Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Hypoxia-induced Jagged2 promotes breast cancer metastasis and self-renewal of cancer stem-like cells

Oncogene volume 30, pages 4075–4086 (2011)Cite this article

Subjects

Abstract

Notch signaling is often and aberrantly activated by hypoxia during tumor progression; however, the exact pathological role of hypoxia-induced Notch signaling in tumor metastasis is as yet poorly understood. In this study, we aimed to define the mechanism of Notch-ligand activation by hypoxia in both primary tumor and bone stromal cells in the metastatic niche and to clarify their roles in tumor progression. We have analyzed the expression profiles of various Notch ligands in 779 breast cancer patients in GEO database and found that the expression of Jagged2 among all five ligands is most significantly correlated with the overall- and metastasis-free survival of breast cancer patients. The results of our immunohistochemical (IHC) analysis for Jagged2 in 61 clinical samples also revealed that both Jagged2 and Notch signaling were strongly upregulated at the hypoxic invasive front. Activation of Jagged2 by hypoxia in tumor cells induced EMT and also promoted cell survival in vitro. Notably, a γ-secretase inhibitor significantly blocked Notch-mediated invasion and survival under hypoxia by promoting expression of E-cadherin and inhibiting Akt phosphorylation. Importantly, Jagged2 was also found to be upregulated in bone marrow stroma under hypoxia and promoted the growth of cancer stem-like cells by activating their Notch signaling. Therefore, hypoxia-induced Jagged2 activation in both tumor invasive front and normal bone stroma has a critical role in tumor progression and metastasis, and Jagged2 is considered to be a valuable prognostic marker and may serve as a novel therapeutic target for metastatic breast cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Artavanis-Tsakonas S, Rand MD, Lake RJ . (1999). Notch signaling: cell fate control and signal integration in development. Science 284: 770–776.

    Article  CAS  PubMed  Google Scholar 

  • Bandyopadhyay S, Wang Y, Zhan R, Pai SK, Watabe M, Iiizumi M et al. (2006). The tumor metastasis suppressor gene Drg-1 down-regulates the expression of activating transcription factor 3 in prostate cancer. Cancer Res 66: 11983–11990.

    Article  CAS  PubMed  Google Scholar 

  • Bedogni B, Warneke JA, Nickoloff BJ, Giaccia AJ, Powell MB . (2008). Notch1 is an effector of Akt and hypoxia in melanoma development. J Clin Invest 118: 3660–3670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bertout JA, Patel SA, Fryer BH, Durham AC, Covello KL, Olive KP et al. (2009). Heterozygosity for hypoxia inducible factor 1alpha decreases the incidence of thymic lymphomas in a p53 mutant mouse model. Cancer Res 69: 3213–3220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cejudo-Martin P, Johnson RS . (2005). A new notch in the HIF belt: how hypoxia impacts differentiation. Dev Cell 9: 575–576.

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, De Marco MA, Graziani I, Gazdar AF, Strack PR, Miele L et al. (2007). Oxygen concentration determines the biological effects of NOTCH-1 signaling in adenocarcinoma of the lung. Cancer Res 67: 7954–7959.

    Article  CAS  PubMed  Google Scholar 

  • Choi K, Ahn YH, Gibbons DL, Tran HT, Creighton CJ, Girard L et al. (2009). Distinct biological roles for the notch ligands Jagged-1 and Jagged-2. J Biol Chem 284: 17766–17774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • D'Souza B, Meloty-Kapella L, Weinmaster G . (2010). Canonical and non-canonical Notch ligands. Curr Top Dev Biol 92: 73–129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Das B, Tsuchida R, Malkin D, Koren G, Baruchel S, Yeger H . (2008). Hypoxia enhances tumor stemness by increasing the invasive and tumorigenic side population fraction. Stem Cells 26: 1818–1830.

    Article  PubMed  Google Scholar 

  • Dickson BC, Mulligan AM, Zhang H, Lockwood G, O'Malley FP, Egan SE et al. (2007). High-level JAG1 mRNA and protein predict poor outcome in breast cancer. Mod Pathol 20: 685–693.

    Article  CAS  PubMed  Google Scholar 

  • Eliasz S, Liang S, Chen Y, De Marco MA, Machek O, Skucha S et al. (2010). Notch-1 stimulates survival of lung adenocarcinoma cells during hypoxia by activating the IGF-1R pathway. Oncogene 29: 2488–2498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD et al. (1991). TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66: 649–661.

    Article  CAS  PubMed  Google Scholar 

  • Felli MP, Maroder M, Mitsiadis TA, Campese AF, Bellavia D, Vacca A et al. (1999). Expression pattern of notch1, 2 and 3 and Jagged1 and 2 in lymphoid and stromal thymus components: distinct ligand-receptor interactions in intrathymic T cell development. Int Immunol 11: 1017–1025.

    Article  CAS  PubMed  Google Scholar 

  • Furuta E, Pai SK, Zhan R, Bandyopadhyay S, Watabe M, Mo YY et al. (2008). Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res 68: 1003–1011.

    Article  CAS  PubMed  Google Scholar 

  • Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J et al. (2005). Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell 9: 617–628.

    Article  CAS  PubMed  Google Scholar 

  • Haase VH . (2009). Oxygen regulates epithelial-to-mesenchymal transition: insights into molecular mechanisms and relevance to disease. Kidney Int 76: 492–499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horree N, van Diest PJ, Sie-Go DM, Heintz AP . (2007). The invasive front in endometrial carcinoma: higher proliferation and associated derailment of cell cycle regulators. Hum Pathol 38: 1232–1238.

    Article  CAS  PubMed  Google Scholar 

  • Kiaris H, Politi K, Grimm LM, Szabolcs M, Fisher P, Efstratiadis A et al. (2004). Modulation of notch signaling elicits signature tumors and inhibits hras1-induced oncogenesis in the mouse mammary epithelium. Am J Pathol 165: 695–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klinakis A, Szabolcs M, Politi K, Kiaris H, Artavanis-Tsakonas S, Efstratiadis A . (2006). Myc is a Notch1 transcriptional target and a requisite for Notch1-induced mammary tumorigenesis in mice. Proc Natl Acad Sci USA 103: 9262–9267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koch U, Radtke F . (2007). Notch and cancer: a double-edged sword. Cell Mol Life Sci 64: 2746–2762.

    Article  CAS  PubMed  Google Scholar 

  • Kominsky SL, Davidson NE . (2006). A ‘bone’ fide predictor of metastasis? Predicting breast cancer metastasis to bone. J Clin Oncol 24: 2227–2229.

    Article  PubMed  Google Scholar 

  • Lambin P, Theys J, Landuyt W, Rijken P, van der Kogel A, van der Schueren E et al. (1998). Colonisation of Clostridium in the body is restricted to hypoxic and necrotic areas of tumours. Anaerobe 4: 183–188.

    Article  CAS  PubMed  Google Scholar 

  • Lee SH, Jeong EG, Yoo NJ, Lee SH . (2007). Mutational analysis of NOTCH1, 2, 3 and 4 genes in common solid cancers and acute leukemias. Apmis 115: 1357–1363.

    Article  CAS  PubMed  Google Scholar 

  • Leong KG, Karsan A . (2006). Recent insights into the role of Notch signaling in tumorigenesis. Blood 107: 2223–2233.

    Article  CAS  PubMed  Google Scholar 

  • Main H, Lee KL, Yang H, Haapa-Paananen S, Edgren H, Jin S et al. (2010). Interactions between Notch- and hypoxia-induced transcriptomes in embryonic stem cells. Exp Cell Res 316: 1610–1624.

    Article  CAS  PubMed  Google Scholar 

  • Maynard MA, Ohh M . (2007). The role of hypoxia-inducible factors in cancer. Cell Mol Life Sci 64: 2170–2180.

