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Interactions between cancer stem cells and their niche govern metastatic colonization

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.

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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. 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)

    CAS  Article  Google Scholar 

  2. 2

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

    Article  Google Scholar 

  3. 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)

    CAS  Article  Google Scholar 

  4. 4

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

    CAS  Article  Google Scholar 

  5. 5

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

    Article  Google Scholar 

  6. 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. 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)

    ADS  CAS  Article  Google Scholar 

  8. 8

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

    ADS  CAS  Article  Google Scholar 

  9. 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)

    CAS  Article  Google Scholar 

  10. 10

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

    ADS  CAS  Article  Google Scholar 

  11. 11

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

    ADS  CAS  Article  Google Scholar 

  12. 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)

    CAS  Article  Google Scholar 

  13. 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)

    CAS  Article  Google Scholar 

  14. 14

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

    ADS  CAS  Article  Google Scholar 

  15. 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)

    CAS  Article  Google Scholar 

  16. 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)

    CAS  Article  Google Scholar 

  17. 17

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

    CAS  Article  Google Scholar 

  18. 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)

    CAS  Article  Google Scholar 

  19. 19

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

    CAS  Article  Google Scholar 

  20. 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)

    CAS  Article  Google Scholar 

  21. 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)

    CAS  Article  Google Scholar 

  22. 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)

    CAS  Article  Google Scholar 

  23. 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)

    CAS  Article  Google Scholar 

  24. 24

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

    CAS  Article  Google Scholar 

  25. 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. 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)

    CAS  Article  Google Scholar 

  27. 27

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

    ADS  CAS  Article  Google Scholar 

  28. 28

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

    ADS  CAS  Article  Google Scholar 

  29. 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)

    CAS  Article  Google Scholar 

  30. 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)

    CAS  Article  Google Scholar 

  31. 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)

    CAS  Article  Google Scholar 

  32. 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)

    CAS  Article  Google Scholar 

  33. 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)

    CAS  Article  Google Scholar 

  34. 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)

    CAS  Article  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.

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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.

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The authors declare no competing financial interests.

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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

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