phenotype due to changes in cell cycle length and progenitor motility. MEK-inhibition rescues these defects suggesting that MAPK-activity mediates GDNF’s effects on progenitors. Moreover, Gdnf hyper mice are infertile likely due to effects of excess GDNF on distal ureter remodeling. Our findings suggest that dysregulation of GDNF levels, for example via alterations in 3′UTR, may account for a subset of congenital anomalies of the kidney and urinary tract (CAKUT) and/or congenital infertility cases in humans and pave way to future studies.
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16
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Huber K, Janoueix-Lerosey I, Kummer W, Rohrer H, Tischler AS. The sympathetic nervous system: malignancy, disease, and novel functions. Cell Tissue Res 2019; 372:163-170. [PMID: 29623426 DOI: 10.1007/s00441-018-2831-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Katrin Huber
- Department of Medicine, University of Fribourg, Route-Albert-Gockel 1, 1700, Fribourg, Switzerland.
| | - Isabelle Janoueix-Lerosey
- SIREDO Oncology Center (Care, Innovation and research for children and AYA with cancer), Inserm U830, PSL Research University, Equipe labellisée Ligue Nationale contre le cancer, Institut Curie, 26 rue d'Ulm, 75005, Paris, France
| | - Wolfgang Kummer
- Institute for Anatomy and Cell Biology, Justus Liebig University Giessen, Aulweg 123, 35385, Giessen, Germany
| | - Hermann Rohrer
- Institute for Clinical Neuroanatomy, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt/M, Germany
| | - Arthur S Tischler
- Department of Pathology and Laboratory Medicine, Tufts Medical Center and Tufts University School of Medicine, Boston, MA, 02111, USA
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17
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Amit M, Na'ara S, Fridman E, Vladovski E, Wasserman T, Milman N, Gil Z. RET, a targetable driver of pancreatic adenocarcinoma. Int J Cancer 2019; 144:3014-3022. [DOI: 10.1002/ijc.32040] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Revised: 11/14/2018] [Accepted: 11/21/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Moran Amit
- Head and Neck SurgeryHouston Methodist Hospital Houston TX USA
- The Laboratory for Applied Cancer Research, The TechnionIsrael Institute of Technology Haifa Israel
- Department of Otolaryngology Head and Neck Surgery, the Head and Neck Center, Rambam Healthcare CampusClinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology Haifa Israel
| | - Shorook Na'ara
- The Laboratory for Applied Cancer Research, The TechnionIsrael Institute of Technology Haifa Israel
- Department of Otolaryngology Head and Neck Surgery, the Head and Neck Center, Rambam Healthcare CampusClinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology Haifa Israel
| | - Eran Fridman
- The Laboratory for Applied Cancer Research, The TechnionIsrael Institute of Technology Haifa Israel
- Department of Otolaryngology Head and Neck Surgery, the Head and Neck Center, Rambam Healthcare CampusClinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology Haifa Israel
| | - Euvgeni Vladovski
- Department of Pathology, Rambam Healthcare Campus, The TechnionIsrael Institute of Technology Haifa Israel
| | - Tanya Wasserman
- Department of Physiology, Biophysics and Systems Biology, Faculty of MedicineTechnion Haifa Israel
| | - Neta Milman
- The Laboratory for Applied Cancer Research, The TechnionIsrael Institute of Technology Haifa Israel
| | - Ziv Gil
- The Laboratory for Applied Cancer Research, The TechnionIsrael Institute of Technology Haifa Israel
- Department of Otolaryngology Head and Neck Surgery, the Head and Neck Center, Rambam Healthcare CampusClinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology Haifa Israel
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18
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Abstract
Cancer is a cumulative manifestation of several complicated disease states that affect multiple organs. Over the last few decades, the fruit fly Drosophila melanogaster, has become a successful model for studying human cancers. The genetic simplicity and vast arsenal of genetic tools available in Drosophila provides a unique opportunity to address questions regarding cancer initiation and progression that would be extremely challenging in other model systems. In this chapter we provide a historical overview of Drosophila as a model organism for cancer research, summarize the multitude of genetic tools available, offer a brief comparison between different model organisms and cell culture platforms used in cancer studies and briefly discuss some of the latest models and concepts in recent Drosophila cancer research.
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19
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Gahete MD, Jimenez-Vacas JM, Alors-Perez E, Herrero-Aguayo V, Fuentes-Fayos AC, Pedraza-Arevalo S, Castaño JP, Luque RM. Mouse models in endocrine tumors. J Endocrinol 2018; 240:JOE-18-0571.R1. [PMID: 30475226 DOI: 10.1530/joe-18-0571] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 11/26/2018] [Indexed: 12/14/2022]
Abstract
Endocrine and neuroendocrine tumors comprise a highly heterogeneous group of neoplasms that can arise from (neuro)endocrine cells, either from endocrine glands or from the widespread diffuse neuroendocrine system, and, consequently, are widely distributed throughout the body. Due to their diversity, heterogeneity and limited incidence, studying in detail the molecular and genetic alterations that underlie their development and progression is still a highly elusive task. This, in turn, hinders the discovery of novel therapeutic options for these tumors. To circumvent these limitations, numerous mouse models of endocrine and neuroendocrine tumors have been developed, characterized and used in pre-clinical, co-clinical (implemented in mouse models and patients simultaneously) and post-clinical studies, for they represent powerful and necessary tools in basic and translational tumor biology research. Indeed, different in vivo mouse models, including cell line-based xenografts (CDXs), patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMs), have been used to delineate the development, progression and behavior of human tumors. Results gained with these in vivo models have facilitated the clinical application in patients of diverse breakthrough discoveries made in this field. Herein, we review the generation, characterization and translatability of the most prominent mouse models of endocrine and neuroendocrine tumors reported to date, as well as the most relevant clinical implications obtained for each endocrine and neuroendocrine tumor type.
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Affiliation(s)
- Manuel D Gahete
- M Gahete, Department of Cell Biology, Physiology and Immunology, University of Córdoba, Cordoba, 14011, Spain
| | - Juan M Jimenez-Vacas
- J Jimenez-Vacas, Department of Cell Biology, Physiology and Immunology, University of Córdoba, Cordoba, Spain
| | - Emilia Alors-Perez
- E Alors-Perez, Department of Cell Biology, Physiology and Inmunology, Maimonides Institute for Biomedical Research of Cordoba (IMIBIC) / University of Cordoba, Cordoba, Spain
| | - Vicente Herrero-Aguayo
- V Herrero-Aguayo, Department of Cell Biology, Physiology and Immunology, University of Córdoba, Cordoba, Spain
| | - Antonio C Fuentes-Fayos
- A Fuentes-Fayos, Department of Cell Biology, Physiology and Immunology, University of Córdoba, Cordoba, Spain
| | - Sergio Pedraza-Arevalo
- S Pedraza-Arevalo, Department of Cell Biology, Physiology and Immunology, University of Córdoba, Cordoba, Spain
| | - Justo P Castaño
- J Castaño, Dpt. of Cell Biology-University of Córdoba, IMIBIC-Maimonides Biomedical Research Institute of Cordoba, Cordoba, E-14004, Spain
| | - Raul M Luque
- R Luque, Dept of Cell Biology, Phisiology and Inmunology, Section of Cell Biology, University of Cordoba, Cordoba, Spain, Cordoba, 14014, Spain
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20
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Rodent models of pheochromocytoma, parallels in rodent and human tumorigenesis. Cell Tissue Res 2018; 372:379-392. [PMID: 29427052 DOI: 10.1007/s00441-018-2797-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 01/16/2018] [Indexed: 12/17/2022]
Abstract
Paragangliomas and pheochromocytomas are rare neuroendocrine tumors characterized by a large spectrum of hereditary predisposition. Based on gene expression profiling classification, they can be classically assigned to either a hypoxic/angiogenic cluster (cluster 1 including tumors with mutations in SDHx, VHL and FH genes) or a kinase-signaling cluster (cluster 2 consisting in tumors related to RET, NF1, TMEM127 and MAX genes mutations, as well as most of the sporadic tumors). The past 15 years have seen the emergence of an increasing number of genetically engineered and grafted models to investigate tumorigenesis and develop new therapeutic strategies. Among them, only cluster 2-related predisposed models have been successful but grafted models are however available to study cluster 1-related tumors. In this review, we present an overview of existing rodent models targeting predisposition genes involved or not in human pheochromocytoma/paraganglioma susceptibility and their contribution to the improvement of pheochromocytoma experimental research.
