嗜铬细胞瘤/副神经节瘤中干细胞标志物的免疫组化表达与SDHx突变相关。
Immunohistochemical expression of stem cell markers in pheochromocytomas/paragangliomas is associated with SDHx mutations.
作者信息
Oudijk L, Neuhofer C M, Lichtenauer U D, Papathomas T G, Korpershoek E, Stoop H, Oosterhuis J W, Smid M, Restuccia D F, Robledo M, de Cubas A A, Mannelli M, Gimenez-Roqueplo A P, Dinjens W N M, Beuschlein F, de Krijger R R
机构信息
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 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
出版信息
Eur J Endocrinol. 2015 Jul;173(1):43-52. doi: 10.1530/EJE-14-1164. Epub 2015 Apr 27.
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.
DESIGN
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.
CONCLUSION
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.
目的
嗜铬细胞瘤（PCC）是发生于肾上腺髓质的神经内分泌肿瘤，而副神经节瘤（PGL）起源于头、颈、胸或腹部的副神经节。在多种肿瘤中，具有干细胞样特性的癌细胞似乎因其自我更新和增殖能力而构成肿瘤起始的基础。特异性靶向这一小细胞群体可能为更有效的治疗方法奠定基础。在本研究中，我们旨在鉴定PCC/PGL中的干细胞。
设计
我们检测了11种干细胞标志物（SOX2、LIN28、NGFR、THY1、PREF1、SOX17、NESTIN、CD117、OCT3/4、NANOG和CD133）在组织微阵列上的免疫组化表达，该组织微阵列包含来自五个欧洲中心的208个具有不同遗传背景的PCC/PGL。
结果
SOX2、LIN28、NGFR和THY1在超过10%的肿瘤中表达，而PREF1、SOX17、NESTIN和CD117在<10%的样本中表达。OCT3/4、NANOG和CD133根本无法检测到。嗜铬粒蛋白A/SOX2和S100/SOX2的双重染色显示，肿瘤细胞和相邻支持细胞中均有SOX2免疫阳性。SOX2、SOX17、NGFR、LIN28、PREF1和THY1的表达与琥珀酸脱氢酶（SDH）基因之一的突变显著相关。此外，NGFR表达与转移性疾病显著相关。
结论
在一部分PCC/PGL中发现了干细胞标志物的免疫组化表达。需要进一步研究来验证某些与干细胞相关的标志物，如SOX2，是否可作为治疗靶点，以及NGFR表达是否可作为恶性肿瘤的预测指标。
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