Hypoxia-inducible factor-1α is a key regulator of metastasis in a transgenic model of cancer initiation and progression
Hypoxia-inducible factor-1α is a key regulator of metastasis in a transgenic model of cancer initiation and progression
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DOI：
10.1158/0008-5472.can-06-2701
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发表时间：
2007-01-15
期刊：
影响因子：
11.2
通讯作者：
Johnson, Randall S.
中科院分区：
文献类型：
--
作者：
Liao, Debbie;Corle, Courtney;Johnson, Randall S.
对缺氧的适应是肿瘤进展中的关键步骤，并且部分地由转录因子缺氧诱导因子-1 α（HIF-1 α）调节。异种移植模型已被广泛用于表征HIF-1 α在实验性癌症中的作用。尽管这些模型提供了对恶性肿瘤终末期肿瘤生长的理解，但它们不能解决肿瘤起始或转移进展。为了阐明这些作用，在转移性乳腺癌转基因小鼠模型的乳腺上皮中有条件地缺失HIF-1 α。乳腺上皮中HIF-1 α的条件性缺失导致肿瘤发病延迟和肿瘤生长迟缓;这与肿瘤细胞增殖减少相关。HIF-1 α条件性缺失的肿瘤在早期肿瘤进展过程中血管也较少。也许最令人惊讶的是，乳腺上皮中HIF-1 α的缺失导致肺转移减少。这些结果表明，虽然HIF-1 α不是乳腺肿瘤生长或肿瘤细胞转移的起始所需的，但HIF-1 α的转录活性是肿瘤进展和转移潜力的显著正调控因子。
Adaptation to hypoxia is a critical step in tumor progression and is, in part, regulated by the transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha). Xenograft models have been extensively used to characterize the role of HIF-1 alpha in experimental cancers. Although these models provide an understanding of tumor growth at terminal stages of malignancy, they do not address tumor initiation or metastatic progression. To elucidate these roles, HIF-1 alpha was conditionally deleted in the mammary epithelium of a transgenic mouse model for metastatic breast cancer. Conditional deletion of HIF-1 alpha in the mammary epithelium resulted in delayed tumor onset and retarded tumor growth; this was correlated with decreased tumor cell proliferation. Tumors with conditional deletion of HIF-1 alpha were also less vascular during early tumor progression. Perhaps most surprisingly, deletion of HIF-1 alpha in the mammary epithelium resulted in decreased pulmonary metastasis. These results show that whereas HIF-1 alpha is not required for the initiation of breast tumor growth or tumor cell metastasis, the transcriptional activity of HIF-1 alpha is a significant positive regulator of tumor progression and metastatic potential.