Histological Characterization of the Tumorigenic "Peri-Necrotic Niche" Harboring Quiescent Stem-Like Tumor Cells in Glioblastoma.
Histological Characterization of the Tumorigenic "Peri-Necrotic Niche" Harboring Quiescent Stem-Like Tumor Cells in Glioblastoma.
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DOI：
10.1371/journal.pone.0147366
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Ikeda E
中科院分区：
文献类型：
--
作者：
Ishii A;Kimura T;Sadahiro H;Kawano H;Takubo K;Suzuki M;Ikeda E
干细胞样肿瘤细胞的小生境特征对于理解和控制胶质母细胞瘤的行为是重要的。细胞周期静止可能是正常和肿瘤干细胞长期维持干细胞功能的共同机制，我们以前的研究表明，低氧诱导因子（HIF）-1α诱导的细胞周期静止与造血干细胞的长期再增殖能力有关。基于此，我们检测了人类星形细胞瘤组织中HIF-1α调节的静止干细胞样肿瘤细胞作为长期致瘤细胞的候选细胞，并从组织学上表征了它们的生态位。采用多色免疫组织化学方法观察星形细胞瘤（WHO分级II-IV）组织中表达HIF-1α（HIF-1α+）的静止干细胞样肿瘤细胞及其小生境。使用培养的胶质母细胞瘤细胞的球状体对该生态位进行建模，并通过球体形成试验评价其对致瘤性的贡献。在胶质母细胞瘤中发现了一个小的HIF-1α+静止干细胞样肿瘤细胞亚群，但在低级别星形细胞瘤中没有发现。这些细胞集中在大的缺血性坏死和血管之间的区域，并且更接近坏死组织而不是血管，这表明适度缺氧的微环境是它们的生态位。我们通过在适当的低氧条件下孵育胶质母细胞瘤细胞球状体，成功地模拟了这种含有HIF-1α+静止干细胞样表型细胞的小生境，并且HIF-1α+静止干细胞样细胞的出现与增强的球体形成活性相关。这些数据表明，“周围坏死龛”窝藏HIF-1α+静止干细胞样细胞赋予胶质母细胞瘤细胞更高的致瘤潜力，因此可能是控制胶质母细胞瘤行为的治疗靶点。
Characterization of the niches for stem-like tumor cells is important to understand and control the behavior of glioblastomas. Cell-cycle quiescence might be a common mechanism underlying the long-term maintenance of stem-cell function in normal and neoplastic stem cells, and our previous study demonstrated that quiescence induced by hypoxia-inducible factor (HIF)-1α is associated with a high long-term repopulation capacity of hematopoietic stem cells. Based on this, we examined human astrocytoma tissues for HIF-1α-regulated quiescent stem-like tumor cells as a candidate for long-term tumorigenic cells and characterized their niche histologically. Multi-color immunohistochemistry was used to visualize HIF-1α-expressing (HIF-1α+) quiescent stem-like tumor cells and their niche in astrocytoma (WHO grade II–IV) tissues. This niche was modeled using spheroids of cultured glioblastoma cells and its contribution to tumorigenicity was evaluated by sphere formation assay. A small subpopulation of HIF-1α+ quiescent stem-like tumor cells was found in glioblastomas but not in lower-grade astrocytomas. These cells were concentrated in the zone between large ischemic necroses and blood vessels and were closer to the necrotic tissues than to the blood vessels, which suggested that a moderately hypoxic microenvironment is their niche. We successfully modeled this niche containing cells of HIF-1α+ quiescent stem-like phenotype by incubating glioblastoma cell spheroids under an appropriately hypoxic condition, and the emergence of HIF-1α+ quiescent stem-like cells was shown to be associated with an enhanced sphere-forming activity. These data suggest that the “peri-necrotic niche” harboring HIF-1α+ quiescent stem-like cells confers a higher tumorigenic potential on glioblastoma cells and therefore may be a therapeutic target to control the behavior of glioblastomas.