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21
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Das TK, Cagan RL. Non-mammalian models of multiple endocrine neoplasia type 2. Endocr Relat Cancer 2018; 25:T91-T104. [PMID: 29348307 PMCID: PMC5935467 DOI: 10.1530/erc-17-0411] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 12/06/2017] [Indexed: 12/14/2022]
Abstract
Twenty-five years ago, RET was identified as the primary driver of multiple endocrine neoplasia type 2 (MEN2) syndrome. MEN2 is characterized by several transformation events including pheochromocytoma, parathyroid adenoma and, especially penetrant, medullary thyroid carcinoma (MTC). Overall, MTC is a rare but aggressive type of thyroid cancer for which no effective treatment currently exists. Surgery, radiation, radioisotope treatment and chemotherapeutics have all shown limited success, and none of these approaches have proven durable in advanced disease. Non-mammalian models that incorporate the oncogenic RET isoforms associated with MEN2 and other RET-associated diseases have been useful in delineating mechanisms underlying disease progression. These models have also identified novel targeted therapies as single agents and as combinations. These studies highlight the importance of modeling disease in the context of the whole animal, accounting for the complex interplay between tumor and normal cells in controlling disease progression as well as response to therapy. With convenient access to whole genome sequencing data from expanded thyroid cancer patient cohorts, non-mammalian models will become more complex, sophisticated and continue to complement future mammalian studies. In this review, we explore the contributions of non-mammalian models to our understanding of thyroid cancer including MTC, with a focus on Danio rerio and Drosophila melanogaster (fish and fly) models.
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Affiliation(s)
- Tirtha K Das
- Department of Cell Developmental and Regenerative Biology, School of Biomedical Sciences, Icahn School of Medicine, New York, New York, USA
| | - Ross L Cagan
- Department of Cell Developmental and Regenerative Biology, School of Biomedical Sciences, Icahn School of Medicine, New York, New York, USA
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22
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Activated ALK signals through the ERK-ETV5-RET pathway to drive neuroblastoma oncogenesis. Oncogene 2018; 37:1417-1429. [PMID: 29321660 PMCID: PMC6168456 DOI: 10.1038/s41388-017-0039-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 07/24/2017] [Accepted: 10/01/2017] [Indexed: 12/28/2022]
Abstract
Activating mutations of the ALK receptor occur in a subset of neuroblastoma tumors. We previously demonstrated that Alk mutations cooperate with MYCN overexpression to induce neuroblastoma in mice and identified Ret as being strongly upregulated in MYCN/Alkmut tumors. By a genetic approach in vivo, we now document an oncogenic cooperation between activated Ret and MYCN overexpression in neuroblastoma formation. We show that MYCN/RetM919T tumors exhibit histological features and expression profiles close to MYCN/Alkmut tumors. We show that RET transcript levels decrease precedes RET protein levels decrease upon ALK inhibition in neuroblastoma cell lines. Etv5 was identified as a candidate transcription factor regulating Ret expression from murine MYCN/Alkmut tumor transcriptomic data. We demonstrate that ETV5 is regulated both at the protein and mRNA levels upon ALK activation or inhibition in neuroblastoma cell lines and that this regulation precedes RET modulation. We document that ALK activation induces ETV5 protein upregulation through stabilization in a MEK/ERK-dependent manner. We show that RNAi-mediated inhibition of ETV5 decreases RET expression. Reporter assays indicate that ETV5 is able to drive RET gene transcription. ChIP-seq analysis confirmed ETV5 binding on the RET promoter and identified an enhancer upstream of the promoter. Finally, we demonstrate that combining RET and ALK inhibitors reduces tumor growth more efficiently than each single agent in MYCN and AlkF1178L-driven murine neuroblastoma. Altogether, these results define the ERK–ETV5–RET pathway as a critical axis driving neuroblastoma oncogenesis downstream of activated ALK.
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23
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Kopra J, Villarta-Aguilera M, Savolainen M, Weingerl S, Myöhänen TT, Rannanpää S, Salvatore MF, Andressoo JO, Piepponen TP. Constitutive Ret signaling leads to long-lasting expression of amphetamine-induced place conditioning via elevation of mesolimbic dopamine. Neuropharmacology 2017; 128:221-230. [PMID: 29031851 DOI: 10.1016/j.neuropharm.2017.10.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 10/06/2017] [Accepted: 10/10/2017] [Indexed: 12/28/2022]
Abstract
Addictive drugs enhance dopamine release in the striatum, which can lead to compulsive drug-seeking after repeated exposure. Glial cell line-derived neurotrophic factor (GDNF) is an important regulator of midbrain dopamine neurons, and may play a mechanistic role in addiction-related behaviors. To elucidate the components of GDNF-signaling that contribute to addiction-related behaviors of place preference and its extinction, we utilized two genetically modified GDNF mouse models in an amphetamine-induced conditioned place preference (CPP) paradigm and evaluated how the behavioral findings correlate with dopamine signaling in the dorsal and ventral striatum. We utilized two knock-in mouse strains to delineate contributions of GDNF and Ret signaling using MEN2B mice (constitutively active GDNF receptor Ret), and GDNF hypermorphic mice (enhanced endogenous GDNF expression). The duration of amphetamine-induced CPP was greatly enhanced in MEN2B mice, but not in the GDNF hypermorphic mice. The enhanced duration of CPP was correlated with increased tyrosine hydroxylase (TH) expression and dopamine content in the ventral striatum. Together, our results suggest that downstream components of GDNF signaling, in this case Ret, may mediate persistent drug-seeking behavior through increased TH expression and dopamine levels in the mesolimbic dopamine neurons.
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Affiliation(s)
- Jaakko Kopra
- Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014, Finland
| | - Marian Villarta-Aguilera
- Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014, Finland
| | - Mari Savolainen
- Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014, Finland
| | - Samo Weingerl
- Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014, Finland
| | - Timo T Myöhänen
- Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014, Finland
| | - Saara Rannanpää
- Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014, Finland
| | - Michael F Salvatore
- Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX 76107, United States; Center for Neuroscience Discovery, University of North Texas Health Science Center, Fort Worth, TX 76107, United States
| | - Jaan-Olle Andressoo
- Institute of Biotechnology, University of Helsinki, 00014, Finland; Faculty of Medicine, University of Helsinki, 00014, Finland; Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 14152, Sweden
| | - T Petteri Piepponen
- Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014, Finland.
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24
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Bennaceur-Griscelli A, Hadoux J, Féraud O, Opolon P, Divers D, Gobbo E, Schlumberger M, Griscelli F, Turhan AG. Generation of an induced pluripotent stem cell line from a patient with hereditary multiple endocrine neoplasia 2B (MEN2B) syndrome with "highest risk" RET mutation. Stem Cell Res 2017; 23:154-157. [PMID: 28925363 DOI: 10.1016/j.scr.2017.07.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Accepted: 07/20/2017] [Indexed: 10/19/2022] Open
Abstract
Multiple Endocrine Neoplasia Type 2B (MEN2B) is a cancer-predisposing syndrome that affects patients with germline RET mutations. The clinical spectrum of the syndrome includes medullary thyroid carcinoma (MTC) and pheochromocytoma. Currently, there is no satisfactory model recapitulating all the features of the disease especially at the level of stem cells. We generated induced pluripotent stem cells (iPSCs) from a patient with RET mutation at codon 918 who developed pheochromocytoma and MTC. These iPSC had normal karyotype, harboured the RETM918T mutation and expressed pluripotency hallmarks. A comprehensive pathological assessment of teratoma was performed after injection in immunodeficient mice.
