Skip to main content

Advertisement

SpringerLink
Log in

Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Intratumoral hypoxia, a frequent finding in metastatic cancer, results in the activation of hypoxia-inducible factors (HIFs). HIFs are implicated in many steps of breast cancer metastasis, including metastatic niche formation through increased expression of lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) proteins, enzymes that remodel collagen at the metastatic site and recruit bone marrow-derived cells (BMDCs) to the metastatic niche. We investigated the effect of two chemically and mechanistically distinct HIF inhibitors, digoxin and acriflavine, on breast cancer metastatic niche formation. Both drugs blocked the hypoxia-induced expression of LOX and LOXL proteins, collagen cross-linking, CD11b+ BMDC recruitment, and lung metastasis in an orthotopic breast cancer model. Patients with HIF-1α-overexpressing breast cancers are at increased risk of metastasis and mortality and our results suggest that such patients may benefit from aggressive therapy that includes a HIF inhibitor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Weigelt B, Peterse JL, van’t Veer LJ (2005) Breast cancer metastasis: markers and models. Nat Rev Cancer 5:591–602

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Vaupel P, Mayer A, Hockel M (2004) Tumor hypoxia and malignant progression. Methods Enzymol 381:335–354

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  5. Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT, Chi JT, Jeffrey SS, Giaccia AJ (2006) Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440:1222–1226

    Article  PubMed  CAS  Google Scholar 

  6. Tafani M, Russo A, Di Vito M, Sale P, Pellegrini L, Schito L, Gentileschi S, Bracaglia R, Marandino F, Garaci E 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  PubMed  CAS  Google Scholar 

  7. Wong CC, Gilkes DM, Zhang H, Chen J, Wei H, Chaturvedi P, Fraley SI, Wong CM, Khoo US, Ng IO et al (2011) Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc Natl Acad Sci USA 108:16369–16374

    Article  PubMed  CAS  Google Scholar 

  8. Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, Le QT, Giaccia AJ (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  PubMed  CAS  Google Scholar 

  9. 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  PubMed  CAS  Google Scholar 

  10. Zhang H, Wong CC, Wei H, Gilkes DM, Korangath P, Chaturvedi P, Schito L, Chen J, Krishnamachary B, Winnard PT Jr. et al. (2011) HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs. Oncogene 2011 Aug 22. doi: 10.1038/onc.2011.365

  11. Moeller BJ, Cao Y, Li CY, Dewhirst MW (2004) Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5:429–441

    Article  PubMed  CAS  Google Scholar 

  12. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827

    Article  PubMed  CAS  Google Scholar 

  13. Csiszar K (2001) Lysyl oxidases: a novel multifunctional amine oxidase family. Prog Nucleic Acid Res Mol Biol 70:1–32

    Article  PubMed  CAS  Google Scholar 

  14. Gao D, Nolan DJ, Mellick AS, Bambino K, McDonnell K, Mittal V (2008) Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 319:195–198

    Article  PubMed  CAS  Google Scholar 

  15. Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L et al (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7:1194–1201

    Article  PubMed  CAS  Google Scholar 

  16. Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, Matrisian LM, Carbone DP, Lin PC (2004) Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6:409–421

    Article  PubMed  CAS  Google Scholar 

  17. Liu C, Yu S, Kappes J, Wang J, Grizzle WE, Zinn KR, Zhang HG (2007) Expansion of spleen myeloid suppressor cells represses NK cell cytotoxicity in tumor-bearing host. Blood 109:4336–4342

    Article  PubMed  CAS  Google Scholar 

  18. Zhang H, Qian DZ, Tan YS, Lee K, Gao P, Ren YR, Rey S, Hammers H, Chang D, Pili R 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  PubMed  CAS  Google Scholar 

  19. Lee K, Zhang H, Qian DZ, Rey S, Liu JO, Semenza GL (2009) Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization. Proc Natl Acad Sci USA 106:17910–17915

    Article  PubMed  CAS  Google Scholar 

  20. Semenza GL, Jiang BH, Leung SW, Passantino R, Concordet JP, Maire P, Giallongo A (1996) Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 271:32529–32537

    Article  PubMed  CAS  Google Scholar 

  21. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449:557–563

    Article  PubMed  CAS  Google Scholar 

  22. Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, Chen H, Omeroglu G, Meterissian S, Omeroglu A et al (2008) Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 14:518–527

    Article  PubMed  CAS  Google Scholar 

  23. Cailleau R, Young R, Olive M, Reeves WJ Jr (1974) Breast tumor cell lines from pleural effusions. J Natl Cancer Inst 53:661–674

    PubMed  CAS  Google Scholar 

  24. Rae JM, Creighton CJ, Meck JM, Haddad BR, Johnson MD (2007) MDA-MB-435 cells are derived from M14 melanoma cells—a loss for breast cancer, but a boon for melanoma research. Breast Cancer Res Treat 104:13–19

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  26. Barry-Hamilton V, Spangler R, Marshall D, McCauley S, Rodriguez HM, Oyasu M, Mikels A, Vaysberg M, Ghermazien H, Wai C et al (2010) Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med 16:1009–1017

    Article  PubMed  CAS  Google Scholar 

  27. Payne SL, Hendrix MJ, Kirschmann DA (2007) Paradoxical roles for lysyl oxidases in cancer—a prospect. J Cell Biochem 101:1338–1354

    Article  PubMed  CAS  Google Scholar 

  28. Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, Semenza GL, van Diest PJ, van der Wall E (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 

