Hypoxia upregulates adhesion ability to peritoneum through a transforming growth factor-β-dependent mechanism in diffuse-type gastric cancer cells
Hypoxia upregulates adhesion ability to peritoneum through a transforming growth factor-β-dependent mechanism in diffuse-type gastric cancer cells
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DOI：
10.1016/j.ejca.2010.01.007
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发表时间：
2010-03-01
影响因子：
8.4
通讯作者：
Hirakawa, Kosei
中科院分区：
文献类型：
--
作者：
Noda, Satoru;Yashiro, Masakazu;Hirakawa, Kosei
离开原发肿瘤的胃癌细胞暴露于腹膜腔中的低氧水平;然而，低氧癌细胞的腹膜转移表型仍不清楚。我们使用了6种胃癌细胞系，包括3种弥漫型胃癌（DGC）和3种非DGC细胞系。使用粘附试验，我们研究了缺氧条件下，他们的能力，坚持腹膜组件的影响。采用逆转录-聚合酶链反应检测癌细胞转化生长因子-β（TGF-β）和整合素mRNA的表达水平。我们进一步研究了抗整联蛋白中和抗体和TGF-β受体抑制剂对缺氧癌细胞粘附能力的影响。DGC细胞的结合能力高于非DGC细胞;与常氧（21%O-2）条件相比，低氧（1%O-2）条件显著增加。相反，在常氧和缺氧条件下，在非DGC细胞中观察到粘附能力没有显著变化。缺氧DGC细胞整合素和TGF-β的表达显著高于常氧DGC细胞。TGF-β增加缺氧DGC细胞的粘附能力和α 2-、α 3-和α 5-整合素表达，而TGF-β受体抑制剂降低它们。针对α 2-、α 3-和α 5-整联蛋白的中和抗体抑制DGC细胞的粘附能力。这些结果表明，低氧条件下促进DGC细胞粘附到腹膜。在低氧条件下TGF-β上调α 2-、α 3-和α 5-整联蛋白可能是低氧DGC细胞向腹膜的高转移潜力的机制之一。(C)2010爱思唯尔有限公司保留所有权利。
Gastric cancer cells leaving the primary tumour are exposed to low oxygen levels in the peritoneal cavity; however, peritoneal metastatic phenotypes of hypoxic cancer cells remain unclear. We used 6 gastric cancer cell lines, including 3 diffuse-type gastric cancer (DGC) and 3 non-DGC cell lines. Using adhesion assay, we examined the effect of hypoxic conditions on their ability to adhere to peritoneal components. The expression level of transforming growth factor-beta (TGF-beta) and integrins mRNA of cancer cells was examined using reverse transcriptase-polymerase chain reaction. We further examined the effect of anti-integrin neutralising antibodies and a TGF-beta receptor inhibitor on the adhesion ability of hypoxic cancer cells. The binding ability of DGC cells was higher than that of non-DGC cells; it was significantly increased by hypoxic (1% O-2) conditions compared to normoxic (21% O-2) conditions. In contrast, no remarkable change in adhesion ability was observed in the non-DGC cells under normoxic and hypoxic conditions. Integrins and TGF-beta expression of hypoxic DGC cells was significantly higher than that of normoxic cells. TGF-beta increased the adhesion ability and alpha 2-, alpha 3- and alpha 5-integrin expression of hypoxic DGC cells, whereas the TGF-beta receptor inhibitor decreased them. Neutralising antibodies against alpha 2-, alpha 3- and alpha 5-integrin inhibited the adhesion ability of DGC cells. These findings suggested that hypoxic conditions promote the adhesion of DGC cells to the peritoneum. The upregulation of alpha 2-, alpha 3- and alpha 5-integrin by TGF-beta under hypoxic conditions may be one of the mechanisms responsible for the high metastatic potential of hypoxic DGC cells to the peritoneum. (C) 2010 Elsevier Ltd. All rights reserved.