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Affiliation(s)
- A Bennaceur-Griscelli
- INSERM U935, Université Paris Sud, 94800, Villejuif, France; ESTeam Paris Sud, INSERM U935, Université Paris Sud, Université Paris-Saclay, 94800, Villejuif, France; INGESTEM National IPSC Infrastructure, 94800 Villejuif, France; Division of Hematology, Paris Sud University Hospitals, Le Kremlin Bicêtre 94275, France; Division of Hematology, Paris Sud University Hospitals, Villejuif 94800, France
| | - J Hadoux
- INSERM U935, Université Paris Sud, 94800, Villejuif, France; Gustave Roussy, Department of Nuclear Medicine and Endocrine Oncology, 94800 Villejuif, France.
| | - O Féraud
- INSERM U935, Université Paris Sud, 94800, Villejuif, France; ESTeam Paris Sud, INSERM U935, Université Paris Sud, Université Paris-Saclay, 94800, Villejuif, France.
| | - P Opolon
- Gustave Roussy, Laboratoire de Pathologie Expérimentale, F-94800 Villejuif, France
| | - D Divers
- INSERM U935, Université Paris Sud, 94800, Villejuif, France; ESTeam Paris Sud, INSERM U935, Université Paris Sud, Université Paris-Saclay, 94800, Villejuif, France.
| | - E Gobbo
- INSERM U935, Université Paris Sud, 94800, Villejuif, France; ESTeam Paris Sud, INSERM U935, Université Paris Sud, Université Paris-Saclay, 94800, Villejuif, France
| | - M Schlumberger
- Gustave Roussy, Department of Nuclear Medicine and Endocrine Oncology, 94800 Villejuif, France.
| | - F Griscelli
- INSERM U935, Université Paris Sud, 94800, Villejuif, France; ESTeam Paris Sud, INSERM U935, Université Paris Sud, Université Paris-Saclay, 94800, Villejuif, France; INGESTEM National IPSC Infrastructure, 94800 Villejuif, France.
| | - A G Turhan
- INSERM U935, Université Paris Sud, 94800, Villejuif, France; ESTeam Paris Sud, INSERM U935, Université Paris Sud, Université Paris-Saclay, 94800, Villejuif, France; INGESTEM National IPSC Infrastructure, 94800 Villejuif, France; Division of Hematology, Paris Sud University Hospitals, Le Kremlin Bicêtre 94275, France; Division of Hematology, Paris Sud University Hospitals, Villejuif 94800, France.
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Hutson JM, Farmer PJ, Peck CJ, Chow CW, Southwell BR. Multiple endocrine neoplasia 2B: Differential increase in enteric nerve subgroups in muscle and mucosa. World J Gastrointest Pathophysiol 2017; 8:142-149. [PMID: 28868184 PMCID: PMC5561435 DOI: 10.4291/wjgp.v8.i3.142] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 05/24/2017] [Accepted: 07/17/2017] [Indexed: 02/06/2023] Open
Abstract
Multiple endocrine neoplasia 2B (MEN2B) is a rare syndrome caused by an activating mutation of the RET gene, leading to enteric gangliomatosis. This child presented with constipation at 1-mo old, was diagnosed with MEN2B by rectal biopsy at 4 mo, had thyroidectomy at 9 mo and a colectomy at 4 years. We studied the extent of neuronal and nerve fibre proliferation and which classes of enteric nerves are affected by examining the colon with multiple neuronal antibodies. Resected transverse colon was fixed, frozen, sectioned and processed for fluorescence immunohistochemistry labelling with antibodies against TUJ1, Hu, ChAT, NOS, VIP, SP and CGRP and cKit. Control transverse colon was from the normal margin of Hirschsprung (HSCR) colon (4-year-old) and a child with familial adenomatous polyposis (FAP, 12 year). Myenteric ganglia were increased in size to as wide as the circular muscle. There was a large increase in nerve cells and nerve fibres. ChAT-, NOS-, VIP- and SP-immunoreactive nerve fibres all increased in the myenteric ganglia. NOS-IR nerves preferentially increased in the muscle, while VIP and SP increased in submucosal ganglia and mucosal nerve fibres. The density of ICC was normal. RET overactivation in MEN2B lead to a large increase in intrinsic nerve fibres in the myenteric and submucosal ganglia, with a relative increase in NOS-IR nerve fibres in the circular muscle and VIP and SP in the submucosal ganglia and mucosa. The changes were associated with severe constipation resulting in colectomy at 4 years.
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26
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Grey W, Hulse R, Yakovleva A, Genkova D, Whitelaw B, Solomon E, Diaz-Cano SJ, Izatt L. The RET E616Q Variant is a Gain of Function Mutation Present in a Family with Features of Multiple Endocrine Neoplasia 2A. Endocr Pathol 2017; 28:41-48. [PMID: 27704398 DOI: 10.1007/s12022-016-9451-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
The REarranged during Transfection (RET) proto-oncogene is a receptor tyrosine kinase involved in growth and differentiation during embryogenesis and maintenance of the urogenital and nervous systems in mammals. Distinct mutations across hotspot RET exons can cause Multiple Endocrine Neoplasia Type 2A (MEN2A) characterised by development of medullary thyroid cancer (MTC), phaeochromocytoma (PCC) and primary hyperparathyroidism (PHPT), with a strong correlation between genotype and phenotype. Here, we report a 42-year-old man presented in the clinic with a unilateral PCC, with subsequent investigations revealing a nodular and cystic thyroid gland. He proceeded to thyroidectomy, which showed bilateral C-cell hyperplasia (CCH) without evidence of MTC. His brother had neonatal Hirschsprung disease (HSCR). Genetic testing revealed the presence of a heterozygous variant of unknown significance (VUS) in the cysteine-rich region of exon 10 in the RET gene (c.1846G>C, p.E616Q), in both affected siblings and their unaffected mother. Exon 10 RET mutations are known to be associated with HSCR and MEN2. Variants in the cysteine-rich region of the RET gene, outside of the key cysteine residues, may contribute to the development of MEN2 in a less aggressive manner, with a lower penetrance of MTC. Currently, a VUS in RET cannot be used to inform clinical management and direct future care. Analysis of RETE616Q reveals a gain of function mutant phenotype for this variant, which has not previously been reported, indicating that this VUS should be considered at risk for future clinical management.
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Affiliation(s)
- William Grey
- Cancer Genetics, Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK
| | - Rosaline Hulse
- Cancer Genetics, Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK
| | - Anna Yakovleva
- Cancer Genetics, Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK
| | - Dilyana Genkova
- Cancer Genetics, Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK
| | | | - Ellen Solomon
- Cancer Genetics, Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK
| | | | - Louise Izatt
- Cancer Genetics, Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK.
- Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust London, Great Maze Pond, London, SE1 9RT, UK.
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27
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Vitale G, Gaudenzi G, Circelli L, Manzoni MF, Bassi A, Fioritti N, Faggiano A, Colao A. Animal models of medullary thyroid cancer: state of the art and view to the future. Endocr Relat Cancer 2017; 24:R1-R12. [PMID: 27799362 DOI: 10.1530/erc-16-0399] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 10/24/2016] [Indexed: 12/16/2022]
Abstract
Medullary thyroid carcinoma is a neuroendocrine tumour originating from parafollicular C cells accounting for 5-10% of thyroid cancers. Increased understanding of disease-specific molecular targets of therapy has led to the regulatory approval of two drugs (vandetanib and cabozantinib) for the treatment of medullary thyroid carcinoma. These drugs increase progression-free survival; however, they are often poorly tolerated and most treatment responses are transient. Animal models are indispensable tools for investigating the pathogenesis, mechanisms for tumour invasion and metastasis and new therapeutic approaches for cancer. Unfortunately, only few models are available for medullary thyroid carcinoma. This review provides an overview of the state of the art of animal models in medullary thyroid carcinoma and highlights future developments in this field, with the aim of addressing salient features and clinical relevance.
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Affiliation(s)
- Giovanni Vitale
- Department of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, Italy
- Laboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Milan, Italy
| | - Germano Gaudenzi
- Department of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, Italy
| | - Luisa Circelli
- Department of Experimental OncologyLaboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, 'Fondazione Pascale' - IRCCS, Naples, Italy
| | - Marco F Manzoni
- Department of Endocrinology and Internal MedicineEndocrine Tumors Unit, San Raffaele Hospital Vita-Salute San Raffaele University, Milan, Italy
| | - Andrea Bassi
- Department of PhysicsPolitecnico di Milano, Milan, Italy
| | | | - Antongiulio Faggiano
- Thyroid and Parathyroid Surgery UnitIstituto Nazionale per lo Studio e la Cura dei Tumori 'Fondazione G. Pascale' - IRCCS, Naples, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and SurgerySection of Endocrinology, 'Federico II' University of Naples, Naples, Italy
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Liu Q, Tong D, Yuan W, Liu G, Yuan G, Lan W, Zhang D, Zhang J, Huang Z, Zhang Y, Jiang J. Different RET gene mutation-induced multiple endocrine neoplasia type 2A in 3 Chinese families. Medicine (Baltimore) 2017; 96:e5967. [PMID: 28099363 PMCID: PMC5279108 DOI: 10.1097/md.0000000000005967] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 12/30/2016] [Accepted: 01/02/2017] [Indexed: 12/29/2022] Open
Abstract
BACKGROUD Multiple endocrine neoplasia type 2A (MEN2A) is a condition with inherited autosomal dominant mutations in RET (rearranged during transfection) gene that predisposes the carrier to extremely high risk of medullary thyroid cancer (MTC) and other MEN2A-associated tumors such as parathyroid cancer and/or pheochromocytoma. Little is reported about MEN2A syndrome in the Chinese population. METHODS All members of the 3 families along with specific probands of MEN2A were analyzed for their clinical, laboratory, and genetic characteristics. Exome sequencing was performed on the 3 probands, and specific mutation in RET was further screened on each of the family members. RESULTS Different mutations in the RET gene were identified: C634S in Family 1, C611Y in Family 2, and C634Y in Family 3. Proband 1 mainly showed pheochromocytoma with MTC, both medullary thyroid carcinoma and pheochromocytoma were seen in proband 2, and proband 3 showed medullary thyroid carcinoma. CONCLUSION The genetic evaluation is strongly recommended for patients with a positive family history, early onset of age, or multiple sites of masses. If the results verified the mutations of RET gene, thyroidectomy should be undertaken as the guide for better prognosis.
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Affiliation(s)
- Qiuli Liu
- Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China
| | - Dali Tong
- Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China
| | - Wenqiang Yuan
- Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China
| | - Gaolei Liu
- Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China
| | - Gang Yuan
- Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China
| | - Weihua Lan
- Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China
| | - Dianzheng Zhang
- Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA
| | - Jun Zhang
- Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China
| | - Zaoming Huang
- Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China
| | - Yao Zhang
- Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China
| | - Jun Jiang
- Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China
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Paragliola RM, Torino F, Papi G, Locantore P, Pontecorvi A, Corsello SM. Mouse models of medullary thyroid cancer and developing new targeted therapies. Expert Opin Drug Discov 2016; 11:917-9. [PMID: 27541085 DOI: 10.1080/17460441.2016.1223036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Affiliation(s)
| | - Francesco Torino
- b Department of Systems Medicine , Università di Roma 'Tor Vergata' , Roma , Italy
| | - Giampaolo Papi
- a Unit of Endocrinology , Università Cattolica del Sacro Cuore , Roma , Italy
| | - Pietro Locantore
- a Unit of Endocrinology , Università Cattolica del Sacro Cuore , Roma , Italy
| | - Alfredo Pontecorvi
- a Unit of Endocrinology , Università Cattolica del Sacro Cuore , Roma , Italy
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30
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Ibiza S, García-Cassani B, Ribeiro H, Carvalho T, Almeida L, Marques R, Misic AM, Bartow-McKenney C, Larson DM, Pavan WJ, Eberl G, Grice EA, Veiga-Fernandes H. Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Nature 2016; 535:440-443. [PMID: 27409807 PMCID: PMC4962913 DOI: 10.1038/nature18644] [Citation(s) in RCA: 288] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Accepted: 06/13/2016] [Indexed: 02/08/2023]
Abstract
Group 3 innate lymphoid cells (ILC3) are major regulators of inflammation and infection at mucosal barriers. ILC3 development is thought to be programmed, but how ILC3 perceive, integrate and respond to local environmental signals remains unclear. Here we show that ILC3 in mice sense their environment and control gut defence as part of a glial–ILC3–epithelial cell unit orchestrated by neurotrophic factors. We found that enteric ILC3 express the neuroregulatory receptor RET. ILC3-autonomous Ret ablation led to decreased innate interleukin-22 (IL-22), impaired epithelial reactivity, dysbiosis and increased susceptibility to bowel inflammation and infection. Neurotrophic factors directly controlled innate Il22 downstream of the p38 MAPK/ERK-AKT cascade and STAT3 activation. Notably, ILC3 were adjacent to neurotrophic-factor-expressing glial cells that exhibited stellate-shaped projections into ILC3 aggregates. Glial cells sensed microenvironmental cues in a MYD88-dependent manner to control neurotrophic factors and innate IL-22. Accordingly, glial-intrinsic Myd88 deletion led to impaired production of ILC3-derived IL-22 and a pronounced propensity towards gut inflammation and infection. Our work sheds light on a novel multi-tissue defence unit, revealing that glial cells are central hubs of neuron and innate immune regulation by neurotrophic factor signals.
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Affiliation(s)
- Sales Ibiza
- Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal
| | - Bethania García-Cassani
- Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal
| | - Hélder Ribeiro
- Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal
| | - Tânia Carvalho
- Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal
| | - Luís Almeida
- Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal
| | - Rute Marques
- Microenvironment and Immunity Unit, Institut Pasteur, 25 Rue du Docteur Roux, 75724 Paris, France
| | - Ana M Misic
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Blvd, 1007 Biomedical Research Building, Philadelphia, PA 19104, US
| | - Casey Bartow-McKenney
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Blvd, 1007 Biomedical Research Building, Philadelphia, PA 19104, US
| | - Denise M Larson
- Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, US
| | - William J Pavan
- Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, US
| | - Gérard Eberl
- Microenvironment and Immunity Unit, Institut Pasteur, 25 Rue du Docteur Roux, 75724 Paris, France
| | - Elizabeth A Grice
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Blvd, 1007 Biomedical Research Building, Philadelphia, PA 19104, US
| | - Henrique Veiga-Fernandes
- Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal
- Champalimaud Research. Champalimaud Centre for the Unknown. 1400-038 Lisbon, Portugal
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31
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Bolon B, Jing S, Asuncion F, Scully S, Pisegna M, Van GY, Hu Z, Yu YB, Min H, Wild K, Rosenfeld RD, Tarpley J, Carnahan J, Duryea D, Hill D, Kaufman S, Yan XQ, Juan T, Christensen K, McCabe J, Simonet WS. The Candidate Neuroprotective Agent Artemin Induces Autonomic Neural Dysplasia without Preventing Peripheral Nerve Dysfunction. Toxicol Pathol 2016; 32:275-94. [PMID: 15204970 DOI: 10.1080/01926230490431475] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Artemin (ART) signals through the GFR α—3/RET receptor complex to support sympathetic neuron development. Here we show that ART also influences autonomic elements in adrenal medulla and enteric and pelvic ganglia. Transgenic mice over-expressing Art throughout development exhibited systemic autonomic neural lesions including fusion of adrenal medullae with adjacent paraganglia, adrenal medullary dysplasia, and marked enlargement of sympathetic (superior cervical and sympathetic chain ganglia) and parasympathetic (enteric, pelvic) ganglia. Changes began by gestational day 12.5 and formed progressively larger masses during adulthood. Art supplementation in wild type adult mice by administering recombinant protein or an Art-bearing retroviral vector resulted in hyperplasia or neuronal metaplasia at the adrenal corticomedullary junction. Expression data revealed that Gfr α—3 is expressed during development in the adrenal medulla, sensory and autonomic ganglia and their projections, while Art is found in contiguous mesenchymal domains (especially skeleton) and in certain nerves. Intrathecal Art therapy did not reduce hypalgesia in rats following nerve ligation. These data (1) confirm that ART acts as a differentiation factor for autonomic (chiefly sympathoadrenal but also parasympathetic) neurons, (2) suggest a role for ART overexpression in the genesis of pheochromocytomas and paragangliomas, and (3) indicate that ART is not a suitable therapy for peripheral neuropathy.
