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RETRACTED ARTICLE: HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs

Oncogene volume 31, pages 1757–1770 (2012)Cite this article

This article was retracted on 23 May 2023

A Correction to this article was published on 15 January 2021

This article has been updated

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.

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References

  • Belanger AJ, Lu H, Date T, Liu LX, Vincent KA, Akita GY et al. (2002). Hypoxia up-regulates expression of peroxisome proliferator-activated receptor gamma angiopoietin-related gene (PGAR) in cardiomyocytes: role of hypoxia inducible factor 1α. J Mol Cell Cardiol 34: 765–774.

    Article  CAS  PubMed  Google Scholar 

  • Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM et al. (2003). Levels of hypoxia-inducible factor 1α independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer 97: 1573–1581.

    Article  PubMed  Google Scholar 

  • Bos R, Zhong H, Hanrahan CF, Mommers EC, Semenza GL, Pinedo HM et al. (2001). Levels of hypoxia-inducible factor 1α during breast carcinogenesis. J Natl Cancer Inst 93: 309–314.

    Article  CAS  PubMed  Google Scholar 

  • Buffa FM, Harris AL, West CM, Miller CJ . (2010). Large meta-analysis of multiple cancers reveals a common, compact and highly prognostic hypoxia metagene. Br J Cancer 102: 428–435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cailleau R, Young R, Olivé M, Reeves Jr WJ . (1978). Breast tumor cell lines from pleural effusions. J Natl Cancer Inst 53: 661–674.

    Article  Google Scholar 

  • Caniggia I, Mostachfi H, Winter J, Gassmann M, Lye SJ, Kuliszewski M et al. (2000). Hypoxia-inducible factor 1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFβ3 . J Clin Invest 105: 577–587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chambers AF . (2009). MDA-MB-435 and M14 cell lines: identical but not M14 melanoma? Cancer Res 69: 5292–5293.

    Article  CAS  PubMed  Google Scholar 

  • Chintala S, Tóth K, Cao S, Durrani FA, Vaughan MM, Jensen RL et al. (2010). Se-methylselenocysteine sensitizes hypoxic tumor cells to irinotecan by targeting hypoxia-inducible factor 1α. Cancer Chemother Pharmacol 66: 899–911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dales JP, Garcia S, Meunier-Carpentier S, Andrac-Meyer L, Haddad O, Lavaut MN et al. (2005). Overexpression of hypoxia-inducible factor HIF-1α predicts early relapse in breast cancer: retrospective study in a series of 745 patients. Int J Cancer 116: 734–739.

    Article  CAS  PubMed  Google Scholar 

  • Dewhirst MW, Cao Y, Moeller B . (2008). Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer 8: 425–437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A et al. (2009). Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15: 35–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Erler JT, Bennewith KL, Nicolau M, Dornhöfer N, Kong C, Le QT et al. (2006). Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440: 1222–1226.

    Article  CAS  PubMed  Google Scholar 

  • Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL . (2007). HIF-1 regulates cytochome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 129: 111–122.

    Article  CAS  PubMed  Google Scholar 

  • Galaup A, Cazes A, Le Jan S, Philippe J, Connault E, Le Coz E et al. (2006). Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness. Proc Natl Acad Sci USA 103: 18721–18726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Generali D, Berruti A, Brizzi MP, Campo L, Bonardi S, Wigfield S et al. (2006). Hypoxia-inducible factor-1α expression predicts a poor response to primary chemoendocrine therapy and disease-free survival in primary human breast cancer. Clin Cancer Res 12: 4562–4568.

    Article  CAS  PubMed  Google Scholar 

  • Giatromanolaki A, Koukourakis MI, Simopoulos C, Polychronidis A, Gatter KC, Harris AL et al. (2004). c-erbB-2 related aggressiveness in breast cancer is hypoxia inducible factor-1α dependent. Clin Cancer Res 10: 7972–7977.

    Article  CAS  PubMed  Google Scholar 

  • Gupta GP, Nguyen DX, Chiang AC, Bos PD, Kim JY, Nadal C et al. (2007). Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446: 765–770.

    Article  CAS  PubMed  Google Scholar 

  • Helczynska K, Larsson AM, Holmquist-Mengelbier L, Bridges E, Fredlund E, Borgquist S et al. (2008). Hypoxia-inducible factor 2α correlates to distant recurrence and poor outcome in invasive breast cancer. Cancer Res 68: 9212–9220.

    Article  CAS  PubMed  Google Scholar 

  • Issa Y, Nummer D, Seibel T, Müerköster SS, Koch M, Schmitz-Winnenthal F et al. (2009). Enhanced L1CAM expression on pancreatic tumor endothelium mediates selective tumor cell transmigration. J Mol Med 87: 99–112.

    Article  CAS  PubMed  Google Scholar 

  • Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH et al. (2006). Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res 66: 2725–2731.

    Article  CAS  PubMed  Google Scholar 

  • Kronblad A, Jirstrom K, Ryden L, Nordenskjold B, Landberg G . (2006). Hypoxia inducible factor-1α is a prognostic marker in premenopausal patients with intermediate to highly differentiated breast cancer but not a predictive marker for tamoxifen response. Int J Cancer 118: 2609–2016.

    Article  CAS  PubMed  Google Scholar 

  • Liao D, Corle C, Seagroves TN, Johnson RS . (2007). Hypoxia-inducible factor-1α is a key regulator of metastasis in a transgenic model of cancer initiation and progression. Cancer Res 67: 563–572.

