Immunohistochemical expression of stem cell markers in pheochromocytomas/paragangliomas is associated with SDHx mutations.
OBJECTIVE
Pheochromocytomas (PCCs) are neuroendocrine tumors that occur in the adrenal medulla, whereas paragangliomas (PGLs) arise from paraganglia in the head, neck, thorax, or abdomen. In a variety of tumors, cancer cells with stem cell-like properties seem to form the basis of tumor initiation because of their ability to self-renew and proliferate. Specifically targeting this small cell population may lay the foundation for more effective therapeutic approaches. In the present study, we intended to identify stem cells in PCCs/PGLs.


METHODS
We examined the immunohistochemical expression of 11 stem cell markers (SOX2, LIN28, NGFR, THY1, PREF1, SOX17, NESTIN, CD117, OCT3/4, NANOG, and CD133) on tissue microarrays containing 208 PCCs/PGLs with different genetic backgrounds from five European centers.


RESULTS
SOX2, LIN28, NGFR, and THY1 were expressed in more than 10% of tumors, and PREF1, SOX17, NESTIN, and CD117 were expressed in <10% of the samples. OCT3/4, NANOG, and CD133 were not detectable at all. Double staining for chromogranin A/SOX2 and S100/SOX2 demonstrated SOX2 immunopositivity in both tumor and adjacent sustentacular cells. The expression of SOX2, SOX17, NGFR, LIN28, PREF1, and THY1 was significantly associated with mutations in one of the succinate dehydrogenase (SDH) genes. In addition, NGFR expression was significantly correlated with metastatic disease.


CONCLUSIONS
Immunohistochemical expression of stem cell markers was found in a subset of PCCs/PGLs. Further studies are required to validate whether some stem cell-associated markers, such as SOX2, could serve as targets for therapeutic approaches and whether NGFR expression could be utilized as a predictor of malignancy.
Department of PathologyErasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, The NetherlandsEndocrine Research UnitMedizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, GermanyDepartment of Medical OncologyErasmus MC Cancer Institute, Cancer Genomics Netherlands, Rotterdam, The NetherlandsHuman Cancer Genetics ProgrammeSpanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainDepartment of Experimental and Clinical Biomedical SciencesUniversity of Florence and Istituto Toscano Tumori, Florence, ItalyAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, FranceINSERMUMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, FranceUniversité Paris DescartesFaculté de Médecine, F-75005 Paris, FranceDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands.
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Oudijk
Department of PathologyErasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, The NetherlandsEndocrine Research UnitMedizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, GermanyDepartment of Medical OncologyErasmus MC Cancer Institute, Cancer Genomics Netherlands, Rotterdam, The NetherlandsHuman Cancer Genetics ProgrammeSpanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainDepartment of Experimental and Clinical Biomedical SciencesUniversity of Florence and Istituto Toscano Tumori, Florence, ItalyAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, FranceINSERMUMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, FranceUniversité Paris DescartesFaculté de Médecine, F-75005 Paris, FranceDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands.
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Neuhofer
Department of PathologyErasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, The NetherlandsEndocrine Research UnitMedizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, GermanyDepartment of Medical OncologyErasmus MC Cancer Institute, Cancer Genomics Netherlands, Rotterdam, The NetherlandsHuman Cancer Genetics ProgrammeSpanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainDepartment of Experimental and Clinical Biomedical SciencesUniversity of Florence and Istituto Toscano Tumori, Florence, ItalyAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, FranceINSERMUMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, FranceUniversité Paris DescartesFaculté de Médecine, F-75005 Paris, FranceDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands.
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Lichtenauer
Department of PathologyErasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, The NetherlandsEndocrine Research UnitMedizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, GermanyDepartment of Medical OncologyErasmus MC Cancer Institute, Cancer Genomics Netherlands, Rotterdam, The NetherlandsHuman Cancer Genetics ProgrammeSpanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainDepartment of Experimental and Clinical Biomedical SciencesUniversity of Florence and Istituto Toscano Tumori, Florence, ItalyAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, FranceINSERMUMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, FranceUniversité Paris DescartesFaculté de Médecine, F-75005 Paris, FranceDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands.
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Papathomas
Department of PathologyErasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, The NetherlandsEndocrine Research UnitMedizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, GermanyDepartment of Medical OncologyErasmus MC Cancer Institute, Cancer Genomics Netherlands, Rotterdam, The NetherlandsHuman Cancer Genetics ProgrammeSpanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainDepartment of Experimental and Clinical Biomedical SciencesUniversity of Florence and Istituto Toscano Tumori, Florence, ItalyAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, FranceINSERMUMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, FranceUniversité Paris DescartesFaculté de Médecine, F-75005 Paris, FranceDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands.
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Korpershoek
Department of PathologyErasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, The NetherlandsEndocrine Research UnitMedizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, GermanyDepartment of Medical OncologyErasmus MC Cancer Institute, Cancer Genomics Netherlands, Rotterdam, The NetherlandsHuman Cancer Genetics ProgrammeSpanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainDepartment of Experimental and Clinical Biomedical SciencesUniversity of Florence and Istituto Toscano Tumori, Florence, ItalyAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, FranceINSERMUMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, FranceUniversité Paris DescartesFaculté de Médecine, F-75005 Paris, FranceDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands.
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Stoop
Department of PathologyErasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, The NetherlandsEndocrine Research UnitMedizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, GermanyDepartment of Medical OncologyErasmus MC Cancer Institute, Cancer Genomics Netherlands, Rotterdam, The NetherlandsHuman Cancer Genetics ProgrammeSpanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainDepartment of Experimental and Clinical Biomedical SciencesUniversity of Florence and Istituto Toscano Tumori, Florence, ItalyAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, FranceINSERMUMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, FranceUniversité Paris DescartesFaculté de Médecine, F-75005 Paris, FranceDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands.
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Oosterhuis
Department of PathologyErasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, The NetherlandsEndocrine Research UnitMedizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, GermanyDepartment of Medical OncologyErasmus MC Cancer Institute, Cancer Genomics Netherlands, Rotterdam, The NetherlandsHuman Cancer Genetics ProgrammeSpanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainDepartment of Experimental and Clinical Biomedical SciencesUniversity of Florence and Istituto Toscano Tumori, Florence, ItalyAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, FranceINSERMUMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, FranceUniversité Paris DescartesFaculté de Médecine, F-75005 Paris, FranceDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands.
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Smid
Department of PathologyErasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, The NetherlandsEndocrine Research UnitMedizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, GermanyDepartment of Medical OncologyErasmus MC Cancer Institute, Cancer Genomics Netherlands, Rotterdam, The NetherlandsHuman Cancer Genetics ProgrammeSpanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainDepartment of Experimental and Clinical Biomedical SciencesUniversity of Florence and Istituto Toscano Tumori, Florence, ItalyAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, FranceINSERMUMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, FranceUniversité Paris DescartesFaculté de Médecine, F-75005 Paris, FranceDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands.
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Restuccia
Department of PathologyErasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, The NetherlandsEndocrine Research UnitMedizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, GermanyDepartment of Medical OncologyErasmus MC Cancer Institute, Cancer Genomics Netherlands, Rotterdam, The NetherlandsHuman Cancer Genetics ProgrammeSpanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainDepartment of Experimental and Clinical Biomedical SciencesUniversity of Florence and Istituto Toscano Tumori, Florence, ItalyAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, FranceINSERMUMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, FranceUniversité Paris DescartesFaculté de Médecine, F-75005 Paris, FranceDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands.
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Robledo
Department of PathologyErasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, The NetherlandsEndocrine Research UnitMedizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, GermanyDepartment of Medical OncologyErasmus MC Cancer Institute, Cancer Genomics Netherlands, Rotterdam, The NetherlandsHuman Cancer Genetics ProgrammeSpanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainDepartment of Experimental and Clinical Biomedical SciencesUniversity of Florence and Istituto Toscano Tumori, Florence, ItalyAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, FranceINSERMUMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, FranceUniversité Paris DescartesFaculté de Médecine, F-75005 Paris, FranceDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands.
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de Cubas
Department of PathologyErasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, The NetherlandsEndocrine Research UnitMedizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, GermanyDepartment of Medical OncologyErasmus MC Cancer Institute, Cancer Genomics Netherlands, Rotterdam, The NetherlandsHuman Cancer Genetics ProgrammeSpanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainDepartment of Experimental and Clinical Biomedical SciencesUniversity of Florence and Istituto Toscano Tumori, Florence, ItalyAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, FranceINSERMUMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, FranceUniversité Paris DescartesFaculté de Médecine, F-75005 Paris, FranceDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands.
