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.

VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche

Abstract

The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1+ cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin α4β1), and that tumour-specific growth factors upregulate fibronectin—a VLA-4 ligand—in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Bone marrow-derived cells form the pre-metastatic niche.
Figure 2: Pre-metastatic clusters are comprised of VEGFR1 + haematopoietic progenitors.
Figure 3: Expression of VEGFR1 in pre-metastatic human tissue.
Figure 4: Inhibition of homing of bone marrow cells prevents metastasis.
Figure 5: The VLA-4/fibronectin pathway mediates cluster formation.
Figure 6: Redirection of LLC metastases to atypical sites.

References

  1. Coussens, L., Tinkle, C., Hanahan, D. & Werb, Z. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103, 481–490 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumour angiogenesis and growth. Nature Med. 7, 1194–1201 (2001)

    Article  CAS  PubMed  Google Scholar 

  3. Autiero, M., Luttun, A., Tjwa, M. & Carmeliet, P. Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders. J. Thromb. Haemost. 1, 1356–1370 (2003)

    Article  CAS  PubMed  Google Scholar 

  4. Neeson, P., Thurlow, P., Jamieson, G. & Bradley, C. Lymphocyte-facilitated tumour cell adhesion to endothelial cells: the role of high affinity leukocyte integrins. Pathology 35, 50–55 (2003)

    PubMed  Google Scholar 

  5. Hattori, K. et al. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1+ stem cells from bone-marrow microenvironment. Nature Med. 8, 841–849 (2002)

    Article  CAS  PubMed  Google Scholar 

  6. Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nature Rev. Cancer 4, 71–78 (2004)

    Article  CAS  Google Scholar 

  7. Hiratsuka, S. et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2, 289–300 (2002)

    Article  CAS  PubMed  Google Scholar 

  8. De Palma, M., Vinneri, M. A., Roca, C. & Naldini, L. Targeting exogenous genes to tumour angiogenesis by transplantation of genetically modified hematopoietic cells. Nature Med. 9, 789–795 (2003)

    Article  CAS  PubMed  Google Scholar 

  9. Burger, J., Spoo, A., Dwenger, A., Burger, M. & Behringer, D. CXCR4 chemokine receptors (CD184) and α4β1 integrins mediate spontaneous migration of human CD34+ progenitors and acute myeloid leukaemia cells beneath marrow stromal cells (pseudoemperipolesis). Br. J. Haematol. 122, 579–589 (2003)

    Article  CAS  PubMed  Google Scholar 

  10. Scott, L., Priestly, G. & Papayannopoulou, T. Deletion of α4 integrins from adult hematopoietic cells reveals roles in homeostasis, regeneration, and homing. Mol. Cell. Biol. 23, 9349–9360 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jonjic, N. et al. Molecules involved in the adhesion and cytotoxicity of activated monocytes on endothelial cells. J. Immunol. 148, 2080–2083 (1992)

    CAS  PubMed  Google Scholar 

  12. Heissig, B. et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 109, 625–637 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bergers, G. et al. Matrix Metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nature Cell Biol. 2, 737–744 (2000)

    Article  CAS  PubMed  Google Scholar 

  14. Huhtala, P. et al. Cooperative signalling by α5β1 and α4β1 integrins regulates metalloproteinase gene expression in fibroblasts adhering to fibronectin. J. Cell Biol. 129, 867–879 (1995)

    Article  CAS  PubMed  Google Scholar 

  15. Yakubenko, V. P., Lobb, R. R., Plow, E. F. & Ugarova, T. P. Differential induction of gelatinase B (MMP-9) and gelatinase A (MMP-2) in T lymphocytes upon α4β1-mediated adhesion to VCAM-1 and the CS-1 peptide of fibronectin. Exp. Cell Res. 260, 73–84 (2000)

    Article  CAS  PubMed  Google Scholar 

  16. Ruzinova, M. B. et al. Effect of angiogenesis inhibition by Id loss and the contribution of bone-marrow-derived endothelial cells in spontaneous murine tumours. Cancer Cell 4, 277–289 (2003)

    Article  CAS  PubMed  Google Scholar 

  17. Lyden, D. et al. Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature 401, 670–677 (1999)

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Ratajczak, M. Z. et al. Stem cell plasticity revisted: CXCR4-positive cells expressing mRNA for early muscle, liver and neural cells ‘hide out’ in the bone marrow. Leukemia 18, 29–40 (2004)

    Article  CAS  PubMed  Google Scholar 

  19. Lapidot, T. & Petit, I. Current understanding of stem cell mobilization: The roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines and stromal cells. Exp. Hematol. 30, 973–981 (2002)

    Article  CAS  PubMed  Google Scholar 

  20. Balkwill, F. The significance of cancer cell expression of the chemokine receptor CXCR4. Semin. Cancer Biol. 14, 171–179 (2004)