  29. Dales JP, Garcia S, Meunier-Carpentier S, Andrac-Meyer L, Haddad O, Lavaut MN, Allasia C, Bonnier P, Charpin C (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  PubMed  CAS  Google Scholar 

  30. Kummar S, Raffeld M, Juwara L, Horneffer Y, Strassberger A, Allen D, Steinberg SM, Rapisarda A, Spencer SD, Figg WD et al (2011) Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1α in advanced solid tumors. Clin Cancer Res 17:5123–5131

    Article  PubMed  CAS  Google Scholar 

  31. Yang J, Weinberg RA (2008) Epithelial–mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14:818–829

    Article  PubMed  CAS  Google Scholar 

  32. Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH, Semenza GL (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  PubMed  CAS  Google Scholar 

  33. Imai T, Horiuchi A, Wang C, Oka K, Ohira S, Nikaido T, Konishi I (2003) Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. Am J Pathol 163:1437–1447

    Article  PubMed  CAS  Google Scholar 

  34. Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, Teng SC, Wu KJ (2008) Direct regulation of TWIST by HIF-1α promotes metastasis. Nat Cell Biol 10:295–305

    Article  PubMed  CAS  Google Scholar 

  35. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3:347–361

    Article  PubMed  Google Scholar 

  36. Krishnamachary B, Berg-Dixon S, Kelly B, Agani F, Feldser D, Ferreira G, Iyer N, LaRusch J, Pak B, Taghavi P et al (2003) Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res 63:1138–1143

    PubMed  CAS  Google Scholar 

  37. Petrella BL, Lohi J, Brinckerhoff CE (2005) Identification of membrane type-1 matrix metalloproteinase as a target of hypoxia-inducible factor-2α in von Hippel–Lindau renal cell carcinoma. Oncogene 24:1043–1052

    Article  PubMed  CAS  Google Scholar 

  38. Shyu KG, Hsu FL, Wang MJ, Wang BW, Lin S (2007) Hypoxia-inducible factor 1α regulates lung adenocarcinoma cell invasion. Exp Cell Res 313:1181–1191

    Article  PubMed  CAS  Google Scholar 

  39. Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613

    PubMed  CAS  Google Scholar 

  40. Lu X, Yan CH, Yuan M, Wei Y, Hu G, Kang Y (2010) In vivo dynamics and distinct functions of hypoxia in primary tumor growth and organotropic metastasis of breast cancer. Cancer Res 70:3905–3914

    Article  PubMed  CAS  Google Scholar 

  41. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SF, Csiszar K, Giaccia A, Weninger W et al (2009) Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:891–906

    Article  PubMed  CAS  Google Scholar 

  42. Peinado H, Iglesias-de DC, la Cruz M, Olmeda D, Csiszar K, Fong KS, Vega S, Nieto MA, Cano A, Portillo F (2005) A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression. EMBO J 24:3446–3458

    Article  PubMed  CAS  Google Scholar 

  43. Schietke R, Warnecke C, Wacker I, Schodel J, Mole DR, Campean V, Amann K, Goppelt-Struebe M, Behrens J, Eckardt KU et al (2010) The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress E-cadherin in hypoxia: insights into cellular transformation processes mediated by HIF-1. J Biol Chem 285:6658–6669

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  45. Riganti C, Campia I, Kopecka J, Gazzano E, Doublier S, Aldieri E, Bosia A, Ghigo D (2011) Pleiotropic effects of cardioactive glycosides. Curr Med Chem 18:872–885

    Article  PubMed  CAS  Google Scholar 

  46. Wainwright M (2001) Acridine—a neglected antibacterial chromophore. J Antimicrob Chemother 47:1–13

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Karen Padgett (Novus Biologicals) for providing antibodies against LOXL2, LOXL4, and CD11b; and Rashmi Bankoti and Sergio Rey for advice. This work was supported by grants from the Emerald Foundation and National Cancer Institute (U54-CA143868) and funds from the Johns Hopkins Institute for Cell Engineering.

Disclosure statement

G.L.S. is the C. Michael Armstrong Professor at Johns Hopkins University School of Medicine and an American Cancer Society Research Professor. C.C.W. is a Croucher Foundation Fellow. All authors confirm that there is no conflict of interest associated with this publication.

Author information

Author notes

  1. Carmen Chak-Lui Wong

    Present address: Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong

  2. Huafeng Zhang

    Present address: School of Life Science, University of Science and Technology of China, Hefei, Anhui, China

Authors and Affiliations

  1. Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Carmen Chak-Lui Wong, Huafeng Zhang, Daniele M. Gilkes, Jasper Chen, Hong Wei, Pallavi Chaturvedi, Maimon E. Hubbi & Gregg L. Semenza

  2. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Carmen Chak-Lui Wong, Daniele M. Gilkes, Jasper Chen, Hong Wei, Pallavi Chaturvedi, Maimon E. Hubbi & Gregg L. Semenza

  3. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Huafeng Zhang & Gregg L. Semenza

  4. Departments of Pediatrics, Medicine, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Gregg L. Semenza

Authors
  1. Carmen Chak-Lui Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huafeng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniele M. Gilkes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jasper Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hong Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pallavi Chaturvedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maimon E. Hubbi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gregg L. Semenza
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gregg L. Semenza.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wong, C.CL., Zhang, H., Gilkes, D.M. et al. Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis. J Mol Med 90, 803–815 (2012). https://doi.org/10.1007/s00109-011-0855-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-011-0855-y

Keywords

Search

Navigation