Molecular mechanisms mediating metastasis of hypoxic breast cancer cells.

Molecular mechanisms mediating metastasis of hypoxic breast cancer cells.
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DOI:
10.1016/j.molmed.2012.08.001
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发表时间:
2012-09
影响因子:
13.6
通讯作者:
Semenza GL
Semenza GL
中科院分区:
医学1区
文献类型:
--
作者:
Semenza GL

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乳腺癌包含肿瘤内低氧区域,其中氧气供应的减少激活了低氧诱导因子HIF-1和HIF-2,这两个因子增加了编码蛋白质的基因的转录,这些蛋白质是癌症进展中许多重要步骤所必需的。最近,HIF通过转录激活编码血管生成素样4和L1细胞黏附分子的基因,促进循环癌细胞从肺血管中渗出,以及赖氨酰氧化酶家族成员LOX、LOXL2和LOXL4,促进肿瘤的侵袭和转移生态位的形成,在乳腺癌向肺转移的过程中发挥关键作用。地高辛是一种抑制HIF-1活性的药物,在体外和体内试验中可以阻止原发肿瘤的生长、血管形成、侵袭和转移。
Breast cancers contain regions of intratumoral hypoxia in which reduced O2 availability activates the hypoxia-inducible factors HIF-1 and HIF-2, which increase the transcription of genes encoding proteins that are required for many important steps in cancer progression. Recently, HIFs have been shown to play critical roles in the metastasis of breast cancer to the lungs through the transcriptional activation of genes encoding angiopoietin-like 4 and L1 cell adhesion molecule, which promote the extravasation of circulating cancer cells from the lung vasculature, and the lysyl oxidase family members LOX, LOXL2, and LOXL4, which promote invasion and metastatic niche formation. Digoxin, a drug that inhibits HIF-1 activity, blocks primary tumor growth, vascularization, invasion, and metastasis in ex vivo and in vivo assays.
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