Hypoxia enhances tumor stemness by increasing the invasive and tumorigenic side population fraction
Hypoxia enhances tumor stemness by increasing the invasive and tumorigenic side population fraction
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DOI：
10.1634/stemcells.2007-0724
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发表时间：
2008-01-01
期刊：
影响因子：
5.2
通讯作者：
Yeger, Herman
中科院分区：
文献类型：
--
作者：
Das, Bikul;Tsuchida, Rika;Yeger, Herman
尽管在了解缺氧在干细胞生态位中的作用方面已经取得了进展，但对于缺氧在维持肿瘤干细胞（TSC）生态位中潜在的类似作用几乎一无所知。在这里，我们发现侧群（SP）细胞的高致瘤性部分位于体内实体瘤的缺氧区。我们首先在不同的实体瘤细胞系（包括神经母细胞瘤、横纹肌肉瘤和小细胞肺癌）中鉴定出缺氧后侧群细胞的高度迁移性、侵袭性和致瘤性部分（SPm[hox]部分）。为了鉴定 SPm(hox) 分数，我们使用了源自经过缺氧和氧化应激处理的骨髓基质细胞的“受损条件培养基”。我们发现高度致瘤性的 SP 部分迁移到博伊登室中受损的条件培养基中。我们发现，只需 100 个 SPm(hox) 细胞即可在体内形成快速生长的肿瘤。体外缺氧暴露显着增加 SPm(hox) 分数。实时定量聚合酶链反应和免疫荧光研究表明，SPm(hox) 细胞表达 Oct-4，这是一种在 TSC 维持中具有潜在作用的“干细胞”基因。在裸鼠异种移植物中，SPm(hox) 细胞定位于缺氧区，如量子点标记后所示。这些结果表明高度致瘤性的 SP 部分迁移到缺氧区域；这种迁移类似于正常骨髓 SP 部分向损伤/缺氧区域的迁移。此外，缺氧微环境可能作为 SP 细胞高致瘤部分的利基。
Although advances have been made in understanding the role of hypoxia in the stem cell niche, almost nothing is known about a potentially similar role of hypoxia in maintaining the tumor stem cell (TSC) niche. Here we show that a highly tumorigenic fraction of side population (SP) cells is localized in the hypoxic zones of solid tumors in vivo. We first identified a highly migratory, invasive, and tumorigenic fraction of post-hypoxic side population cells (SPm[hox] fraction) in a diverse group of solid tumor cell lines, including neuroblastoma, rhabdomyosarcoma, and small-cell lung carcinoma. To identify the SPm(hox) fraction, we used an "injured conditioned medium" derived from bone marrow stromal cells treated with hypoxia and oxidative stress. We found that a highly tumorigenic SP fraction migrates to the injured conditioned medium in a Boyden chamber. We show that as few as 100 SPm(hox) cells form rapidly growing tumors in vivo. In vitro exposure to hypoxia increases the SPm(hox) fraction significantly. Quantitative real-time polymerase chain reaction and immunofluorescence studies showed that SPm(hox) cells expressed Oct-4, a "stemness" gene having a potential role in TSC maintenance. In nude mice xenografts, SPm(hox) cells were localized to the hypoxic zones, as demonstrated after quantum dot labeling. These results suggest that a highly tumorigenic SP fraction migrates to the area of hypoxia; this migration is similar to the migration of normal bone marrow SP fraction to the area of injury/hypoxia. Furthermore, the hypoxic microenvironment may serve as a niche for the highly tumorigenic fraction of SP cells.