← Back to Search
Hypoxia And Hypoxia-inducible Factor-1 Expression Enhance Osteolytic Bone Metastases Of Breast Cancer.
T. Hiraga, S. Kizaka-Kondoh, K. Hirota, M. Hiraoka, T. Yoneda
Published 2007 · Medicine
Download PDFAnalyze on Scholarcy
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.
This paper references
Increasing levels of hypoxia in prostate carcinoma correlate significantly with increasing clinical stage and patient age
B. Movsas (2000)
Efficient generation of recombinant adenoviruses using adenovirus DNA-terminal protein complex and a cosmid bearing the full-length virus genome.
S. Miyake (1996)
The effect of Neovastat (AE-941) on an experimental metastatic bone tumor model.
M. H. Weber (2002)
Metastasis: Metastasis to bone: causes, consequences and therapeutic opportunities
G. R. Mundy (2002)
Hypoxia is a major stimulator of osteoclast formation and bone resorption
T. Arnett (2003)
Transient Changes in Oxygen Tension Inhibit Osteogenic Differentiation and Runx2 Expression in Osteoblasts*
A. Salim (2004)
Ultrastructural and cytobiological studies on possible interactions between PTHrP-secreting tumor cells, stromal cells, and bone cells
M. Ito (2003)
Angiogenesis inhibitor TNP-470 inhibits human breast cancer osteolytic bone metastasis in nude mice through the reduction of bone resorption.
A. Sasaki (1998)
The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma.
E. Tian (2003)
Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts.
H. Takayanagi (2002)
Hypoxic stress enhances osteoclast differentiation via increasing IGF2 production by non-osteoclastic cells.
Hayato Fukuoka (2005)
Levels of Hypoxia-Inducible Factor-1α During Breast Carcinogenesis
R. Bos (2001)
Increasing levels of hypoxia in prostate carcinoma correlate significantly with increasing clinical stage and patient age: an Eppendorf pO(2) study.
B. Movsas (2000)
Convergent signaling by acidosis and receptor activator of NF-kappaB ligand (RANKL) on the calcium/calcineurin/NFAT pathway in osteoclasts.
S. Komarova (2005)
Stimulation of cyclooxygenase-2 expression by bone-derived transforming growth factor-beta enhances bone metastases in breast cancer.
T. Hiraga (2006)
Metabolic Acidosis Stimulates RANKL RNA Expression in Bone Through a Cyclo‐oxygenase‐Dependent Mechanism
K. K. Frick (2003)
Oxygen tension regulates osteoblast function.
O. Tuncay (1994)
Increased expression of bone morphogenetic protein-7 in bone metastatic prostate cancer
増田 広 (2004)
Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism.
J. Dai (2005)
Overexpression of hypoxia-inducible factor 1alpha is associated with an unfavorable prognosis in lymph node-positive breast cancer.
M. Schindl (2002)
Increased expression of bone morphogenetic protein‐7 in bone metastatic prostate cancer
H. Masuda (2003)
Antitumor effect of TAT-oxygen-dependent degradation-caspase-3 fusion protein specifically stabilized and activated in hypoxic tumor cells.
H. Harada (2002)
Hypoxia decreases Runx2/Cbfa1 expression in human osteoblast-like cells
J. H. Park (2002)
Hypoxiainducible factor 1a in high-risk breast cancer: an independent prognostic parameter? Breast Cancer Res 2004;6:R191–8
G Gruber (2004)
Targeting HIF-1 for cancer therapy
G. Semenza (2003)
Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2.
T. Oshima (2005)
Angiogenesis as a therapeutic target
N. Ferrara (2005)
Nitric Oxide Induces Hypoxia-inducible Factor 1 Activation That Is Dependent on MAPK and Phosphatidylinositol 3-Kinase Signaling*
K. Kasuno (2004)
Protection against ischemic brain injury by protein therapeutics
S. Asoh (2002)
Hypoxia-inducible Factor and Its Biomedical Relevance*
L. E. Huang (2003)
Hypoxia regulates osteoblast gene expression.
S. Warren (2001)
Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases.
H. Zhong (1999)
Tumor hypoxia: A target for selective cancer therapy
S. Kizaka-Kondoh (2003)
Hypoxia in breast cancer: pathogenesis, characterization and biological/therapeutic implications.
P. Vaupel (2002)
Reciprocal Roles of Msx2 in Regulation of Osteoblast and Adipocyte Differentiation*
Fumitaka Ichida (2004)
In vivo protein transduction: delivery of a biologically active protein into the mouse.
S. Schwarze (1999)
Hypoxia-inducible factor 1 alpha in high-risk breast cancer: an independent prognostic parameter?
G. Gruber (2003)
Exploiting tumour hypoxia in cancer treatment
J. M. Brown (2004)
YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1.
