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.

Interactions between cancer stem cells and their niche govern metastatic colonization

Nature volume 481, pages 85–89 (2012)Cite this article

Subjects

Abstract

Metastatic growth in distant organs is the major cause of cancer mortality. The development of metastasis is a multistage process with several rate-limiting steps1. Although dissemination of tumour cells seems to be an early and frequent event2, the successful initiation of metastatic growth, a process termed ‘metastatic colonization’, is inefficient for many cancer types and is accomplished only by a minority of cancer cells that reach distant sites3,4. Prevalent target sites are characteristic of many tumour entities5, suggesting that inadequate support by distant tissues contributes to the inefficiency of the metastatic process. Here we show that a small population of cancer stem cells is critical for metastatic colonization, that is, the initial expansion of cancer cells at the secondary site, and that stromal niche signals are crucial to this expansion process. We find that periostin (POSTN), a component of the extracellular matrix, is expressed by fibroblasts in the normal tissue and in the stroma of the primary tumour. Infiltrating tumour cells need to induce stromal POSTN expression in the secondary target organ (in this case lung) to initiate colonization. POSTN is required to allow cancer stem cell maintenance, and blocking its function prevents metastasis. POSTN recruits Wnt ligands and thereby increases Wnt signalling in cancer stem cells. We suggest that the education of stromal cells by infiltrating tumour cells is an important step in metastatic colonization and that preventing de novo niche formation may be a novel strategy for the treatment of metastatic disease.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: Cancer stem cells initiate metastasis.
Figure 2: POSTN is a stromal niche component that is induced on metastasis formation.
Figure 3: POSTN is required for metastatic colonization by affecting CSC maintenance.
Figure 4: POSTN promotes stem cell maintenance and metastasis formation by augmenting Wnt signalling.

References

  1. Chambers, A. F., Groom, A. C. & MacDonald, I. C. Dissemination and growth of cancer cells in metastatic sites. Nature Rev. Cancer 2, 563–572 (2002)

    Article  CAS  Google Scholar 

  2. Hüsemann, Y. et al. Systemic spread is an early step in breast cancer. Cancer Cell 13, 58–68 (2008)

    Article  Google Scholar 

  3. Kouros-Mehr, H. et al. GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell 13, 141–152 (2008)

    Article  CAS  Google Scholar 

  4. Nguyen, D. X., Bos, P. D. & Massague, J. Metastasis: from dissemination to organ-specific colonization. Nature Rev. Cancer 9, 274–284 (2009)

    Article  CAS  Google Scholar 

  5. Hess, K. R. et al. Metastatic patterns in adenocarcinoma. Cancer 106, 1624–1633 (2006)

    Article  Google Scholar 

  6. Lin, E. Y. et al. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am. J. Pathol. 163, 2113–2126 (2003)

    Article  Google Scholar 

  7. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003)

    Article  ADS  CAS  Google Scholar 

  8. Reya, T. & Clevers, H. Wnt signalling in stem cells and cancer. Nature 434, 843–850 (2005)

    Article  ADS  CAS  Google Scholar 

  9. Cho, R. W. et al. Isolation and molecular characterization of cancer stem cells in MMTV-Wnt-1 murine breast tumors. Stem Cells 26, 364–371 (2008)

    Article  CAS  Google Scholar 

  10. Shackleton, M. et al. Generation of a functional mammary gland from a single stem cell. Nature 439, 84–88 (2006)

    Article  ADS  CAS  Google Scholar 

  11. Stingl, J. et al. Purification and unique properties of mammary epithelial stem cells. Nature 439, 993–997 (2006)

    Article  ADS  CAS  Google Scholar 

  12. Liu, J. C., Deng, T., Lehal, R. S., Kim, J. & Zacksenhaus, E. Identification of tumorsphere- and tumor-initiating cells in HER2/Neu-induced mammary tumors. Cancer Res. 67, 8671–8681 (2007)

    Article  CAS  Google Scholar 

  13. Zhang, M. et al. Identification of tumor-initiating cells in a p53-null mouse model of breast cancer. Cancer Res. 68, 4674–4682 (2008)

    Article  CAS  Google Scholar 

  14. Podsypanina, K. et al. Seeding and propagation of untransformed mouse mammary cells in the lung. Science 321, 1841–1844 (2008)

    Article  ADS  CAS  Google Scholar 

  15. Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nature Cell Biol. 12, 468–476 (2010)

    Article  CAS  Google Scholar 

  16. Visvader, J. E. & Lindeman, G. J. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nature Rev. Cancer 8, 755–768 (2008)

    Article  CAS  Google Scholar 

  17. Psaila, B. & Lyden, D. The metastatic niche: adapting the foreign soil. Nature Rev. Cancer 9, 285–293 (2009)

    Article  CAS  Google Scholar 

  18. Takeshita, S., Kikuno, R., Tezuka, K. & Amann, E. Osteoblast-specific factor 2: cloning of a putative bone adhesion protein with homology with the insect protein fasciclin I. Biochem. J. 294, 271–278 (1993)