    Article  CAS  PubMed  Google Scholar 

  • Mullendore ME, Koorstra JB, Li YM, Offerhaus GJ, Fan X, Henderson CM et al. (2009). Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer. Clin Cancer Res 15: 2291–2301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nam DH, Jeon HM, Kim S, Kim MH, Lee YJ, Lee MS et al. (2008). Activation of notch signaling in a xenograft model of brain metastasis. Clin Cancer Res 14: 4059–4066.

    Article  CAS  PubMed  Google Scholar 

  • Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD . (2007). Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci USA 104: 5431–5436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pouyssegur J, Dayan F, Mazure NM . (2006). Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441: 437–443.

    Article  CAS  PubMed  Google Scholar 

  • Reedijk M, Odorcic S, Chang L, Zhang H, Miller N, McCready DR et al. (2005). High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res 65: 8530–8537.

    Article  CAS  PubMed  Google Scholar 

  • Roodman GD . (2004). Mechanisms of bone metastasis. N Engl J Med 350: 1655–1664.

    Article  CAS  PubMed  Google Scholar 

  • Sahlgren C, Gustafsson MV, Jin S, Poellinger L, Lendahl U . (2008). Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA 105: 6392–6397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Stylianou S, Clarke RB, Brennan K . (2006). Aberrant activation of notch signaling in human breast cancer. Cancer Res 66: 1517–1525.

    Article  CAS  PubMed  Google Scholar 

  • Tomes L, Emberley E, Niu Y, Troup S, Pastorek J, Strange K et al. (2003). Necrosis and hypoxia in invasive breast carcinoma. Breast Cancer Res Treat 81: 61–69.

    Article  PubMed  Google Scholar 

  • Wang Z, Li Y, Ahmad A, Azmi AS, Banerjee S, Kong D et al. (2010). Targeting Notch signaling pathway to overcome drug resistance for cancer therapy. Biochim Biophys Acta 1806: 258–267.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yin T, Li L . (2006). The stem cell niches in bone. J Clin Invest 116: 1195–1201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu X, Zou J, Ye Z, Hammond H, Chen G, Tokunaga A et al. (2008). Notch signaling activation in human embryonic stem cells is required for embryonic, but not trophoblastic, lineage commitment. Cell Stem Cell 2: 461–471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao N, Guo Y, Zhang M, Lin L, Zheng Z . (2010). Akt-mTOR signaling is involved in Notch-1-mediated glioma cell survival and proliferation. Oncol Rep 23: 1443–1447.

    Article  CAS  PubMed  Google Scholar 

  • Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D et al. (1999). Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59: 5830–5835.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH (R01CA124650, R01CA129000 to KW), the US Department of Defense (BC085424, BC085590 to KW) and Susan Komen Foundation (KG080477 to KW).

Author information

Authors and Affiliations

  1. Department of Medical Microbiology, Immunology & Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA

    F Xing, H Okuda, M Watabe, A Kobayashi, S K Pai, W Liu, P R Pandey, K Fukuda, Y-Y Mo & K Watabe

  2. Iwate Medical University, School of Medicine, Iwate, Japan

    S Hirota, T Sugai, G Wakabayshi, K Koeda, M Kashiwaba, K Suzuki, T Chiba & M Endo

Authors
  1. F Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Okuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Watabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S K Pai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. W Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P R Pandey
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K Fukuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S Hirota
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. T Sugai
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. G Wakabayshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. K Koeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. M Kashiwaba
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. K Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. T Chiba
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. M Endo
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Y-Y Mo
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. K Watabe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K Watabe.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xing, F., Okuda, H., Watabe, M. et al. Hypoxia-induced Jagged2 promotes breast cancer metastasis and self-renewal of cancer stem-like cells. Oncogene 30, 4075–4086 (2011). https://doi.org/10.1038/onc.2011.122

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.122

Keywords

This article is cited by

Search

Advanced search

Quick links