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Affiliation(s)
- Brad Bolon
- Department of Pathology, Amgen Inc., Thousand Oaks, California 91320-1799, USA
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Wigerup C, Påhlman S, Bexell D. Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther 2016; 164:152-69. [PMID: 27139518 DOI: 10.1016/j.pharmthera.2016.04.009] [Citation(s) in RCA: 480] [Impact Index Per Article: 53.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Insufficient tissue oxygenation, or hypoxia, contributes to tumor aggressiveness and has a profound impact on clinical outcomes in cancer patients. At decreased oxygen tensions, hypoxia-inducible factors (HIFs) 1 and 2 are stabilized and mediate a hypoxic response, primarily by acting as transcription factors. HIFs exert differential effects on tumor growth and affect important cancer hallmarks including cell proliferation, apoptosis, differentiation, vascularization/angiogenesis, genetic instability, tumor metabolism, tumor immune responses, and invasion and metastasis. As a consequence, HIFs mediate resistance to chemo- and radiotherapy and are associated with poor prognosis in cancer patients. Intriguingly, perivascular tumor cells can also express HIF-2α, thereby forming a "pseudohypoxic" phenotype that further contributes to tumor aggressiveness. Therefore, therapeutic targeting of HIFs in cancer has the potential to improve treatment efficacy. Different strategies to target hypoxic cancer cells and/or HIFs include hypoxia-activated prodrugs and inhibition of HIF dimerization, mRNA or protein expression, DNA binding capacity, and transcriptional activity. Here we review the functions of HIFs in the progression and treatment of malignant solid tumors. We also highlight how HIFs may be targeted to improve the management of patients with therapy-resistant and metastatic cancer.
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Affiliation(s)
- Caroline Wigerup
- Translational Cancer Research, Medicon Village 404:C3, Lund University, Lund, Sweden
| | - Sven Påhlman
- Translational Cancer Research, Medicon Village 404:C3, Lund University, Lund, Sweden.
| | - Daniel Bexell
- Translational Cancer Research, Medicon Village 404:C3, Lund University, Lund, Sweden
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Arnheim N, Calabrese P. Germline Stem Cell Competition, Mutation Hot Spots, Genetic Disorders, and Older Fathers. Annu Rev Genomics Hum Genet 2016; 17:219-43. [PMID: 27070266 DOI: 10.1146/annurev-genom-083115-022656] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Some de novo human mutations arise at frequencies far exceeding the genome average mutation rate. Examples include the common mutations at one or a few sites in the genes that cause achondroplasia, Apert syndrome, multiple endocrine neoplasia type 2B, and Noonan syndrome. These mutations are recurrent, provide a gain of function, are paternally derived, and are more likely to be transmitted as the father ages. Recent experiments have tested whether the high mutation frequencies are due to an elevated mutation rate per cell division, as expected, or to an advantage of the mutant spermatogonial stem cells over wild-type stem cells. The evidence, which includes the surprising discovery of testis mutation clusters, rules out the former model but not the latter. We propose how the mutations might alter spermatogonial stem cell function and discuss how germline selection contributes to the paternal age effect, the human mutational load, and adaptive evolution.
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Affiliation(s)
- Norman Arnheim
- Molecular and Computational Biology Program, University of Southern California, Los Angeles, California 90089-2910; ,
| | - Peter Calabrese
- Molecular and Computational Biology Program, University of Southern California, Los Angeles, California 90089-2910; ,
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34
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Wiedemann T, Pellegata NS. Animal models of multiple endocrine neoplasia. Mol Cell Endocrinol 2016; 421:49-59. [PMID: 26184857 DOI: 10.1016/j.mce.2015.07.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 06/23/2015] [Accepted: 07/03/2015] [Indexed: 10/23/2022]
Abstract
Multiple endocrine neoplasia (MEN) syndromes are autosomal dominant diseases with high penetrance characterized by proliferative lesions (usually hyperplasia or adenoma) arising in at least two endocrine tissues. Four different MEN syndromes have been so far identified: MEN type 1 (MEN1), MEN2A (also referred to as MEN2), MEN2B (or MEN3) and MEN4, which have slightly varying tumor spectra and are caused by mutations in different genes. MEN1 associates with loss-of-function mutations in the MEN1 gene encoding the tumor suppressor menin. The MEN2A and MEN2B syndromes are due to activating mutations in the proto-oncogene RET (Rearranged in Transfection) and are characterized by different phenotypic features of the affected patients. MEN4 was the most recent addition to the family of the MEN syndromes. It was discovered less than 10 years ago thanks to studies of a rat strain that spontaneously develops multiple endocrine tumors (named MENX). These studies identified an inactivating mutation in the Cdkn1b gene, encoding the putative tumor suppressor p27, as the causative mutation of the rat syndrome. Subsequently, germline mutations in the human ortholog CDKN1B were also found in a subset of patients with a MEN-like phenotype and this led to the identification of MEN4. Small animal models have been instrumental in understanding important biochemical, physiological and pathological processes of cancer onset and spread in intact living organisms. Moreover, they have provided us with insight into gene function(s) and molecular mechanisms of disease progression. We here review the currently available animal models of MEN syndromes and their impact on the elucidation of the pathophysiology of these diseases, with a special focus on the rat MENX syndrome that we have been characterizing.
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Affiliation(s)
- Tobias Wiedemann
- Institute of Pathology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany
| | - Natalia S Pellegata
- Institute of Pathology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.
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35
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Lepoutre-Lussey C, Thibault C, Buffet A, Morin A, Badoual C, Bénit P, Rustin P, Ottolenghi C, Janin M, Castro-Vega LJ, Trapman J, Gimenez-Roqueplo AP, Favier J. From Nf1 to Sdhb knockout: Successes and failures in the quest for animal models of pheochromocytoma. Mol Cell Endocrinol 2016; 421:40-8. [PMID: 26123588 DOI: 10.1016/j.mce.2015.06.027] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 06/02/2015] [Accepted: 06/02/2015] [Indexed: 01/19/2023]
Abstract
Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors characterized by a high frequency of hereditary forms. Based on transcriptome classification, PPGL can be classified in two different clusters. Cluster 1 tumors are caused by mutations in SDHx, VHL and FH genes and are characterized by a pseudohypoxic signature. Cluster 2 PPGL carry mutations in RET, NF1, MAX or TMEM127 genes and display an activation of the MAPK and mTOR signaling pathways. Many genetically engineered and allografted mouse models have been generated these past 30 years to investigate the mechanisms of PPGL tumorigenesis and test new therapeutic strategies. Among them, only Cluster 2-related models have been successful while no Cluster 1-related knockout mouse was so far reported to develop a PPGL. In this review, we present an overview of existing, successful or not, PPGL models, and a description of our own experience on the quest of Sdhb knockout mouse models of PPGL.
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Affiliation(s)
- Charlotte Lepoutre-Lussey
- INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France
| | - Constance Thibault
- INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France
| | - Alexandre Buffet
- INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France
| | - Aurélie Morin
- INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France
| | - Cécile Badoual
- INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'anatomo-pathologie, F-75015 Paris, France
| | - Paule Bénit
- INSERM, UMR1141, Hôpital Robert Debré, F-75019 Paris, France; Université Paris 7, Faculté de Médecine Denis Diderot, Paris, France
| | - Pierre Rustin
- INSERM, UMR1141, Hôpital Robert Debré, F-75019 Paris, France; Université Paris 7, Faculté de Médecine Denis Diderot, Paris, France
| | - Chris Ottolenghi
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France; Metabolic Biochemistry, Hôpital Necker-Enfants Malades, Paris, France; INSERM, Unit 1124, Paris, France
| | - Maxime Janin
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France; Metabolic Biochemistry, Hôpital Necker-Enfants Malades, Paris, France; INSERM, Unit 1124, Paris, France
| | - Luis-Jaime Castro-Vega
- INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France
| | - Jan Trapman
- Department of Pathology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Anne-Paule Gimenez-Roqueplo
- INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, France
| | - Judith Favier
- INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, F-75006 Paris, France.
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Kirschner LS, Qamri Z, Kari S, Ashtekar A. Mouse models of thyroid cancer: A 2015 update. Mol Cell Endocrinol 2016; 421:18-27. [PMID: 26123589 PMCID: PMC4691568 DOI: 10.1016/j.mce.2015.06.029] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 05/28/2015] [Accepted: 06/11/2015] [Indexed: 02/06/2023]
Abstract
Thyroid cancer is the most common endocrine neoplasm, and its rate is rising at an alarming pace. Thus, there is a compelling need to develop in vivo models which will not only enable the confirmation of the oncogenic potential of driver genes, but also point the way towards the development of new therapeutics. Over the past 20 years, techniques for the generation of mouse models of human diseases have progressed substantially, accompanied by parallel advances in the genetics and genomics of human tumors. This convergence has enabled the development of mouse lines carrying mutations in the genes that cause thyroid cancers of all subtypes, including differentiated papillary and follicular thyroid cancers, poorly differentiated/anaplastic cancers, and medullary thyroid cancers. In this review, we will discuss the state of the art of mouse modeling of thyroid cancer, with the eventual goal of providing insight into tumor biology and treatment.
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Affiliation(s)
- Lawrence S Kirschner
- Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA; Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA.
| | - Zahida Qamri
- Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA
| | - Suresh Kari
- Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA
| | - Amruta Ashtekar
- Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, USA
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Kameda Y. Cellular and molecular events on the development of mammalian thyroid C cells. Dev Dyn 2016; 245:323-41. [PMID: 26661795 DOI: 10.1002/dvdy.24377] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 08/05/2015] [Indexed: 12/12/2022] Open
Abstract
Thyroid C cells synthesize and secrete calcitonin, a serum calcium-lowering hormone. This review provides our current understanding of mammalian thyroid C cells from the molecular and morphological perspectives. Several transcription factors and signaling molecules involved in the development of C cells have been identified, and genes expressed in the pharyngeal pouch endoderm, neural crest-derived mesenchyme in the pharyngeal arches, and ultimobranchial body play critical roles for the development of C cells. It has been generally accepted, without much-supporting evidence, that mammalian C cells, as well as the avian cells, are derived from the neural crest. However, by fate mapping of neural crest cells in both Wnt1-Cre/R26R and Connexin(Cxn)43-lacZ transgenic mice, we showed that neural crest cells colonize neither the fourth pharyngeal pouch nor the ultimobranchial body. E-cadherin, an epithelial cell marker, is expressed in thyroid C cells and their precursors, the fourth pharyngeal pouch and ultimobranchial body. Furthermore, E-cadherin is colocalized with calcitonin in C cells. Recently, lineage tracing in Sox17-2A-iCre/R26R mice has clarified that the pharyngeal endoderm-derived cells give rise to C cells. Together, these findings indicate that mouse thyroid C cells are endodermal in origin.
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Affiliation(s)
- Yoko Kameda
- Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
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Kumar A, Kopra J, Varendi K, Porokuokka LL, Panhelainen A, Kuure S, Marshall P, Karalija N, Härma MA, Vilenius C, Lilleväli K, Tekko T, Mijatovic J, Pulkkinen N, Jakobson M, Jakobson M, Ola R, Palm E, Lindahl M, Strömberg I, Võikar V, Piepponen TP, Saarma M, Andressoo JO. GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function. PLoS Genet 2015; 11:e1005710. [PMID: 26681446 PMCID: PMC4682981 DOI: 10.1371/journal.pgen.1005710] [Citation(s) in RCA: 92] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Accepted: 11/06/2015] [Indexed: 12/14/2022] Open
Abstract
Degeneration of nigrostriatal dopaminergic system is the principal lesion in Parkinson’s disease. Because glial cell line-derived neurotrophic factor (GDNF) promotes survival of dopamine neurons in vitro and in vivo, intracranial delivery of GDNF has been attempted for Parkinson’s disease treatment but with variable success. For improving GDNF-based therapies, knowledge on physiological role of endogenous GDNF at the sites of its expression is important. However, due to limitations of existing genetic model systems, such knowledge is scarce. Here, we report that prevention of transcription of Gdnf 3’UTR in Gdnf endogenous locus yields GDNF hypermorphic mice with increased, but spatially unchanged GDNF expression, enabling analysis of postnatal GDNF function. We found that increased level of GDNF in the central nervous system increases the number of adult dopamine neurons in the substantia nigra pars compacta and the number of dopaminergic terminals in the dorsal striatum. At the functional level, GDNF levels increased striatal tissue dopamine levels and augmented striatal dopamine release and re-uptake. In a proteasome inhibitor lactacystin-induced model of Parkinson’s disease GDNF hypermorphic mice were protected from the reduction in striatal dopamine and failure of dopaminergic system function. Importantly, adverse phenotypic effects associated with spatially unregulated GDNF applications were not observed. Enhanced GDNF levels up-regulated striatal dopamine transporter activity by at least five fold resulting in enhanced susceptibility to 6-OHDA, a toxin transported into dopamine neurons by DAT. Further, we report how GDNF levels regulate kidney development and identify microRNAs miR-9, miR-96, miR-133, and miR-146a as negative regulators of GDNF expression via interaction with Gdnf 3’UTR in vitro. Our results reveal the role of GDNF in nigrostriatal dopamine system postnatal development and adult function, and highlight the importance of correct spatial expression of GDNF. Furthermore, our results suggest that 3’UTR targeting may constitute a useful tool in analyzing gene function. Intracranial delivery of GDNF has been attempted for Parkinson’s disease (PD) treatment but with variable success. For improving GDNF-based therapies, knowledge on physiological role of endogenous GDNF at the sites of its expression is important. However, due to limitations of existing genetic model systems, such knowledge is scarce. Here, we utilize an innovative genetic approach by targeting the 3’UTR regulation of Gdnf in mice. Such animals express elevated levels of Gdnf exclusively in natively Gdnf-expressing cells, enabling dissection of endogenous GDNF functions in vivo. We show that endogenous GDNF regulates dopamine system development and function and protects mice in a rodent PD model without side effects associated with ectopic GDNF applications. Further, we report how GDNF levels regulate kidney development and identify microRNAs which control GDNF expression. Our study highlights the importance of correct spatial expression of GDNF and opens a novel approach to study gene function in mice.
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Affiliation(s)
- Anmol Kumar
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Jaakko Kopra
- Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Kärt Varendi
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | | | - Anne Panhelainen
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Satu Kuure
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Pepin Marshall
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Nina Karalija
- Department of Histology and Cell Biology, Umeå University, Umeå, Sweden
| | - Mari-Anne Härma
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Carolina Vilenius
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Kersti Lilleväli
- Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Triin Tekko
- Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Jelena Mijatovic
- Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Nita Pulkkinen
- Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Madis Jakobson
- Department of Biochemistry and Developmental Biology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland
| | - Maili Jakobson
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Roxana Ola
- Department of Biochemistry and Developmental Biology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland
| | - Erik Palm
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Maria Lindahl
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Ingrid Strömberg
- Department of Histology and Cell Biology, Umeå University, Umeå, Sweden
| | - Vootele Võikar
- Neuroscience Center and Department of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - T. Petteri Piepponen
- Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Mart Saarma
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Jaan-Olle Andressoo
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
- * E-mail:
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Kramer ER, Liss B. GDNF-Ret signaling in midbrain dopaminergic neurons and its implication for Parkinson disease. FEBS Lett 2015; 589:3760-72. [DOI: 10.1016/j.febslet.2015.11.006] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 10/29/2015] [Accepted: 11/03/2015] [Indexed: 12/11/2022]
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Tischler AS, Favier J. Models of pheochromocytoma: what's on the horizon? INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY 2015. [DOI: 10.2217/ije.15.14] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Affiliation(s)
- Arthur S Tischler
- Department of Pathology & Laboratory Medicine, Tufts Medical Center, 800 Washington St, Boston, MA 02111, USA
| | - Judith Favier
- DR2 Inserm, INSERM UMR970 – PARCC, Team 13 -Pheochromocytomas and Paragangliomas, 56 rue Leblanc, 75737 Paris Cedex 15, France
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Abstract
The thyroid parafollicular cell, or commonly named "C-cell," functions in serum calcium homeostasis. Elevations in serum calcium trigger release of calcitonin from the C-cell, which in turn functions to inhibit absorption of calcium by the intestine, resorption of bone by the osteoclast, and reabsorption of calcium by renal tubular cells. Oncogenic transformation of the thyroid C-cell is thought to progress through a hyperplastic process prior to malignancy with increasing levels of serum calcitonin serving as a biomarker for tumor burden. The discovery that multiple endocrine neoplasia type 2 is caused by activating mutations of the RET gene serves to highlight the RET-RAS-MAPK signaling pathway in both initiation and progression of medullary thyroid carcinoma (MTC). Thyroid C-cells are known to express RET at high levels relative to most cell types; therefore, aberrant activation of this receptor is targeted primarily to the C-cell, providing one possible cause of tissue-specific oncogenesis. The role of RET signaling in normal C-cell function is unknown though calcitonin gene transcription appears to be sensitive to RET activation. Beyond RET, the modeling of oncogenesis in animals and screening of human tumors for candidate gene mutations have uncovered mutation of RAS family members and inactivation of Rb1 regulatory pathway as potential mediators of C-cell transformation. A growing understanding of how RET interacts with these pathways, both in normal C-cell function and during oncogenic transformation, will help in the development of novel molecular-targeted therapies.