    Article  CAS  PubMed  Google Scholar 

  • Liotta LA, Kohn EC . (2000) In: Bast, RC, Kufe, DW, Pollock, RE, Weichselbaum, RR, Holland, JF, Frei E(ed). Cancer Medicine. B.C. Decker: Hamilton, Canada, pp 121–131.

    Google Scholar 

  • Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ et al. (2005). Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105: 659–669.

    Article  CAS  PubMed  Google Scholar 

  • Melillo G . (2007). Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Rev 26: 341–352.

    Article  CAS  PubMed  Google Scholar 

  • Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD et al. (2005). Genes that mediate breast cancer metastasis to lung. Nature 436: 518–524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishi H, Nakada T, Hokamura M, Osakabe Y, Itokazu O, Huang LE et al. (2004). Hypoxia-inducible factor-1 transactivates transforming growth factor-beta3 in trophoblast. Endocrinology 145: 4113–4118.

    Article  CAS  PubMed  Google Scholar 

  • Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR et al. (2008). TGFβ primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133: 66–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pal SK, Childs BH, Pegram M . (2011). Triple negative breast cancer: unmet medical needs. Breast Cancer Res Treat 125: 627–636.

    Article  CAS  PubMed  Google Scholar 

  • Palmieri C, Krell J, James CR, Harper-Wynne C, Misra V, Cleator S et al. (2010). Rechallenging with anthacyclines and taxanes in metastatic breast cancer. Nat Rev Clin Oncol 7: 561–574.

    Article  CAS  PubMed  Google Scholar 

  • Schindl M, Schoppmann SF, Samonigg H, Hausmaninger H, Kwasny W, Gnant M et al. (2002). Overexpression of hypoxia-inducible factor 1α is associated with an unfavorable prognosis in lymph node-positive breast cancer. Clin Cancer Res 8: 1831–1837.

    CAS  PubMed  Google Scholar 

  • Semenza GL . (2010). Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29: 625–634.

    Article  CAS  PubMed  Google Scholar 

  • Subarsky P, Hill RP . (2003). The hypoxic tumor microenvironment and metastatic progression. Clin Exp Metastasis 20: 237–250.

    Article  CAS  PubMed  Google Scholar 

  • Tafani M, Russo A, Di Vito M, Sale P, Pellegrini L, Schito L et al. (2010). Up-regulation of pro-inflammatory genes as adaptation to hypoxia in MCF-7 cells and in human mammary invasive carcinoma microenvironment. Cancer Sci 101: 1014–1023.

    Article  CAS  PubMed  Google Scholar 

  • Talmadge JE, Fidler IJ . (2010). AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res 70: 5649–5669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trastour C, Benizri E, Ettore F, Ramaioli A, Chamorey E, Pouyssegur J et al. (2007). HIF-1α and CA IX staining in invasive breast carcinomas: Prognosis and treatment outcome. Int J Cancer 120: 1443–1450.

    Article  Google Scholar 

  • Ueno M, Maeno T, Nomura M, Aoyagi-Ikeda K, Matsui H, Hara K et al. (2011). Hypoxia-inducible factor-1α mediates TGF-β-induced PAI-1 production in alveolar macrophages in pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 300: L740–L752.

    Article  CAS  PubMed  Google Scholar 

  • Vaupel P, Mayer A, Höckel M . (2004). Tumor hypoxia and malignant progression. Meth Enzymol 381: 355–354.

    Google Scholar 

  • Verheul HM, Salumbides B, Van Erp K, Hammers H, Qian DZ, Sanni T et al. (2008). Combination strategy targeting the hypoxia inducible factor-1α with mammalian target of rapamycin and histone deacetylase inhibitors. Clin Cancer Res 14: 3589–3597.

    Article  CAS  PubMed  Google Scholar 

  • Vleugel MM, Greijer AE, Shvarts A, van der Groep P, van Berkel M, Aarbodem Y et al. (2005). Differential prognostic impact of hypoxia induced and diffuse HIF-1α expression in invasive breast cancer. J Clin Pathol 58: 172–177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang GL, Jiang BH, Rue EA, Semenza GL . (1995). Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92: 5510–5514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamamoto Y, Ibusuki M, Okumura Y, Kawasoe T, Kai K, Ivama K et al. (2008). Hypoxia-inducible factor 1α is closely linked to an aggressive phenotype in breast cancer. Breast Cancer Res Treat 110: 465–475.

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Qian DZ, Tan YS, Lee K, Gao P, Ren YR et al. (2008). Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth. Proc Natl Acad Sci USA 105: 19579–19586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to Karen Padgett of Novus Biologicals for generous gifts of antibodies against HIF-1α, HIF-2α 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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Authors and Affiliations

  1. Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    H Zhang, C C L Wong, H Wei, D M Gilkes, P Chaturvedi, L Schito, J Chen & G L Semenza

  2. Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    H Zhang, P Korangath, S Sukumar & G L Semenza

  3. McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    C C L Wong, H Wei, D M Gilkes, P Chaturvedi, J Chen & G L Semenza

  4. Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    B Krishnamachary, P T Winnard Jr & V Raman

  5. School of Life Science, The University of Science and Technology of China, Hefei, Anhui, China

    H Zhang

  6. University of Rome ‘La Sapienza’, Rome, Italy

    L Schito

  7. Division of Physiology, The Johns Hopkins University School of Public Health, Baltimore, MD, USA

    L Zhen & W A Mitzner

  8. Departments of Pediatrics, Medicine, Radiation Oncology, and Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    G L Semenza

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Correspondence to G L Semenza.

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Zhang, H., Wong, C., Wei, H. et al. RETRACTED ARTICLE: HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs. Oncogene 31, 1757–1770 (2012). https://doi.org/10.1038/onc.2011.365

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