Hypoxia and hypoxia-inducible factor-1 expression enhance osteolytic bone metastases of breast cancer
Hypoxia and hypoxia-inducible factor-1 expression enhance osteolytic bone metastases of breast cancer
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DOI：
10.1158/0008-5472.can-06-2355
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发表时间：
2007-05-01
期刊：
影响因子：
11.2
通讯作者：
Yoneda, Toshiyuki
中科院分区：
文献类型：
--
作者：
Hiraga, Toru;Kizaka-Kondoh, Shinae;Yoneda, Toshiyuki
缺氧是实体瘤的共同特征，并与其恶性表型相关。转录因子缺氧诱导因子-1 （HIF-1）是适应缺氧的主要调节因子，并与癌症的恶性进展有关。在这里，我们研究缺氧和HIF-1表达是否促进骨转移的发展，使用一个具有良好特征的MDA-MB-231人乳腺癌细胞骨转移动物模型。为了研究缺氧在骨转移中的作用，我们测试了融合蛋白（TOP3）、HIF-1 α与HIV-TAT融合的氧依赖降解结构域和procaspase-3的影响。TOP3选择性诱导体外缺氧肿瘤细胞凋亡，显著减少体内骨转移。接下来，我们通过建立过表达构成型活性或显性阴性RIF-Io的MDA-MB-231细胞，研究了HIF-1在骨转移中的作用。（MDA/CA-HIF或MDA/DN-HIF）。随着cd31阳性血管数量的增加，MDA/CA-HIF骨转移明显增加。相比之下，MDA/DN-HIF组骨转移明显减少。由于溶解性骨转移的进展部分是由于骨形成和骨吸收之间的不平衡，我们研究了缺氧和HIF-1对成骨细胞和破骨细胞分化的影响。缺氧和CA-HIF过表达明显抑制成骨细胞分化，而缺氧则增加破骨细胞样细胞的形成。总之，这些结果表明肿瘤相关的缺氧和HIF-1的表达促进了乳腺癌骨转移的进展。我们的研究结果还表明，缺氧和HIF-1通过抑制成骨细胞分化和促进破骨细胞发生而导致溶骨转移的发生。
Hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. The transcription factor hypoxia-inducible factor-1 (HIF-1) is a major regulator of adaptation to hypoxia and is implicated in the malignant progression of cancers. Here, we studied whether hypoxia and HIF-1 expression contribute to the development of bone metastases using a well-characterized animal model of bone metastasis in MDA-MB-231 human breast cancer cells. To study the role of hypoxia in bone metastases, we tested the effects of the fusion protein (TOP3), the oxygen-dependent degradation domain of HIF-1 alpha fused with HIV-TAT, and procaspase-3. TOP3 selectively induced apoptosis in hypoxic tumor cells in vitro and significantly reduced bone metastases in vivo. We next examined the role of HIF-1 in bone metastases by establishing MDA-MB-231 cells overexpressing constitutively active or dominant-negative RIF-Io. (MDA/CA-HIF or MDA/DN-HIF, respectively). Bone metastases of MDA/CA-HIF were significantly increased with elevated number of CD31-positive blood vessels. In contrast, bone metastases were significantly reduced in MDA/DN-HIF. Because the progression of osteolytic bone metastases is due in part to the imbalance between bone formation and bone resorption, we examined the effects of hypoxia and HIF-1 on the differentiation of osteoblasts and osteoclasts. Hypoxia and CA-HIF overexpression markedly inhibited osteoblastic differentiation, whereas hypoxia increased osteoclast-like cell formation. In conclusion, these results suggest that tumor-associated hypoxia and HIF-1 expression promote the progression of bone metastases in breast cancer. Our results also suggest that hypoxia and HIF-1 lead to the development of osteolytic bone metastases by suppressing osteoblast differentiation and promoting osteoclastogenesis.