Chronic hypoxia promotes an aggressive phenotype in rat prostate cancer cells
Chronic hypoxia promotes an aggressive phenotype in rat prostate cancer cells
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DOI：
10.1080/10715760701361531
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发表时间：
2007-01-01
影响因子：
3.3
通讯作者：
Singh, Gurmit
中科院分区：
文献类型：
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作者：
Alqawi, Omar;Wang, Hong P.;Singh, Gurmit
一般说来，肿瘤细胞抵抗凋亡和增加血管生成是导致恶性表型的低氧反应的结果。在这项研究中，我们建立了一种慢性低氧细胞模型(HMLL)，通过将前列腺癌MatLyLu细胞培养在低氧室内(1%O-2)超过3周。每代细胞筛选存活细胞，在低氧条件下生长至8周。这一策略导致只有5%的细胞存活。存活的低氧细胞表现出对低氧适应反应的更大刺激，包括葡萄糖转运蛋白1(Glut1)的表达和血管内皮生长因子(VEGF)的分泌。此外，Matrigel实验显示慢性低氧HMLL细胞的侵袭活性高于急性低氧(1%O-2，5h)下的MatLyLu细胞。为了进一步研究HIF-1α在肿瘤进展中的作用，将显性-阴性形式的HIF-1α(DNHIF-1α)导入MatLyLu和HMLL细胞。DNHIF-1α可显著减弱慢性低氧诱导的Matrigel侵袭活性。这些结果表明，导致低氧反应的信号通路可能在慢性低氧细胞和急性低氧细胞中受到不同的调节。慢性低氧可能比急性低氧在促进肿瘤细胞侵袭性表型方面发挥更大的作用。这一观察模拟了放射治疗后的肿瘤细胞在低氧条件下的临床情景。治疗后肿瘤的复发通常会导致肿瘤细胞更具侵袭性和转移性。
In general, tumors cells that are resistant to apoptosis and increase angiogenesis are a result of the hypoxic responses contributing to the malignant phenotype. In this study, we developed a chronic hypoxic cell model (HMLL), by incubating the prostate cancer MatLyLu cells in a hypoxic chamber (1% O-2) over 3 weeks. Surviving cells were selected through each cell passage and were grown in the hypoxic condition up to 8 weeks. This strategy resulted in survival of only 5% of the cells. The surviving hypoxic cells displayed a greater stimulation on hypoxic adaptive response, including a greater expression of glucose transporter1 (Glut1) and VEGF secretion. In addition, higher invasion activity was observed in the chronic hypoxic HMLL cells as compared to MatLyLu cells exposed to acute hypoxia (1% O-2, 5 h) using the matrigel assay. To further examine the role of HIF-1 alpha in tumor progression, both MatLyLu and HMLL cells were transfected with dominant- negative form of HIF-1 alpha (DNHIF-1 alpha). The Matrigel invasion activity induced by chronic hypoxia was significantly attenuated by DNHIF-1 alpha. These results suggest that signaling pathways leading to hypoxic response may be differentially regulated in chronic hypoxic cells and acute hypoxic cells. Chronic hypoxia may play a greater role than acute hypoxia in promoting the aggressive phenotype of tumor cells. This observation mimics the clinical scenario where tumor cells following treatment with radiation are subjected to hypoxic conditions. The reemergence of tumor following treatment usually results in tumor cells that are more aggressive and metastatic.