Eun-Jin Yeo (2003)
Hypoxia — a key regulatory factor in tumour growth
A. Harris (2002)
Hypoxia in Human Prostate Carcinoma: An Eppendorf Po2 Study
B. Movsas (2001)
Cell Type–Specific Regulation of Angiogenic Growth Factor Gene Expression and Induction of Angiogenesis in Nonischemic Tissue by a Constitutively Active Form of Hypoxia-Inducible Factor 1
Brian D Kelly (2003)
Reduced expression of hypoxia-inducible factor-1alpha in perinecrotic regions of solid tumors.
S. Sobhanifar (2005)
This paper is referenced by
Hypoxia in microscopic tumors.
X. Li (2008)
Does Loss of CD151 Expression Promote the Metastasis of Hypoxic Colon Cancer Cells?
G. Semenza (2008)
Breast cancer cells promote osteoblastic differentiation via Sema 3A signaling pathway in vitro.
W. Shen (2015)
The HIF-1-active microenvironment: an environmental target for cancer therapy.
S. Kizaka-Kondoh (2009)
Hypoxia‐inducible factor is expressed in giant cell tumour of bone and mediates paracrine effects of hypoxia on monocyte–osteoclast differentiation via induction of VEGF
H. Knowles (2008)
Identification of a Novel Biomarker Signature Associated with Risk for Bone Metastasis in Patients with Renal Cell Carcinoma
B. Paule (2010)
Inhibitors of Growth 1b Suppresses Peroxisome Proliferator-Activated Receptor-β/δ Expression Through Downregulation of Hypoxia-Inducible Factor 1α in Osteoblast Differentiation.
B. Qu (2016)
Subtypes of breast cancer show preferential site of relapse.
M. Smid (2008)
Molecular and Cellular Pathobiology CollagenProlyl HydroxylasesAreEssential for BreastCancer Metastasis
Daniele M Gilkes (2013)
Tumor necrosis factor stimulates osteoclastogenesis from human bone marrow cells under hypoxic conditions.
Takayuki Nomura (2014)
Role of TGF-β in breast cancer bone metastases
A. Chiechi (2013)
Role of Hypoxia-Inducible Transcription Factors in TAM Function
N. Rohwer (2011)
The impact of O2 availability on human cancer
Jessica A. Bertout (2008)
Bone Metastases: Molecular Mechanisms and Novel Therapeutic Interventions
D. Papachristou (2012)
Inhibition of osteoclastogenesis by prolyl hydroxylase inhibitor dimethyloxallyl glycine
A. Leger (2010)
Novel Anti-Cancer Strategy in Bone Tumors by Targeting Molecular and Cellular Modulators of Bone Resorption
Brounais Benedicte (2008)
Cell Death and Survival Procollagen Lysyl Hydroxylase 2 Is Essential for Hypoxia-Induced Breast Cancer Metastasis
Daniele M Gilkes (2013)
Role of hypoxia inducible factor-1α for interferon synthesis in mouse dendritic cells
Regina Wobben (2013)
Hypoxia and Bone Metastatic Disease
R. Johnson (2017)
Quantification of Changes in Vertebral Bone Quality in the Presence of Metastases
Mikhail Burke (2018)
Therapeutic targeting of hypoxia and hypoxia-inducible factor 1 alpha in multiple myeloma.
E. Borsi (2015)
Hypoxia Potentiates LPS-Mediated Cytotoxicity of BV2 Microglial Cells In Vitro by Synergistic Effects on Glial Cytokine and Nitric Oxide System.
Daniel Frey (2015)
Acute hypoxia and osteoclast activity: a balance between enhanced resorption and increased apoptosis
H. Knowles (2009)
MDA-MB-231 breast cancer cells fuel osteoclast metabolism and activity: A new rationale for the pathogenesis of osteolytic bone metastases.
Silvia Lemma (2017)
Effet de l'inhibition par ARN interférence de la thrombospondine-1 sur la potentialisation de la réponse immune dans un contexte tumoral
E. Marcheteau (2019)
Bone metastases: When and how lung cancer interacts with bone.
I. Roato (2014)
Hypoxia Selectively Enhances Integrin α5β1 Receptor Expression in Breast Cancer to Promote Metastasis
Julia A Ju (2017)
Cancer–stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis
G. Semenza (2013)
Viral-based gene delivery and regulated gene expression for targeted cancer therapy
Y. Lu (2010)
TGF-β in the Bone Microenvironment: Role in Breast Cancer Metastases
J. Buijs (2011)
SEPT9_v1 Up-regulates Hypoxia-inducible Factor 1 by Preventing Its RACK1-mediated Degradation*
S. Amir (2009)
Hypoxia response pathway in border cell migration
I. Djagaeva (2010)See more