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Affiliation(s)
- Gilbert J Cote
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1461, Houston, TX, 77030, USA.
| | - Elizabeth G Grubbs
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1484, Houston, TX, 77030, USA
| | - Marie-Claude Hofmann
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1461, Houston, TX, 77030, USA
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42
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Krampitz GW, Norton JA. RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. Cancer 2014; 120:1920-1931. [DOI: 10.1002/cncr.28661] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Abstract
This article summarizes the major clinical, pathological, and molecular features of medullary thyroid carcinoma (MTC), based on a review of the most significant advances in our understanding of this tumor type over the last 25 years. MTC is a neuroendocrine carcinoma that shows evidence of C-cell differentiation. The tumor has a distinctive morphologic appearance, including the presence of amyloid deposits. Immunostaining for calcitonin, carcinoembryonic antigen, calcitonin gene-related peptide, and thyroid transcription factor 1 is helpful in differential diagnosis. Identification of RET mutations in familial and sporadic MTC has brought important changes in early diagnosis and treatment. Surgery remains the cornerstone of effective therapy. Understanding the molecular basis of MTC will allow identification of novel approaches for individualized treatment.
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Affiliation(s)
- Xavier Matias-Guiu
- Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida IRBLLEIDA, Av Alcalde Rovira Roure 80, Lleida, 25198, Spain,
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44
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Abstract
The neuroendocrine tumours pheochromocytomas and paragangliomas carry the highest degree of heritability in human neoplasms, enabling genetic alterations to be traced to clinical phenotypes through their transmission in families. Mutations in more than a dozen distinct susceptibility genes have implicated multiple pathways in these tumours, offering insights into kinase downstream signalling interactions and hypoxia regulation, and uncovering links between metabolism, epigenetic remodelling and cell growth. These advances extend to co-occurring tumours, including renal, thyroid and gastrointestinal malignancies. Hereditary pheochromocytomas and paragangliomas are powerful models for recognizing cancer driver events, which can be harnessed for diagnostic purposes and for guiding the future development of targeted therapies.
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Affiliation(s)
- Patricia L M Dahia
- Department of Medicine/Division of Hematology and Medical Oncology, Cancer Therapy and Research Center, Greehey Children Cancer Research Institute, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Lab 5053-R3, MC 7880, San Antonio-TX 78229-3900, USA
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45
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Akeno N, Miller AL, Ma X, Wikenheiser-Brokamp KA. p53 suppresses carcinoma progression by inhibiting mTOR pathway activation. Oncogene 2014; 34:589-99. [PMID: 24469052 PMCID: PMC4112184 DOI: 10.1038/onc.2013.589] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Revised: 10/18/2013] [Accepted: 12/18/2013] [Indexed: 12/24/2022]
Abstract
Genetic alterations in human cancers and murine models indicate that Rb and p53 have critical tumor suppressive functions in retinoblastoma, a tumor of neural origin, and neuroendocrine tumors including small cell lung cancer and medullary thyroid cancer (MTC). Rb inactivation is the initiating lesion in retinoblastoma and current models propose that induction of apoptosis is a key p53 tumor suppressive function. Genetic studies in mice, however, indicate that other undefined p53 tumor suppressive functions are operative in vivo. How p53 loss cooperates with Rb inactivation to promote carcinogenesis is also not fully understood. In the current study, genetically engineered mice were generated to determine the role of Rb and p53 in MTC pathogenesis and test the hypothesis that p53 suppresses carcinogenesis by inhibiting mTOR signaling. Conditional Rb ablation resulted in thyroid tumors mimicking human MTC, and additional p53 loss led to rapid tumor progression. p53 suppressed tumorigenesis by inhibiting cell cycle progression, but did not induce apoptosis. On the contrary, p53 loss led to increased apoptosis that had to be overcome for tumor progression. mTOR activity was markedly increased in p53 deficient tumors and rapamycin treatment suppressed tumor cell growth identifying mTOR inhibition as a critical p53 tumor suppressive function. Rapamycin treatment did not result in AKT/MAPK activation providing evidence that this feedback mechanism operative in other cancers is not a general response to mTORC1 inhibition. Together, these studies provide mechanistic links between genetic alterations and aberrant signaling pathways critical in carcinogenesis, and identify essential Rb and p53 tumor suppressive functions in vivo.
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Affiliation(s)
- N Akeno
- Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - A L Miller
- Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - X Ma
- Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - K A Wikenheiser-Brokamp
- 1] Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA [2] Pulmonary Biology, Cincinnati Children's Hospital Medical Center and Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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46
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Borrello MG, Ardini E, Locati LD, Greco A, Licitra L, Pierotti MA. RET inhibition: implications in cancer therapy. Expert Opin Ther Targets 2013; 17:403-19. [PMID: 23461584 DOI: 10.1517/14728222.2013.758715] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION The RET gene encodes a receptor tyrosine kinase essential for ontogenesis of the enteric nervous system and kidney. Following identification of RET, it was found that somatic rearrangements of this gene, conventionally designated as RET/PTC, are frequently present in papillary thyroid carcinoma. Subsequently, activating germ line point mutations of RET were identified as being responsible for the hereditary medullary thyroid carcinoma syndromes MEN2A, MEN2B and FMTC. RET rearrangements have recently been identified in a small fraction of lung adenocarcinomas. AREA COVERED The authors review the current field concerning the RET gene and protein, its involvement in cancer and the preclinical and clinical studies which highlight its role as a potentially important therapeutic target for several cancers. EXPERT OPINION Many multitargeted inhibitors which crossreact with RET have been developed and investigated in clinical trials targeting many cancer indications. In particular, VEGFR/PDGFR inhibitors, widely explored as antiangiogenics, have been intensively studied in thyroid carcinoma patients. Notwithstanding the efficacy observed with such agents, their common clinical activity in thyroid carcinoma is of short duration and includes frequent and severe side effects, limiting their therapeutic action. These findings are discussed and the need for improved, more specific RET-targeting drugs is highlighted.
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Affiliation(s)
- Maria Grazia Borrello
- UO Molecular Mechanisms, Experimental Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via GA. Amadeo, 42-20133 Milano, Italy.
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Almeida ARM, Arroz-Madeira S, Fonseca-Pereira D, Ribeiro H, Lasrado R, Pachnis V, Veiga-Fernandes H. RET/GFRα signals are dispensable for thymic T cell development in vivo. PLoS One 2012; 7:e52949. [PMID: 23300832 PMCID: PMC3531415 DOI: 10.1371/journal.pone.0052949] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Accepted: 11/22/2012] [Indexed: 11/18/2022] Open
Abstract
Identification of thymocyte regulators is a central issue in T cell biology. Interestingly, growing evidence indicates that common key molecules control neuronal and immune cell functions. The neurotrophic factor receptor RET mediates critical functions in foetal hematopoietic subsets, thus raising the possibility that RET-related molecules may also control T cell development. We show that Ret, Gfra1 and Gfra2 are abundantly expressed by foetal and adult immature DN thymocytes. Despite the developmentally regulated expression of these genes, analysis of foetal thymi from Gfra1, Gfra2 or Ret deficient embryos revealed that these molecules are dispensable for foetal T cell development. Furthermore, analysis of RET gain of function and Ret conditional knockout mice showed that RET is also unnecessary for adult thymopoiesis. Finally, competitive thymic reconstitution assays indicated that Ret deficient thymocytes maintained their differentiation fitness even in stringent developmental conditions. Thus, our data demonstrate that RET/GFRα signals are dispensable for thymic T cell development in vivo, indicating that pharmacological targeting of RET signalling in tumours is not likely to result in T cell production failure.
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Affiliation(s)
| | - Sílvia Arroz-Madeira
- Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Lisboa, Portugal
| | | | - Hélder Ribeiro
- Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Lisboa, Portugal
| | - Reena Lasrado
- Division of Molecular Neurobiology, Medical Research Council (MRC), National Institute for Medical Research, London, United Kingdom
| | - Vassilis Pachnis
- Division of Molecular Neurobiology, Medical Research Council (MRC), National Institute for Medical Research, London, United Kingdom
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Macià A, Gallel P, Vaquero M, Gou-Fabregas M, Santacana M, Maliszewska A, Robledo M, Gardiner JR, Basson MA, Matias-Guiu X, Encinas M. Sprouty1 is a candidate tumor-suppressor gene in medullary thyroid carcinoma. Oncogene 2012; 31:3961-72. [PMID: 22158037 PMCID: PMC3378485 DOI: 10.1038/onc.2011.556] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2011] [Revised: 10/07/2011] [Accepted: 10/31/2011] [Indexed: 12/30/2022]
Abstract
Medullary thyroid carcinoma (MTC) is a malignancy derived from the calcitonin-producing C-cells of the thyroid gland. Oncogenic mutations of the Ret proto-oncogene are found in all heritable forms of MTC and roughly one half of the sporadic cases. However, several lines of evidence argue for the existence of additional genetic lesions necessary for the development of MTC. Sprouty (Spry) family of genes is composed of four members in mammals (Spry1-4). Some Spry family members have been proposed as candidate tumor-suppressor genes in a variety of cancerous pathologies. In this work, we show that targeted deletion of Spry1 causes C-cell hyperplasia, a precancerous lesion preceding MTC, in young adult mice. Expression of Spry1 restrains proliferation of the MTC-derived cell line, TT. Finally, we found that the Spry1 promoter is frequently methylated in MTC and that Spry1 expression is consequently decreased. These findings identify Spry1 as a candidate tumor-suppressor gene in MTC.
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MESH Headings
- Adaptor Proteins, Signal Transducing
- Animals
- Carcinoma, Medullary/genetics
- Carcinoma, Medullary/pathology
- Carcinoma, Neuroendocrine
- Cell Line, Tumor
- Cell Proliferation
- DNA Methylation
- Female
- Genes, Tumor Suppressor
- Humans
- Hyperplasia
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Mice
- Mice, Knockout
- Mice, SCID
- Phosphoproteins/genetics
- Phosphoproteins/metabolism
- Precancerous Conditions/pathology
- Promoter Regions, Genetic
- Proto-Oncogene Mas
- Proto-Oncogene Proteins c-ret/genetics
- RNA Interference
- RNA, Small Interfering
- Sequence Deletion
- Thyroid Gland/metabolism
- Thyroid Gland/pathology
- Thyroid Neoplasms/genetics
- Thyroid Neoplasms/pathology
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Affiliation(s)
- Anna Macià
- Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Lleida, Spain
| | - Pilar Gallel
- Department of Pathology and Molecular Genetics, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Lleida, Spain
| | - Marta Vaquero
- Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Lleida, Spain
| | - Myriam Gou-Fabregas
- Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Lleida, Spain
| | - Maria Santacana
- Department of Pathology and Molecular Genetics, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Lleida, Spain
| | - Agnieszka Maliszewska
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
| | - Mercedes Robledo
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
| | | | - M. Albert Basson
- Department of Craniofacial Development, King’s College London, UK
| | - Xavier Matias-Guiu
- Department of Pathology and Molecular Genetics, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Lleida, Spain
| | - Mario Encinas
- Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Lleida, Spain
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49
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Sin3a acts through a multi-gene module to regulate invasion in Drosophila and human tumors. Oncogene 2012; 32:3184-97. [PMID: 22890320 DOI: 10.1038/onc.2012.326] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Chromatin remodeling proteins regulate multiple aspects of cell homeostasis, making them ideal candidates for misregulation in transformed cells. Here, we explore Sin3A, a member of the Sin3 family of proteins linked to tumorigenesis that are thought to regulate gene expression through their role as histone deacetylases (HDACs). We identified Drosophila Sin3a as an important mediator of oncogenic Ret receptor in a fly model of Multiple Endocrine Neoplasia Type 2. Reducing Drosophila Sin3a activity led to metastasis-like behavior and, in the presence of Diap1, secondary tumors distant from the site of origin. Genetic and Chip-Seq analyses identified previously undescribed Sin3a targets including genes involved in cell motility and actin dynamics, as well as signaling pathways including Src, Jnk and Rho. A key Sin3a oncogenic target, PP1B, regulates stability of β-Catenin/Armadillo: the outcome is to oppose T-cell factor (TCF) function and Wg/Wnt pathway signaling in both fly and mammalian cancer cells. Reducing Sin3A strongly increased the invasive behavior of A549 human lung adenocarcinoma cells. We show that Sin3A is downregulated in a variety of human tumors and that Src, JNK, RhoA and PP1B/β-Catenin are regulated in a manner analogous to our Drosophila models. Our data suggest that Sin3A influences a specific step of tumorigenesis by regulating a module of genes involved in cell invasion. Tumor progression may commonly rely on such 'modules of invasion' under the control of broad transcriptional regulators.
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Choi SK, Yoon SR, Calabrese P, Arnheim N. Positive selection for new disease mutations in the human germline: evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2B. PLoS Genet 2012; 8:e1002420. [PMID: 22359510 PMCID: PMC3280958 DOI: 10.1371/journal.pgen.1002420] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2011] [Accepted: 10/19/2011] [Indexed: 01/15/2023] Open
Abstract
Multiple endocrine neoplasia type 2B (MEN2B) is a highly aggressive thyroid cancer syndrome. Since almost all sporadic cases are caused by the same nucleotide substitution in the RET proto-oncogene, the calculated disease incidence is 100-200 times greater than would be expected based on the genome average mutation frequency. In order to determine whether this increased incidence is due to an elevated mutation rate at this position (true mutation hot spot) or a selective advantage conferred on mutated spermatogonial stem cells, we studied the spatial distribution of the mutation in 14 human testes. In donors aged 36-68, mutations were clustered with small regions of each testis having mutation frequencies several orders of magnitude greater than the rest of the testis. In donors aged 19-23 mutations were almost non-existent, demonstrating that clusters in middle-aged donors grew during adulthood. Computational analysis showed that germline selection is the only plausible explanation. Testes of men aged 75-80 were heterogeneous with some like middle-aged and others like younger testes. Incorporating data on age-dependent death of spermatogonial stem cells explains the results from all age groups. Germline selection also explains MEN2B's male mutation bias and paternal age effect. Our discovery focuses attention on MEN2B as a model for understanding the genetic and biochemical basis of germline selection. Since RET function in mouse spermatogonial stem cells has been extensively studied, we are able to suggest that the MEN2B mutation provides a selective advantage by altering the PI3K/AKT and SFK signaling pathways. Mutations that are preferred in the germline but reduce the fitness of offspring increase the population's mutational load. Our approach is useful for studying other disease mutations with similar characteristics and could uncover additional germline selection pathways or identify true mutation hot spots.
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Affiliation(s)
- Soo-Kyung Choi
- Molecular and Computational Biology Program, University of Southern California, Los Angeles, California, United States of America
| | - Song-Ro Yoon
- Molecular and Computational Biology Program, University of Southern California, Los Angeles, California, United States of America
| | - Peter Calabrese
- Molecular and Computational Biology Program, University of Southern California, Los Angeles, California, United States of America
| | - Norman Arnheim
- Molecular and Computational Biology Program, University of Southern California, Los Angeles, California, United States of America
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