Hypoxia Induces Tumor Aggressiveness and the Expansion of CD133-Positive Cells in a Hypoxia-Inducible Factor-1α-Dependent Manner in Pancreatic Cancer Cells
Hypoxia Induces Tumor Aggressiveness and the Expansion of CD133-Positive Cells in a Hypoxia-Inducible Factor-1α-Dependent Manner in Pancreatic Cancer Cells
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DOI：
10.1159/000325538
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发表时间：
2011-01-01
期刊：
影响因子：
5
通讯作者：
Hori, Yuichi
中科院分区：
文献类型：
--
作者：
Hashimoto, Okito;Shimizu, Kazuya;Hori, Yuichi
背景：已知肿瘤内缺氧可导致侵袭性增加和远处转移。然而，这些行动背后的相互作用仍然是未知的。目的：我们探讨了癌细胞是否可能在缺氧条件下获得干细胞样表型，从而导致侵袭性表型，包括侵袭和转移。研究方法：在常氧（20%O-2）和低氧（1%O-2）条件下，采用RT-PCR和免疫组化方法检测人胰腺癌细胞系CD 133（肿瘤干细胞标志物）、CXC趋化因子受体4（CXCR 4）和低氧诱导因子-1 α（HIF-1 α）的表达。我们还研究了缺氧是否促进CD 133+癌细胞的侵袭。此外，我们通过逆转录病毒基因转移转染显性活性HIF-1 α（HIF-1 α Delta ODD），并检查体外和体内的效果。结果：与常氧组相比，低氧组CD 133、CXCR 4和HIF-1 α表达均升高。此外，缺氧促进CD 133+胰腺癌细胞的侵袭。HIF-1 α δ ODD转染细胞在常氧条件下的行为与缺氧条件下的亲本细胞的行为相容。此外，HIF-1 α δ ODD细胞的异种移植模型显示出侵袭性，包括转移和高度致瘤能力。结论：缺氧诱导肿瘤侵袭性与CD 133+胰腺癌细胞以主要HIF-1 α依赖性方式扩增相关。版权所有（C）2011 S. Karger AG，巴塞尔
Background: Intratumoral hypoxia is known to lead to increased aggressiveness and distant metastasis. However, the interplay underlying these actions is still unknown. Objective: We explored whether cancer cells might acquire a stem-like phenotype under hypoxia, consequently leading to an aggressive phenotype, including invasiveness and metastasis. Methods: Under normoxia (20% O-2) or hypoxia (1% O-2), the expression of CD133 (cancer stem cell marker), CXC chemokine receptor 4 (CXCR4) and hypoxia-inducible factor-1 alpha (HIF-1 alpha) was examined by RT-PCR and immunostaining using human pancreatic cancer cell lines. We also examined if hypoxia facilitates the invasiveness of CD133+ cancer cells. Furthermore, we transfected dominant active HIF-1 alpha (HIF-1 alpha Delta ODD) by the retroviral gene transfer and examined the effects both in vitro and in vivo. Results: Compared with normoxia, hypoxia elevated the expression of CD133, CXCR4 and HIF-1 alpha. Moreover, hypoxia facilitated the invasiveness of CD133+ pancreatic cancer cells. The behavior of HIF-1 alpha Delta ODD-transfected cells under normoxia was compatible with that of the parent cells under hypoxia. Furthermore, a xenograft model of HIF-1 alpha Delta ODD cells showed aggressiveness, including metastasis and highly tumorigenic ability. Conclusion: Hypoxia induces tumor aggressiveness associated with the expansion of CD133+ pancreatic cancer cells in a predominantly HIF-1 alpha-dependent manner. Copyright (C) 2011 S. Karger AG, Basel