Enrichment of c-Met+ tumorigenic stromal cells of giant cell tumor of bone and targeting by cabozantinib.
Enrichment of c-Met+ tumorigenic stromal cells of giant cell tumor of bone and targeting by cabozantinib.
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DOI：
10.1038/cddis.2014.440
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发表时间：
2014-10-16
影响因子：
9
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中科院分区：
文献类型：
--
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骨巨细胞瘤（GCTB）是一种非常罕见的肿瘤实体，由于缺乏已建立的细胞系和小鼠模型以及可用的原代细胞系的限制，对其进行的研究很少。 GCTB 的基质细胞负责侵袭性生长和转移，强调了癌症干细胞群的存在。为了识别和靶向此类肿瘤起始细胞，从八个新鲜切除的 GCTB 组织中分离出基质细胞。通过集落和球体形成、分化、迁移、MTT（3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四唑）测定、免疫组织化学、抗体蛋白阵列、Alu 原位杂交、FACS 分析和异种移植到受精鸡蛋和小鼠中检查致瘤特性。肿瘤基质细胞的亚群形成球体和集落，分化为成骨细胞，迁移到受伤区域并表达转移标记物CXC趋化因子受体4型，表明自我更新、侵袭和分化潜力。与贴壁生长的细胞相比，球状细胞中的多能性、干性和癌症进展标记物（包括 CSC 表面标记物 c-Met）增强。这种富含 c-Met 的亚群在受精鸡蛋和小鼠中形成异种移植肿瘤。卡博替尼 (Cabozantinib) 是一种处于 II 期试验中的 c-Met 抑制剂，消除了 CSC 特征，且治疗效果高于标准化疗。这项研究确定了基质 GCTB 细胞内的 c-Met+ 致瘤亚群，并建议 c-Met 抑制剂卡博替尼作为靶向消除不可切除或复发性 GCTB 的新治疗选择。
Giant cell tumor of bone (GCTB) is a very rare tumor entity, which is little examined owing to the lack of established cell lines and mouse models and the restriction of available primary cell lines. The stromal cells of GCTB have been made responsible for the aggressive growth and metastasis, emphasizing the presence of a cancer stem cell population. To identify and target such tumor-initiating cells, stromal cells were isolated from eight freshly resected GCTB tissues. Tumorigenic properties were examined by colony and spheroid formation, differentiation, migration, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, immunohistochemistry, antibody protein array, Alu in situ hybridization, FACS analysis and xenotransplantation into fertilized chicken eggs and mice. A sub-population of the neoplastic stromal cells formed spheroids and colonies, differentiated to osteoblasts, migrated to wounded regions and expressed the metastasis marker CXC-chemokine receptor type 4, indicating self-renewal, invasion and differentiation potential. Compared with adherent-growing cells, markers for pluripotency, stemness and cancer progression, including the CSC surface marker c-Met, were enhanced in spheroidal cells. This c-Met-enriched sub-population formed xenograft tumors in fertilized chicken eggs and mice. Cabozantinib, an inhibitor of c-Met in phase II trials, eliminated CSC features with a higher therapeutic effect than standard chemotherapy. This study identifies a c-Met+ tumorigenic sub-population within stromal GCTB cells and suggests the c-Met inhibitor cabozantinib as a new therapeutic option for targeted elimination of unresectable or recurrent GCTB.
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影响因子：
29.4
作者：
Mueller, Maria-Theresa;Hermann, Patrick C.;Heeschen, Christopher
通讯作者：
Heeschen, Christopher
影响因子：
29.4
作者：
Li, Chenwei;Wu, Jing-Jiang;Simeone, Diane M.
通讯作者：
Simeone, Diane M.
影响因子：
11.2
作者：
Li, Chenwei;Heidt, David G.;Simeone, Diane M.
通讯作者：
Simeone, Diane M.
影响因子：
6.4
作者：
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通讯作者：
Herr, Ingrid
影响因子：
6.2
作者：
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通讯作者：
Findlay, DM