    Article  CAS  PubMed  Google Scholar 

  21. Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Hynes, R. O. Metastatic potential: generic predisposition of the primary tumour or rare, metastatic variants—or both? Cell 113, 821–823 (2003)

    Article  CAS  PubMed  Google Scholar 

  23. Bergers, G., Song, S., Meyer-Morse, N., Bergsland, E. & Hanahan, D. Benefits of targeting both pericytes and endothelial cells in the tumour vasculature with kinase inhibitors. J. Clin. Invest. 111, 1287–1295 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fidler, I. The organ microenvironment and cancer metastasis. Differentiation 70, 498–505 (2002)

    Article  PubMed  Google Scholar 

  25. Duda, D. G. et al. Differential transplantability of tumour-associated stromal cells. Cancer Res. 64, 5920–5924 (2004)

    Article  CAS  PubMed  Google Scholar 

  26. Folkman, J. Role of angiogenesis in tumour growth and metastasis. Semin. Oncol. 29, 515–518 (2002)

    Article  Google Scholar 

  27. Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. Borsig, L., Wong, R., Hynes, R. O., Varki, N. M. & Varki, A. Synergistic effects of L- and P-selectin in facilitating tumour metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis. Proc. Natl Acad. Sci. USA 99, 2193–2198 (2000)

    Article  ADS  Google Scholar 

  29. Lin, E. Y., Ngyuen, A. V., Russell, R. G. & Pollard, J. W. Colony stimulating factor 1 promoted progression of mammary tumours to malignancy. J. Exp. Med. 193, 727–740 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Qian, F., Hanahan, D. & Weissman, I. L. L-selectin can facilitate metastasis to lymph nodes in a transgenic mouse model of carcinogenesis. Proc. Natl Acad. Sci. USA 98, 3976–3981 (2002)

    Article  ADS  Google Scholar 

  31. Schoppmann, S. et al. Tumour-associated macrophages express lymphatic endothelial growth factors and are related to peritumoural lymphangiogenesis. Am. J. Pathol. 161, 947–956 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tam, P. P., Parameswaran, M., Kinder, S. J. & Weinberger, R. P. The allocation of epiblast cells to the embryonic heart and other mesodermal lineages: the role of ingression and tissue movement during gastrulation. Development 124, 1631–1642 (1999)

    Google Scholar 

  33. Kessinger, A., Mann, S., Murphy, B. O., Jackson, J. D. & Sharp, J. G. Circulating factors may be responsible for murine strain-specific responses to mobilizing cytokines. Exp. Hematol. 29, 775–778 (2001)

    Article  CAS  PubMed  Google Scholar 

  34. Hashimoto, N., Jin, H., Liu, T., Chensue, S. W. & Phan, S. H. Bone marrow-derived progenitor cells in pulmonary fibrosis. J. Clin. Invest. 113, 243–252 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jensen, K. K. et al. The human herpes virus 8-encoded chemokine receptor is required for angioproliferation in a murine model of Kaposi's sarcoma. J. Immunol. 174, 3686–3694 (2005)

    Article  CAS  PubMed  Google Scholar 

  36. Huaux, F., Tianju, L., McGarry, B., Ullenbruch, M. & Phan, S. H. Dual roles of IL-4 in lung injury and fibrosis. J. Immunol. 170, 2083–2092

Download references

Acknowledgements

We thank M. Barna for critical reading of the manuscript and L. Breda, S. Rivella and S. Neustein for discussions. R.N.K. is a recipient of the Laura Rosenberg Fellowship award and supported by a grant from the American Hellenic Educational Progressive Association (Fifth District) and the LTC Foundation. D.L. is supported by the Doris Duke Charitable Foundation, the Children's Blood Foundation, the Emerald Foundation, the Theodore A. Rapp Foundation and a grant from the National Cancer Institute. S.R. is an investigator of the Howard Hughes Medical Institute and supported by grants from the American Cancer Society, the Leukemia and Lymphoma Society, and the National Institutes of Health.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Shahin Rafii or David Lyden.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

Tumour and VEGFR2+ cells arrive after VEGFR1+ HPCs. (PDF 139 kb)

Supplementary Figure 2

VEGFR1 antibody inhibits metastasis in B16 tumours. (PDF 129 kb)

Supplementary Figure 3

Inhibition of VLA-4 and MMP-9 inhibits metastasis. B16 melanoma induces fibronectin expression in the lung. (PDF 128 kb)

Supplementary Figure 4

Bone marrow-derived VEGFR1+ cells attract tumour cells. (PDF 159 kb)

Supplemental Figure 5

Tumours vary in their chemokine profile and fibronectin expression pattern. (PDF 101 kb)

Supplementary Table 1

Id3 deficient mice have decreased mobilization of CD11b+ VEGFR1+ hematopoietic progenitors. (PDF 33 kb)

Supplementary Methods

Additional details of the methods used in this study. (DOC 35 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kaplan, R., Riba, R., Zacharoulis, S. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005). https://doi.org/10.1038/nature04186

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04186

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

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing