論文 - 詳細
| RRC ID | 42966 |
|---|---|
| 著者 | Hiraga T, Kizaka-Kondoh S, Hirota K, Hiraoka M, Yoneda T. |
| タイトル | Hypoxia and hypoxia-inducible factor-1 expression enhance osteolytic bone metastases of breast cancer. |
| ジャーナル | Cancer Res |
| Abstract |
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-1alpha 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 HIF-1alpha (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. |
| 巻・号 | 67(9) |
| ページ | 4157-63 |
| 公開日 | 2007-5-1 |
| DOI | 10.1158/0008-5472.CAN-06-2355 |
| PII | 67/9/4157 |
| PMID | 17483326 |
| MeSH | Animals Bone Neoplasms / genetics Bone Neoplasms / metabolism* Bone Neoplasms / secondary* Breast Neoplasms / genetics Breast Neoplasms / metabolism* Breast Neoplasms / pathology* Caspase 3 / metabolism Cell Hypoxia / physiology Cell Line, Tumor Female Humans Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis* Hypoxia-Inducible Factor 1, alpha Subunit / genetics Indazoles / pharmacology Mice Mice, Inbred C3H Mice, Nude Recombinant Fusion Proteins / metabolism Recombinant Fusion Proteins / pharmacology Transfection |
| IF | 9.727 |
| 引用数 | 157 |
| WOS 分野 | ONCOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | 10T1/2(RCB0247) |