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Mannelli
Department of PathologyErasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, The NetherlandsEndocrine Research UnitMedizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, GermanyDepartment of Medical OncologyErasmus MC Cancer Institute, Cancer Genomics Netherlands, Rotterdam, The NetherlandsHuman Cancer Genetics ProgrammeSpanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainDepartment of Experimental and Clinical Biomedical SciencesUniversity of Florence and Istituto Toscano Tumori, Florence, ItalyAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, FranceINSERMUMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, FranceUniversité Paris DescartesFaculté de Médecine, F-75005 Paris, FranceDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands Department of PathologyErasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, The NetherlandsEndocrine Research UnitMedizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, GermanyDepartment of Medical OncologyErasmus MC Cancer Institute, Cancer Genomics Netherlands, Rotterdam, The NetherlandsHuman Cancer Genetics ProgrammeSpanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainDepartment of Experimental and Clinical Biomedical SciencesUniversity of Florence and Istituto Toscano Tumori, Florence, ItalyAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, FranceINSERMUMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, FranceUniversité Paris DescartesFaculté de Médecine, F-75005 Paris, FranceDepartment of PathologyRein
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Gimenez-Roqueplo
Department of PathologyErasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, The NetherlandsEndocrine Research UnitMedizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, GermanyDepartment of Medical OncologyErasmus MC Cancer Institute, Cancer Genomics Netherlands, Rotterdam, The NetherlandsHuman Cancer Genetics ProgrammeSpanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainDepartment of Experimental and Clinical Biomedical SciencesUniversity of Florence and Istituto Toscano Tumori, Florence, ItalyAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, FranceINSERMUMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, FranceUniversité Paris DescartesFaculté de Médecine, F-75005 Paris, FranceDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands.
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Dinjens
Department of PathologyErasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, The NetherlandsEndocrine Research UnitMedizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, GermanyDepartment of Medical OncologyErasmus MC Cancer Institute, Cancer Genomics Netherlands, Rotterdam, The NetherlandsHuman Cancer Genetics ProgrammeSpanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainDepartment of Experimental and Clinical Biomedical SciencesUniversity of Florence and Istituto Toscano Tumori, Florence, ItalyAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, FranceINSERMUMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, FranceUniversité Paris DescartesFaculté de Médecine, F-75005 Paris, FranceDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands.
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Beuschlein
Department of PathologyErasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, The NetherlandsEndocrine Research UnitMedizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, GermanyDepartment of Medical OncologyErasmus MC Cancer Institute, Cancer Genomics Netherlands, Rotterdam, The NetherlandsHuman Cancer Genetics ProgrammeSpanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainDepartment of Experimental and Clinical Biomedical SciencesUniversity of Florence and Istituto Toscano Tumori, Florence, ItalyAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, FranceINSERMUMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, FranceUniversité Paris DescartesFaculté de Médecine, F-75005 Paris, FranceDepartment of PathologyReinier de Graaf Hospital, Delft, The Netherlands Department of PathologyErasmus MC Cancer Institute, University Medical Center Rotterdam, Postbus 2040, 3000 CA Rotterdam, The NetherlandsEndocrine Research UnitMedizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, D-80336 Munich, GermanyDepartment of Medical OncologyErasmus MC Cancer Institute, Cancer Genomics Netherlands, Rotterdam, The NetherlandsHuman Cancer Genetics ProgrammeSpanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, SpainDepartment of Experimental and Clinical Biomedical SciencesUniversity of Florence and Istituto Toscano Tumori, Florence, ItalyAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, F-75015 Paris, FranceINSERMUMR970, Paris-Cardiovascular Research Center at HEGP, F-75015 Paris, FranceUniversité Paris DescartesFaculté de Médecine, F-75005 Paris, FranceDepartment of PathologyRein
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de Krijger
D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism*; D005060:Europe; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010235:Paraganglioma / Q000235:genetics* / Q000378:metabolism*; D010673:Pheochromocytoma / Q000235:genetics* / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism*; D013385:Succinate Dehydrogenase / Q000235:genetics*
D014408:Biomarkers, Tumor; D017475:Receptors, Nerve Growth Factor; D013385:Succinate Dehydrogenase