    Article  CAS  Google Scholar 

  19. Shimazaki, M. & Kudo, A. Impaired capsule formation of tumors in periostin-null mice. Biochem. Biophys. Res. Commun. 367, 736–742 (2008)

    Article  CAS  Google Scholar 

  20. Oka, T. et al. Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling. Circ. Res. 101, 313–321 (2007)

    Article  CAS  Google Scholar 

  21. Rios, H. et al. Periostin null mice exhibit dwarfism, incisor enamel defects, and an early-onset periodontal disease-like phenotype. Mol. Cell. Biol. 25, 11131–11144 (2005)

    Article  CAS  Google Scholar 

  22. Zhao, W. et al. Suppression of in vivo tumorigenicity of rat hepatoma cell line KDH-8 cells by soluble TGF-beta receptor type II. Cancer Immunol. Immunother. 51, 381–388 (2002)

    Article  CAS  Google Scholar 

  23. Muraoka, R. S. et al. Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. J. Clin. Invest. 109, 1551–1559 (2002)

    Article  CAS  Google Scholar 

  24. Pece, S. et al. Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell 140, 62–73 (2010)

    Article  CAS  Google Scholar 

  25. Milovanovic, T. et al. Expression of Wnt genes and frizzled 1 and 2 receptors in normal breast epithelium and infiltrating breast carcinoma. Int. J. Oncol. 25, 1337–1342 (2004)

    CAS  PubMed  Google Scholar 

  26. Zeng, Y. A. & Nusse, R. Wnt proteins are self-renewal factors for mammary stem cells and promote their long-term expansion in culture. Cell Stem Cell 6, 568–577 (2010)

    Article  CAS  Google Scholar 

  27. Malanchi, I. et al. Cutaneous cancer stem cell maintenance is dependent on β-catenin signaling. Nature 452, 650–653 (2008)

    Article  ADS  CAS  Google Scholar 

  28. Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009)

    Article  ADS  CAS  Google Scholar 

  29. Wels, J., Kaplan, R. N., Rafii, S. & Lyden, D. Migratory neighbors and distant invaders: tumor-associated niche cells. Genes Dev. 22, 559–574 (2008)

    Article  CAS  Google Scholar 

  30. Oskarsson, T. et al. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nature Med. 17, 867–874 (2011)

    Article  CAS  Google Scholar 

  31. Guy, C. T., Cardiff, R. D. & Muller, W. J. Induction of mammary tumours by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol. Cell. Biol. 12, 954–961 (1992)

    Article  CAS  Google Scholar 

  32. Tsukamoto, A. S., Grosschedl, R., Guzman, R. C., Parslow, T. & Varmus, H. E. Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell 55, 619–625 (1988)

    Article  CAS  Google Scholar 

  33. Okabe, M., Ikawa, M., Kominami, K., Nakanishi, T. & Nishimune, Y. ‘Green mice’ as a source of ubiquitous green cells. FEBS Lett. 407, 313–319 (1997)

    Article  CAS  Google Scholar 

  34. Jeannet, G. et al. Long-term, multilineage hematopoiesis occurs in the combined absence of β-catenin and γ-catenin. Blood 111, 142–149 (2008)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to U. Koch for advice on FACS, to M. Moniatte for advice on mass spectrometry and to S. Leuba for technical assistance with histology. I.M., E.S., A.S.-M. and J.H. were supported in part by the Swiss League against Cancer, the SNF, the NCCR in Molecular Oncology and the Anna Fuller Fund. J.H. holds the EPFL chair for Signal Transduction in Oncogenesis sponsored by Debiopharm.

Author information

Author notes

  1. Ilaria Malanchi and Albert Santamaria-Martínez: These authors contributed equally to this work.

Authors and Affiliations

  1. Ecole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research and National Center of Competence in Research ‘Molecular Oncology’, Lausanne, 1015, Switzerland

    Ilaria Malanchi, Albert Santamaria-Martínez, Evelyn Susanto, Hong Peng & Joerg Huelsken

  2. Department of Otorhinolaryngology, Nanfang Hospital, Head and Neck Surgery, Southern Medical University, Guangzhou, 510515, China

    Hong Peng

  3. University Institute of Pathology, CHUV, University of Lausanne, Lausanne, 1011, Switzerland

    Hans-Anton Lehr

  4. Department of Gynecology and Obstetrics, Centre Hospitalier Universitaire Vaudois, Lausanne, 1011, Switzerland

    Jean-Francois Delaloye

Authors
  1. Ilaria Malanchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Albert Santamaria-Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Evelyn Susanto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hong Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hans-Anton Lehr
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jean-Francois Delaloye
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Joerg Huelsken
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

I.M., A.S.-M. and J.H. designed and performed most of the experiments, analysed data and prepared the manuscript; E.S. and H.P. performed experiments; H.-A.L. performed experiments and analysed data; J.-F.D. provided clinical samples; and J.H. designed and supervised the study.

Corresponding author

Correspondence to Joerg Huelsken.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-32 with legends. This file was replaced on 19 January. (PDF 7539 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Malanchi, I., Santamaria-Martínez, A., Susanto, E. et al. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481, 85–89 (2012). https://doi.org/10.1038/nature10694

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10694

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer