{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T16:42:43Z","timestamp":1773160963515,"version":"3.50.1"},"reference-count":111,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2019,2,26]],"date-time":"2019-02-26T00:00:00Z","timestamp":1551139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["IG16932"],"award-info":[{"award-number":["IG16932"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>In this review, we propose that paraganglioma is a fundamentally organized, albeit aberrant, tissue composed of neoplastic vascular and neural cell types that share a common origin from a multipotent mesenchymal-like stem\/progenitor cell. This view is consistent with the pseudohypoxic footprint implicated in the molecular pathogenesis of the disease, is in harmony with the neural crest origin of the paraganglia, and is strongly supported by the physiological model of carotid body hyperplasia. Our immunomorphological and molecular studies of head and neck paragangliomas demonstrate in all cases relationships between the vascular and the neural tumor compartments, that share mesenchymal and immature vasculo-neural markers, conserved in derived cell cultures. This immature, multipotent phenotype is supported by constitutive amplification of NOTCH signaling genes and by loss of the microRNA-200s and -34s, which control NOTCH1, ZEB1, and PDGFRA in head and neck paraganglioma cells. Importantly, the neuroepithelial component is distinguished by extreme mitochondrial alterations, associated with collapse of the \u0394\u03a8m. Finally, our xenograft models of head and neck paraganglioma demonstrate that mesenchymal-like cells first give rise to a vasculo-angiogenic network, and then self-organize into neuroepithelial-like clusters, a process inhibited by treatment with imatinib.<\/jats:p>","DOI":"10.3390\/cancers11030273","type":"journal-article","created":{"date-parts":[[2019,2,26]],"date-time":"2019-02-26T11:00:44Z","timestamp":1551178844000},"page":"273","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["A Developmental Perspective on Paragangliar Tumorigenesis"],"prefix":"10.3390","volume":"11","author":[{"given":"Lavinia Vittoria","family":"Lotti","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, \u201cLa Sapienza\u201d University, Viale Regina Elena 324, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6146-9302","authenticated-orcid":false,"given":"Simone","family":"Vespa","sequence":"additional","affiliation":[{"name":"Center of Sciences on Aging and Translational Medicine (CeSI-MeT), \u201cG. d\u2019Annunzio\u201d University, Via Luigi Polacchi 11, 66100 Chieti, Italy"},{"name":"Department of Medical, Oral and Biotechnological Sciences, \u201cG. d\u2019Annunzio\u201d University, Via dei Vestini 31, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2706-4683","authenticated-orcid":false,"given":"Mattia Russel","family":"Pantalone","sequence":"additional","affiliation":[{"name":"Department of Medicine (Solna), Division of Microbial Pathogenesis, BioClinicum, Karolinska Institutet, 17164 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Perconti","sequence":"additional","affiliation":[{"name":"Center of Sciences on Aging and Translational Medicine (CeSI-MeT), \u201cG. d\u2019Annunzio\u201d University, Via Luigi Polacchi 11, 66100 Chieti, Italy"},{"name":"Department of Medical, Oral and Biotechnological Sciences, \u201cG. d\u2019Annunzio\u201d University, Via dei Vestini 31, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana Liberata","family":"Esposito","sequence":"additional","affiliation":[{"name":"Center of Sciences on Aging and Translational Medicine (CeSI-MeT), \u201cG. d\u2019Annunzio\u201d University, Via Luigi Polacchi 11, 66100 Chieti, Italy"},{"name":"Department of Medical, Oral and Biotechnological Sciences, \u201cG. d\u2019Annunzio\u201d University, Via dei Vestini 31, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa","family":"Visone","sequence":"additional","affiliation":[{"name":"Center of Sciences on Aging and Translational Medicine (CeSI-MeT), \u201cG. d\u2019Annunzio\u201d University, Via Luigi Polacchi 11, 66100 Chieti, Italy"},{"name":"Department of Medical, Oral and Biotechnological Sciences, \u201cG. d\u2019Annunzio\u201d University, Via dei Vestini 31, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelo","family":"Veronese","sequence":"additional","affiliation":[{"name":"Department of Medicine and Aging Sciences, \u201cG. d\u2019Annunzio\u201d University, Via Luigi Polacchi 11, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo Terenzio","family":"Paties","sequence":"additional","affiliation":[{"name":"Department of Oncology-Hematology, Service of Anatomic Pathology, \u201cGuglielmo da Saliceto\u201d Hospital, Via Taverna 49, 29100 Piacenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Sanna","sequence":"additional","affiliation":[{"name":"Skull Base Unit, \u201cGruppo Otologico\u201d Piacenza-Roma, Via Antonio Emmanueli, 42, 29121 Piacenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio","family":"Verginelli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, \u201cG. d\u2019Annunzio\u201d University, Via dei Vestini 31, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cecilia Soderberg","family":"Naucl\u00e9r","sequence":"additional","affiliation":[{"name":"Department of Medicine (Solna), Division of Microbial Pathogenesis, BioClinicum, Karolinska Institutet, 17164 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4440-1848","authenticated-orcid":false,"given":"Renato","family":"Mariani-Costantini","sequence":"additional","affiliation":[{"name":"Center of Sciences on Aging and Translational Medicine (CeSI-MeT), \u201cG. d\u2019Annunzio\u201d University, Via Luigi Polacchi 11, 66100 Chieti, Italy"},{"name":"Department of Medical, Oral and Biotechnological Sciences, \u201cG. d\u2019Annunzio\u201d University, Via dei Vestini 31, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1101\/gad.1182504","article-title":"Conserved mechanisms across development and tumorigenesis revealed by a mouse development perspective of human cancers","volume":"18","author":"Kho","year":"2004","journal-title":"Genes Dev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1002\/ijc.30067","article-title":"Tumour angiogenesis-Origin of blood vessels","volume":"139","author":"Nagare","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/nature03100","article-title":"Tissue repair and stem cell renewal in carcinogenesis","volume":"432","author":"Beachy","year":"2004","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.biosystems.2012.04.005","article-title":"Morphogenetic fields in embryogenesis, regeneration, and cancer: Non-local control of complex patterning","volume":"109","author":"Levin","year":"2012","journal-title":"Biosystems"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nrm2354","article-title":"The role of oxygen availability in embryonic development and stem cell function","volume":"9","author":"Simon","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1016\/j.devcel.2010.05.012","article-title":"Tumors as organs: Complex tissues that interface with the entire organism","volume":"18","author":"Egeblad","year":"2010","journal-title":"Dev. Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/dvdy.24226","article-title":"Tumors of the neural crest: Common themes in development and cancer","volume":"244","author":"Maguire","year":"2015","journal-title":"Dev. Dyn."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ydbio.2012.02.035","article-title":"Neural crest progenitors and stem cells: From early development to adulthood","volume":"366","author":"Dupin","year":"2010","journal-title":"Dev. Biol."},{"key":"ref_9","first-page":"425","article-title":"Regeneration and cancer","volume":"42","author":"Wolsky","year":"1978","journal-title":"Growth"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1056\/NEJM198612253152606","article-title":"Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing","volume":"315","author":"Dvorak","year":"1986","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1146\/annurev-cellbio-100913-013132","article-title":"\u201cMesenchymal\u201d stem cells","volume":"30","author":"Bianco","year":"2014","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1016\/j.stemcr.2016.05.011","article-title":"No Identical \u201cMesenchymal Stem Cells\u201d at Different Times and Sites: Human Committed Progenitors of Distinct Origin and Differentiation Potential Are Incorporated as Adventitial Cells in Microvessels","volume":"14","author":"Sacchetti","year":"2016","journal-title":"Stem Cell Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.currproblcancer.2014.01.001","article-title":"Pheochromocytoma and paraganglioma: Diagnosis, genetics, management, and treatment","volume":"38","author":"Martucci","year":"2014","journal-title":"Curr. Probl. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1196\/annals.1410.081","article-title":"Pheochromocytoma: An endocrine stress mimicking disorder","volume":"1148","author":"Kantorovich","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.amjsurg.2010.04.012","article-title":"Malignant pheochromocytoma: A review","volume":"201","author":"Harari","year":"2011","journal-title":"Am. J. Surg."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kim, K.Y., Kim, J.H., Hong, A.R., Seong, M.W., Lee, K.E., Kim, S.J., Kim, S.W., Shin, C.S., and Kim, S.Y. (2016). Disentangling of Malignancy from Benign Pheochromocytomas\/Paragangliomas. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0168413"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kimura, N., Takekoshi, K., and Naruse, M. (2018). Risk Stratification on Pheochromocytoma and Paraganglioma from Laboratory and Clinical Medicine. J. Clin. Med., 7.","DOI":"10.20944\/preprints201807.0478.v1"},{"key":"ref_18","unstructured":"DeLellis, R.A., and Lloyd, R.V. (2004). Malignant adrenal phaeochromocytoma. World Health Organization Classification of Tumours Pathology & Genetics, Tumours of Endocrine Organs, IARC. [3rd ed.]."},{"key":"ref_19","unstructured":"Lloyd, R.V., Osamura, R.Y., and Kloppel, G. (2017). Extraadrenal paraganglioma. WHO Classification of Tumors of Endocrine Organs, IARC Press. [4th ed.]."},{"key":"ref_20","unstructured":"Lloyd, R.V., Osamura, R.Y., and Kloppel, G. (2017). Phaeochromocytoma. WHO Classification of Tumors of Endocrine Organs, IARC Press. [4th ed.]."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1210\/jc.2014-1498","article-title":"Pheochromocytoma and paraganglioma: An endocrine society clinical practice guideline","volume":"99","author":"Lenders","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s00401-013-1165-y","article-title":"Integrative genetic, epigenetic and pathological analysis of paraganglioma reveals complex dysregulation of NOTCH signaling","volume":"126","author":"Cama","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nrendo.2014.188","article-title":"Paraganglioma and phaeochromocytoma: From genetics to personalized medicine","volume":"11","author":"Favier","year":"2015","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"25756","DOI":"10.18632\/oncotarget.15201","article-title":"Molecular markers of paragangliomas\/pheochromocytomas","volume":"8","author":"Zhikrivetskaya","year":"2017","journal-title":"Oncotarget"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.trecan.2017.11.001","article-title":"Genomic Landscape of Pheochromocytoma and Paraganglioma","volume":"4","author":"Jochmanova","year":"2018","journal-title":"Trends Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Bayley, J.-P., Oldenburg, R.A., Nuk, J., Hoekstra, A.S., van der Meer, C.A., Korpershoek, E., McGillivray, B., Corssmit, E.P.M., Dinjens, W.N.M., and de Krijger, R.R. (2014). Paraganglioma and pheochromocytoma upon maternal transmission of SDHD mutations. BMC Med. Genet., 15.","DOI":"10.1186\/s12881-014-0111-8"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1136\/jmedgenet-2018-105427","article-title":"Bayesian approach to determining penetrance of pathogenic SDH variants","volume":"55","author":"Benn","year":"2018","journal-title":"J. Med. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"200","DOI":"10.3389\/fonc.2014.00200","article-title":"Genetically Modeled Mice with Mutations in Mitochondrial Metabolic Enzymes for the Study of Cancer","volume":"4","author":"Piruat","year":"2014","journal-title":"Front. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S0046-8177(73)80012-7","article-title":"High altitude hypoxia and chemodectomas","volume":"4","author":"Saldana","year":"1973","journal-title":"Hum. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1002\/1097-0142(197406)33:6<1635::AID-CNCR2820330625>3.0.CO;2-J","article-title":"Hereditary tumors of the carotid bodies and chronic obstructive pulmonary disease","volume":"33","author":"Chedid","year":"1974","journal-title":"Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.2214\/ajr.134.5.1073","article-title":"Bilateral carotid body tumors and cyanotic heart disease","volume":"134","author":"Hirsch","year":"1980","journal-title":"AJR Am. J. Roentgenol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4148","DOI":"10.1158\/1078-0432.CCR-10-0637","article-title":"Mutation of SDHB is a Cause of Hypoxia-Related High-Altitude Paraganglioma","volume":"16","author":"Figuera","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.ccr.2005.06.015","article-title":"Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: Developmental culling and cancer","volume":"8","author":"Lee","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/s12105-009-0130-5","article-title":"Paraganglioma: Carotid body tumor","volume":"3","author":"Wieneke","year":"2009","journal-title":"Head Neck Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.cell.2007.07.043","article-title":"Glia-like stem cells sustain physiologic neurogenesis in the adult mammalian carotid body","volume":"131","author":"Pardal","year":"2007","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.celrep.2017.03.065","article-title":"Physiological Plasticity of Neural-Crest-Derived Stem Cells in the Adult Mammalian Carotid Body","volume":"19","author":"Annese","year":"2017","journal-title":"Cell Rep."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Sobrino, V., Annese, V., Navarro-Guerrero, E., Platero-Luengo, A., and Pardal, R. (2018). The carotid body: A physiologically relevant germinal niche in the adult peripheral nervous system. Cell. Mol. Life Sci., 1\u201313.","DOI":"10.1007\/s00018-018-2975-9"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1962","DOI":"10.1002\/stem.1977","article-title":"Brain vascular pericytes following ischemia have multipotential stem cell activity to differentiate into neural and vascular lineage cells","volume":"33","author":"Nakagomi","year":"2015","journal-title":"Stem Cells"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1002\/cne.24565","article-title":"Neural microvascular pericytes contribute to human adult neurogenesis","volume":"527","author":"Farahani","year":"2019","journal-title":"J. Comp. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1242\/jeb.086165","article-title":"Ontogeny of O2 and CO2\/\/H+ chemosensitivity in adrenal chromaffin cells: Role of innervation","volume":"217","author":"Salman","year":"2014","journal-title":"J. Exp. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"eaal3753","DOI":"10.1126\/science.aal3753","article-title":"Multipotent peripheral glial cells generate neuroendocrine cells of the adrenal medulla","volume":"357","author":"Furlan","year":"2017","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Hockman, D., Adameyko, I., Kaucka, M., Barraud, P., Otani, T., Hunt, A., Hartwig, A.C., Sock, E., Waithe, D., and Franck, M.C.M. (2018). Striking parallels between carotid body glomus cell and adrenal chromaffin cell development. Dev. Biol.","DOI":"10.1016\/j.ydbio.2018.05.016"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.gde.2010.02.008","article-title":"Warburg tumours and the mechanisms of mitochondrial tumour suppressor genes. Barking up the right tree?","volume":"20","author":"Bayley","year":"2010","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/S0046-8177(98)90411-7","article-title":"Paragangliomas of the head and neck region show complete loss of heterozygosity at 11q22-q23 in chief cells and the flowsorted DNA aneuploid fraction","volume":"29","author":"Beekman","year":"1998","journal-title":"Hum. Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1002\/path.1535","article-title":"Multiparameter DNA flow-sorting demonstrates diploidy and SDHD wild-type gene retention in the sustentacular cell compartment of head and neck paragangliomas: Chief cells are the only neoplastic component","volume":"202","author":"Corver","year":"2004","journal-title":"J. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1111\/his.13277","article-title":"Succinate dehydrogenase (SDH)-deficient neoplasia","volume":"72","author":"Gill","year":"2018","journal-title":"Histopathology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/nrc1092","article-title":"Vasculogenic mimicry and tumour-cell plasticity: Lessons from melanoma","volume":"3","author":"Hendrix","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Kuratani, S., Kusakabe, R., and Hirasawa, T. (2018). The neural crest and evolution of the head\/trunk interface in vertebrates. Dev. Biol., in press.","DOI":"10.1016\/j.ydbio.2018.01.017"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ccell.2017.01.001","article-title":"Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma","volume":"31","author":"Fishbein","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"30502","DOI":"10.18632\/oncotarget.8461","article-title":"Epithelial-to-endothelial transition and cancer stem cells: Two cornerstones of vasculogenic mimicry in malignant tumors","volume":"8","author":"Sun","year":"2016","journal-title":"Oncotarget"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"302","DOI":"10.4158\/EP15725.OR","article-title":"Characteristics and outcomes of metastatic SDHB and sporadic pheochromcytoma\/paraganglioma: An National Institutes of Halth Study","volume":"22","author":"Turkova","year":"2016","journal-title":"Endocr. Pract."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.cancergen.2016.04.058","article-title":"ATRX driver mutation in a composite malignant pheochromocytoma","volume":"209","author":"Tejera","year":"2016","journal-title":"Cancer Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1071\/RD14383","article-title":"Metabolic determinants of embryonic development and stem cell fate","volume":"27","author":"Folmes","year":"2014","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1146\/annurev-immunol-042617-053127","article-title":"Connections Between Metabolism and Epigenetics in Programming Cellular Differentiation","volume":"36","author":"Chisolm","year":"2018","journal-title":"Annu. Rev. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1146\/annurev-cellbio-100814-125544","article-title":"Metabolism and Epigenetics","volume":"31","author":"Janke","year":"2015","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1007\/s00401-017-1799-2","article-title":"Paragangliomas arise through an autonomous vasculo-angio-neurogenic program inhibited by imatinib","volume":"135","author":"Verginelli","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/j.tcb.2017.06.003","article-title":"Metabolic Interactions in the Tumor Microenvironment","volume":"27","author":"Lyssiotis","year":"2017","journal-title":"Trends Cell Biol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Lopes-Coelho, F., Gouveia-Fernandes, S., and Serpa, J. (2018). Metabolic cooperation between cancer and non-cancerous stromal cells is pivotal in cancer progression. Tumour Biol., 40.","DOI":"10.1177\/1010428318756203"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1210\/er.2014-1026","article-title":"Current Approaches and Recent Developments in the Management of Head and Neck Paragangliomas","volume":"35","author":"Kaliski","year":"2014","journal-title":"Endocr. Rev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1002\/stem.1661","article-title":"Concise review: Evidence for CD34 as a common marker for diverse progenitors","volume":"32","author":"Sidney","year":"2014","journal-title":"Stem Cells"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"448","DOI":"10.4103\/0366-6999.176084","article-title":"The Implication and Significance of Beta 2 Microglobulin: A Conservative Multifunctional Regulator","volume":"129","author":"Li","year":"2016","journal-title":"Chin. Med. J."},{"key":"ref_62","first-page":"ra47","article-title":"Perinuclear mitochondrial clustering creates an oxidant-rich nuclear domain required for hypoxia-induced transcription","volume":"5","author":"Pastukh","year":"2012","journal-title":"Sci. Signal."},{"key":"ref_63","unstructured":"Clarke, L.A. (2018, December 12). Mucopolysaccharidosis Type I, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1162\/."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1111\/j.1742-4658.2012.08529.x","article-title":"Glycosaminoglycans: Key players in cancer cell biology and treatment","volume":"279","author":"Afratis","year":"2012","journal-title":"FEBS J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.matbio.2013.10.004","article-title":"Heparan sulfate proteoglycan as a cell-surface endocytosis receptor","volume":"35","author":"Christianson","year":"2014","journal-title":"Matrix Biol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"He, H., Huang, M., Sun, S., Wu, Y., and Lin, X. (2017). Epithelial heparan sulfate regulates Sonic Hedgehog signaling in lung development. PLoS Genet., 13.","DOI":"10.1371\/journal.pgen.1006992"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"de la Mata, M., Cot\u00e1n, D., Villanueva-Paz, M., de Lavera, I., \u00c1lvarez-C\u00f3rdoba, M., Luz\u00f3n-Hidalgo, R., Su\u00e1rez-Rivero, J.M., Tiscornia, G., and Oropesa-\u00c1vila, M. (2016). Mitochondrial Dysfunction in Lysosomal Storage Disorders. Diseases, 4.","DOI":"10.3390\/diseases4040031"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1016\/j.bbagen.2013.10.041","article-title":"Mitochondrial quality control and communications with the nucleus are important in maintaining mitochondrial function and cell health","volume":"1840","author":"Kotiadis","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"805602","DOI":"10.1155\/2012\/805602","article-title":"Notch regulation of hematopoiesis, endothelial precursor cells, and blood vessel formation: Orchestrating the vasculature","volume":"2012","author":"Caolo","year":"2012","journal-title":"Stem Cells Int."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1177\/1947601911423030","article-title":"Notch signaling in developmental and tumor angiogenesis","volume":"2","author":"Kofler","year":"2011","journal-title":"Genes Cancer"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s12035-011-8186-0","article-title":"The role of Notch signaling in adult neurogenesis","volume":"44","author":"Imayoshi","year":"2011","journal-title":"Mol. Neurobiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1158\/1541-7786.MCR-10-0508","article-title":"JAG2 induction in hypoxic tumor cells alters Notch signaling and enhances endothelial cell tube formation","volume":"9","author":"Pietras","year":"2011","journal-title":"Mol. Cancer Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1038\/nn.2875","article-title":"Mammalian Gcm genes induce Hes5 expression by active DNA demethylation and induce neural stem cells","volume":"14","author":"Hitoshi","year":"2011","journal-title":"Nat. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/j.cellsig.2009.11.021","article-title":"Dishevelled: The hub of Wnt signaling","volume":"22","author":"Gao","year":"2010","journal-title":"Cell. Signal."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1158\/1535-7163.MCT-16-0592","article-title":"The role of CtBP1 in oncogenic processes and its potential as a therapeutic target","volume":"16","author":"Blevins","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"7614","DOI":"10.12659\/MSM.912735","article-title":"C-Terminal Binding Protein 1 Modulates Cellular Redox via Feedback Regulation of MPC1 and MPC2 in Melanoma Cells","volume":"24","author":"Deng","year":"2018","journal-title":"Med. Sci. Monit."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.ymben.2016.11.005","article-title":"Dual loss of succinate dehydrogenase (SDH) and complex I activity is necessary to recapitulate the metabolic phenotype of SDH mutant tumors","volume":"43","author":"Lorendeau","year":"2017","journal-title":"Metab. Eng."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3423","DOI":"10.1158\/1078-0432.CCR-17-3406","article-title":"Targeting NAD+\/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma","volume":"24","author":"Pang","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"6882","DOI":"10.1073\/pnas.0910060107","article-title":"Notch-activated signaling cascade interacts with mitochondrial remodeling proteins to regulate cell survival","volume":"107","author":"Perumalsamy","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"7320","DOI":"10.1074\/jbc.M113.519405","article-title":"Alteration of mitochondrial proteome due to activation of Notch1 signaling pathway","volume":"289","author":"Basak","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"6083","DOI":"10.1038\/s41388-018-0400-3","article-title":"Notch signaling promotes a HIF2\u03b1-driven hypoxic response in multiple tumor cell types","volume":"37","author":"Mutvei","year":"2018","journal-title":"Oncogene"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/j.cmet.2015.09.004","article-title":"Oxygen Sensing by Arterial Chemoreceptors Depends on Mitochondrial Complex I Signaling","volume":"22","author":"Gao","year":"2015","journal-title":"Cell Metab."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1101\/gad.1640608","article-title":"The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2","volume":"22","author":"Park","year":"2008","journal-title":"Genes Dev."},{"key":"ref_84","first-page":"718","article-title":"Notch and epithelial-mesenchyme transition in development and tumor progression: Another turn of the screw","volume":"3","author":"Timmerman","year":"2004","journal-title":"Cell Cycle"},{"key":"ref_85","first-page":"214","article-title":"The p53\/miR-34 axis in development and disease","volume":"6","author":"Rokavec","year":"2014","journal-title":"J. Mol. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"362753","DOI":"10.1155\/2015\/362753","article-title":"Platelet-Derived Growth Factor Receptor Alpha as a Marker of Mesenchymal Stem Cells in Development and Stem Cell Biology","volume":"2015","author":"Farahani","year":"2015","journal-title":"Stem Cells Int."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.trecan.2017.11.006","article-title":"Gastrointestinal Stromal Tumors: The GIST of Precision Medicine","volume":"4","author":"Mei","year":"2018","journal-title":"Trends Cancer"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/stem.261","article-title":"Notch promotes radioresistance of glioma stem cells","volume":"28","author":"Wang","year":"2010","journal-title":"Stem Cells"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/nature04923","article-title":"Endothelial tubes assemble from intracellular vacuoles in vivo","volume":"442","author":"Kamei","year":"2006","journal-title":"Nature"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2851","DOI":"10.1242\/dev.070680","article-title":"Tubulogenesis","volume":"140","author":"Beitel","year":"2013","journal-title":"Development"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"169","DOI":"10.3389\/fonc.2014.00169","article-title":"Nestin(+) tissue-resident multipotent stem cells contribute to tumor progression by differentiating into pericytes and smooth muscle cells resulting in blood vessel remodeling","volume":"4","author":"Klein","year":"2014","journal-title":"Front. Oncol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1007\/s10456-014-9428-3","article-title":"Intussusceptive angiogenesis: Expansion and remodeling of microvascular networks","volume":"17","author":"Mentzer","year":"2014","journal-title":"Angiogenesis"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"9271","DOI":"10.1158\/0008-5472.CAN-09-1605","article-title":"Hypoxia-regulated delta-like 1 homologue enhances cancer cell stemness and tumorigenicity","volume":"69","author":"Kim","year":"2009","journal-title":"Cancer Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1158\/1541-7786.MCR-13-0236","article-title":"The pathobiology of collagens in glioma","volume":"11","author":"Payne","year":"2013","journal-title":"Mol. Cancer Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2879","DOI":"10.1007\/s00018-010-0367-x","article-title":"Basement membrane components are key players in specialized extracellular matrices","volume":"67","author":"Kruegel","year":"2010","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1016\/j.celrep.2016.02.003","article-title":"NRF2 Orchestrates the Metabolic Shift during Induced Pluripotent Stem Cell Reprogramming","volume":"14","author":"Hawkins","year":"2016","journal-title":"Cell Rep."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.tcb.2014.11.007","article-title":"Regulation of tissue morphogenesis by endothelial cell-derived signals","volume":"25","author":"Ramasamy","year":"2015","journal-title":"Trends Cell Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1038\/sj.leu.2404606","article-title":"The anticancer drug imatinib induces cellular autophagy","volume":"21","author":"Ertmer","year":"2007","journal-title":"Leukemia"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.ceb.2011.04.003","article-title":"Extracellular matrix receptors in branched organs","volume":"23","author":"Pozzi","year":"2011","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.cell.2017.08.026","article-title":"A Unifying Theory of Branching Morphogenesis","volume":"171","author":"Hannezo","year":"2017","journal-title":"Cell"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/nrc3277","article-title":"Spatial regulation of receptor tyrosine kinases in development and cancer","volume":"12","author":"Casaletto","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/s12038-013-9403-y","article-title":"Competing views on cancer","volume":"39","author":"Sonnenschein","year":"2014","journal-title":"J. Biosci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1038\/ncomms3427","article-title":"Tumour angiogenesis regulation by the miR-200 family","volume":"4","author":"Pecot","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"E110","DOI":"10.1152\/ajpendo.00192.2010","article-title":"MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1","volume":"299","author":"Zhao","year":"2010","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1080\/15384101.2015.1006048","article-title":"ZEB1: At the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance","volume":"14","author":"Zhang","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/nrc3958","article-title":"The tumour microenvironment after radiotherapy: Mechanisms of resistance and recurrence","volume":"15","author":"Barker","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1124\/pr.114.010215","article-title":"The great escape; the hallmarks of resistance to antiangiogenic therapy","volume":"67","author":"Huijbers","year":"2015","journal-title":"Pharmacol. Rev."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"277","DOI":"10.3389\/fendo.2018.00277","article-title":"Treatment for Patients with Malignant Pheochromocytomas and Paragangliomas: A Perspective from the Hallmarks of Cancer","volume":"9","author":"Jimenez","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1097\/MAO.0000000000000386","article-title":"The role of wait-and-scan and the efficacy of radiotherapy in the treatment of temporal bone paragangliomas","volume":"35","author":"Prasad","year":"2014","journal-title":"Otol. Neurotol."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Favier, J., Briere, J.J., Burnichon, N., Riviere, J., Vescovo, L., Benit, P., Giscos-Douriez, I., De Reynies, A., Bertherat, J., and Badoual, C. (2009). The Warburg effect is genetically determined in inherited pheochromocytomas. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0007094"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1038\/ncb3233","article-title":"Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis","volume":"17","author":"Cardaci","year":"2015","journal-title":"Nat. Cell Biol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/3\/273\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:34:46Z","timestamp":1760186086000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/3\/273"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,26]]},"references-count":111,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2019,3]]}},"alternative-id":["cancers11030273"],"URL":"https:\/\/doi.org\/10.3390\/cancers11030273","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,26]]}}}