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RETRACTED ARTICLE: HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs
Open accessAbstract
Most cases of breast cancer (BrCa) mortality are due to vascular metastasis. BrCa cells must intravasate through endothelial cells (ECs) to enter a blood vessel in the primary tumor and then adhere to ECs and extravasate at the metastatic site. In this study we demonstrate that inhibition of hypoxia-inducible factor (HIF) activity in BrCa cells by RNA interference or digoxin treatment inhibits primary tumor growth and also inhibits the metastasis of BrCa cells to the lungs by blocking the expression of angiopoietin-like 4 (ANGPTL4) and L1 cell adhesion molecule (L1CAM). ANGPTL4 is a secreted factor that inhibits EC-EC interaction, whereas L1CAM increases the adherence of BrCa cells to ECs. Interference with HIF, ANGPTL4 or L1CAM expression inhibits vascular metastasis of BrCa cells to the lungs.
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In the citing paper
“HIF-1α-dependent expression of angiopoietin-like 4 and the L1 cell adhesion molecule further modulate intra-and extravasation (Zhang et al., 2012).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Zhang et al., 2012
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“HIF-1α inhibition has shown success as a therapeutic strategy in mouse models of metastatic breast cancer6, 7.”
From Liposomal Formulation of HIF-1α Inhibitor Echinomycin Eliminates Established Metastases of Triple-negative Breast Cancer (2020) · cites this paper as [6]
The cited source says what the claim attributes to it.
In the citing paper
“Double-knockdown of HIF1A and HIF2A in MDA-MB-231 cells was reported to impair primary tumor growth and lung metastasis in vivo6.”
From Liposomal Formulation of HIF-1α Inhibitor Echinomycin Eliminates Established Metastases of Triple-negative Breast Cancer (2020) · cites this paper as [6]
In the citing paper
“whereas inactivation of HIF decreases the metastatic potential of tumor cells”
From Hypoxic control of metastasis (2016) · cites this paper as [45]
In the citing paper
“Knockdown of HIF-1α, HIF-2α, or both in human MDA-MB-231 BCCs significantly decreased the number of spontaneous lung metastases and total lung metastatic burden in immunodeficient mice after mammary fat pad injection [35].”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [35]
In the citing paper
“Exposure of MDA-MB-231 cells to 1% O2 for 48 hours increased their adherence to vascular ECs, due to the HIF-dependent activation of L1 cell adhesion molecule (L1CAM) expression [35].”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [35]
In the citing paper
“ANGPTL4 expression is induced by hypoxia in a HIF-dependent manner [35].”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [35]
In the citing paper
“In order for BCCs to migrate between adjacent ECs, they secrete angiopoietin-like 4 (ANGPTL4), which binds to receptors on ECs and inhibits EC-EC interactions [35, 76].”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [35]
In the citing paper
“Knockdown of ANGPTL4 expression in MDA-MB-231 cells had no effect on primary tumor growth but dramatically impaired hypoxia-induced extravasation after intravenous injection and lung metastasis after mammary fat pad implantation [35, 76].”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [35]
In the citing paper
“Knockdown of L1CAM markedly impaired adherence of BCCs to vascular ECs ex vivo, reduced lung colonization after intravenous injection, and decreased the number of spontaneous lung metastases after mammary fat pad implantation [35].”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [35]
In the citing paper
“There are now several drugs (acriflavine, digoxin, and ganetespib) that have been shown to inhibit HIF-1 and shown to block breast cancer primary tumor growth, angiogenesis, pre-metastatic niche formation, and local invasion as well as metastasis to lymph nodes and lungs in orthotopic mouse models [31, 35, 60, 104].”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [35]
In the citing paper
“There are now several drugs (acriflavine, digoxin, and ganetespib) that have been shown to inhibit HIF-1 and shown to block breast cancer primary tumor growth, angiogenesis, pre-metastatic niche formation, and local invasion as well as metastasis to lymph nodes and lungs in orthotopic mouse models [31, 35, 60, 104].”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [35]
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Cites
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Self-citation
Metadata
- Authors
- Zhang, H., Wong, C. C. L., Wei, H., Gilkes, D. M., Korangath, P., Chaturvedi, P., Schito, L., Chen, J., Krishnamachary, B., Winnard, P. T., Raman, V, Zhen, L., Mitzner, W. A., Sukumar, S., & Semenza, G. L.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Semenza, G L
- ORCID
- Venue
- Oncogene
- Published
- 2011-08-22
- Volume
- 31
- Issue
- 14
- Pages
- 1757-1770
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC3223555
- OpenAlex
- W2020105314
- Cited by
- 326
- References
- 44
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 13 · 2023: 15 · 2022: 29 · 2021: 30 · 2020: 33 · 2019: 25 · 2018: 21 · 2017: 26 · 2016: 29 · 2015: 24 · 2014: 27 · 2013: 30 · 2012: 20
- FWCI
- 9.99
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Johns Hopkins University
- Emerald Foundation
- National Cancer Institute (U54CA143868, T32CA130840)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- breast cancer, vascular metastasis, HIF-1, ANGPTL4, L1CAM, hypoxia, lung metastasis, endothelial cells, tumor cell adhesion, intravasation, digoxin, retracted article
- MeSH terms
- Angiopoietin-like Proteins, Angiopoietin-Like Protein 3, Animals, Breast Neoplasms, Female, Humans, Lung Neoplasms, Neoplasm Transplantation, Spermidine, Cell Hypoxia, RNA Interference, Angiopoietins, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1
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