HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs

H. Zhang; C. C.L. Wong; H. Wei; D. M. Gilkes; P. Korangath; P. Chaturvedi; L. Schito; J. Chen; B. Krishnamachary; P. T. Winnard; V. Raman; L. Zhen; W. A. Mitzner; S. Sukumar; G. L. Semenza

doi:10.1038/onc.2011.365

HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs

H. Zhang, C. C.L. Wong, H. Wei, D. M. Gilkes, P. Korangath, P. Chaturvedi, L. Schito, J. Chen, B. Krishnamachary, P. T. Winnard, V. Raman, L. Zhen, W. A. Mitzner, S. Sukumar, G. L. Semenza

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Abstract

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.

Original language	English (US)
Pages (from-to)	1757-1770
Number of pages	14
Journal	Oncogene
Volume	31
Issue number	14
DOIs	https://doi.org/10.1038/onc.2011.365
State	Published - Apr 5 2012

Keywords

breast cancer
hypoxia
metastasis

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

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10.1038/onc.2011.365

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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. (2012). HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs. Oncogene, 31(14), 1757-1770. https://doi.org/10.1038/onc.2011.365

Zhang, H, Wong, CCL, Wei, H, Gilkes, DM , Korangath, P, Chaturvedi, P, Schito, L, Chen, J, Krishnamachary, B , Winnard, PT , Raman, V, Zhen, L, Mitzner, WA , Sukumar, S & Semenza, GL 2012, 'HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs', Oncogene, vol. 31, no. 14, pp. 1757-1770. https://doi.org/10.1038/onc.2011.365

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title = "HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs",

abstract = "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.",

keywords = "breast cancer, hypoxia, metastasis",

author = "H. Zhang and Wong, {C. C.L.} and H. Wei and Gilkes, {D. M.} and P. Korangath and P. Chaturvedi and L. Schito and J. Chen and B. Krishnamachary and Winnard, {P. T.} and V. Raman and L. Zhen and Mitzner, {W. A.} and S. Sukumar and Semenza, {G. L.}",

note = "Funding Information: We are grateful to Karen Padgett of Novus Biologicals for generous gifts of antibodies against HIF-1a, HIF-2a and L1CAM. This work was supported by the Emerald Foundation, the National Institutes of Health (U54-CA143868) and the Johns Hopkins Institute for Cell Engineering. DMG was supported by the Postdoctoral Training Program in Nanotechnology for Cancer Medicine (T32-CA130840). GLS is the C Michael Armstrong Professor at Johns Hopkins University School of Medicine.",

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AU - Gilkes, D. M.

AU - Korangath, P.

AU - Chaturvedi, P.

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AU - Zhen, L.

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AU - Sukumar, S.

AU - Semenza, G. L.

N1 - Funding Information: We are grateful to Karen Padgett of Novus Biologicals for generous gifts of antibodies against HIF-1a, HIF-2a and L1CAM. This work was supported by the Emerald Foundation, the National Institutes of Health (U54-CA143868) and the Johns Hopkins Institute for Cell Engineering. DMG was supported by the Postdoctoral Training Program in Nanotechnology for Cancer Medicine (T32-CA130840). GLS is the C Michael Armstrong Professor at Johns Hopkins University School of Medicine.

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HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs

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