| 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
|
| リソース情報 |
| ヒト・動物細胞 |
10T1/2(RCB0247) |
