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  • Review Article
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Pre-metastatic niches: organ-specific homes for metastases

Nature Reviews Cancer volume 17, pages 302–317 (2017)Cite this article

Subjects

Key Points

  • Organs of future metastasis are selectively and actively modified by the primary tumour before metastatic spread has occurred.

  • Tumours induce the formation of microenvironments in distant organs that are conducive to the survival and outgrowth of tumour cells before their arrival at these sites. These microenvironments are termed pre-metastatic niches (PMNs).

  • PMN formation is a stepwise process resulting from the combined systemic effects of tumour-secreted factors and tumour-shed extracellular vesicles.

  • PMN formation is initiated with local changes such as the induction of vascular leakiness, remodelling of stroma and extracellular matrix, followed by systemic effects on the immune system.

  • The development of new technologies and approaches to identify PMNs in distant organ sites in patients could revolutionize cancer treatment and lead to pre-emptive treatments to hinder metastasis.

  • The PMN is a new paradigm for the initiation of metastasis. Our ability to fight metastasis would benefit greatly from understanding the pathological processes occurring before the development of macrometastases.

Abstract

It is well established that organs of future metastasis are not passive receivers of circulating tumour cells, but are instead selectively and actively modified by the primary tumour before metastatic spread has even occurred. Sowing the 'seeds' of metastasis requires the action of tumour-secreted factors and tumour-shed extracellular vesicles that enable the 'soil' at distant metastatic sites to encourage the outgrowth of incoming cancer cells. In this Review, we summarize the main processes and new mechanisms involved in the formation of the pre-metastatic niche.

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Figure 1: Factors involved in PMN formation.
Figure 2: Model of PMN formation.

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Acknowledgements

The authors gratefully acknowledge support from the following funding sources: the US National Cancer Institute (CA169538 to D.L., M.J.B. and H.P. and CA169416 to D.L. and H.P.), the US Department of Defense (W81XWH-13-1-0427 to Y.K., D.L. and J.B., W81XWH-13-1-0249 and W81XWH-14-1-0199 to D.L.), the Hartwell Foundation, the Manning Foundation, the Sohn Foundation, the STARR Consortium, the POETIC Consortium, the Paduano Foundation, Alex's Lemonade Stand Foundation, the Champalimaud Foundation, the 5th District AHEPA Cancer Research Foundation (all to D.L.) and the Daedalus Fund (Weill Cornell Medicine, to D.L and H.Z). H.P. is supported by grants from MINECO (SAF2014-54541-R), ATRES-MEDIA – AXA, Asociación Española Contra el Cáncer, WHRI Academy and Worldwide Cancer Research. A.H. is supported by a Susan Komen Foundation For the Cure Fellowship. J.T.E. is supported by a Novo Nordisk Foundation Hallas Møller stipend. G.R. is supported by a Peter Oppenheimer Fellowship, awarded by the American Portuguese Biomedical Research Fund. C.M.G is supported by a US Department of Defense Breast Cancer Research Program Era of Hope Scholar Award (W81XWH-15-1-0201), the US National Cancer Institute (CA193461-01), the National Breast Cancer Coalition's Artemis Project and the Pink Gene Foundation.

Author information

Author notes

  1. Héctor Peinado, Haiying Zhang and Irina R. Matei: These authors contributed equally to this work seeds

Authors and Affiliations

  1. Departments of Pediatrics, Children's Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, 10021, New York, USA

    Héctor Peinado, Haiying Zhang, Irina R. Matei, Bruno Costa-Silva, Ayuko Hoshino, Goncalo Rodrigues & David Lyden

  2. Department of Molecular Oncology, Microenvironment and Metastasis Group, Spanish National Cancer Research Center (CNIO), Madrid, 28029, Spain

    Héctor Peinado

  3. Systems Oncology Group, Champalimaud Research, Champalimaud Centre for the Unknown, Avenida Brasília, Doca de Pedrouços, Lisbon, 1400-038, Portugal

    Bruno Costa-Silva

  4. Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, 4099-003, Portugal

    Goncalo Rodrigues

  5. Department of Medicine, Centre for Haematology, Hammersmith Hospital, Imperial College London, London, W12 0HS, UK

    Bethan Psaila

  6. Center for Cancer Research, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Building 10-Hatfield CRC, Room 1-3940, Bethesda, 20892, Maryland, USA

    Rosandra N. Kaplan

  7. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, 10065, New York, USA

    Jacqueline F. Bromberg

  8. Department of Molecular Biology, Princeton University, Princeton, 08544, New Jersey, USA

    Yibin Kang

  9. Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, 08903, USA

    Yibin Kang

  10. Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, 94720, California, USA

    Mina J. Bissell

  11. Cancer Division, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, 2010, NSW, Australia

    Thomas R. Cox

  12. Department of Radiation Oncology, Stanford University, Stanford, 94305, California, USA

    Amato J. Giaccia

  13. Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), Copenhagen, 2200, Denmark

    Janine T. Erler

  14. Department of Pharmacology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Tokyo, 162-8666, Japan

    Sachie Hiratsuka

  15. Public Health Sciences Division/Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, 98109, Washington, USA

    Cyrus M. Ghajar

  16. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, 10065, New York, USA

    David Lyden

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  1. Héctor Peinado
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PowerPoint slides

Glossary

Disseminated tumour cells

(DTCs). Thought to originate from CTCs that reach distant organs and survive in these new distant microenvironments.

Tumour-secreted factors

Also known as the tumour secretome. The totality of factors released by tumour cells into their immediate environment or into the systemic circulation. They include growth factors, hormones, cytokines, chemokines and extracellular matrix components, as well as extracellular vesicles.

Extracellular vesicles

(EVs). A heterogeneous population of membrane- surrounded structures released by cells into the intercellular space and the circulation. Their sizes range from 30 nm to 5 μm in diameter and they include exosomes (typically 30–150 nm), microvesicles (150–1,000 nm) and apoptotic bodies (1–5 μm).

Vascular leakiness

Loss of vascular integrity resulting in increased permeability of vessels to macromolecules and cells that normally face resistance or do not cross endothelial barriers.

Circulating tumour cells

(CTCs). Rare cells shed by solid tumours into the systemic circulation at an estimated frequency of 1:500,000–1:1,000,000 circulating cells.

Metastatic niche

Microenvironment in distant organs that supports the survival and outgrowth of tumour cells.

Extracellular matrix

(ECM). Comprising molecules, specifically proteoglycans and fibrous proteins (fibronectin, collagen, elastin and laminin) secreted by stromal cells into the microenvironment, that generate an intricate network of macromolecules that fill the intercellular space.

Orthotopic

Derived from the Greek orthos, meaning right and topos, meaning place, this terminology refers to grafting a tumour into the place in the body where it would normally arise and grow.

Transgenic

Relating to or denoting an organism that contains genetic material into which DNA from an unrelated organism has been artificially introduced.

Omental tissues

A double fold of peritoneum attached to the stomach and connecting it with certain organs of the abdominal viscera, composed of the greater and the lesser omentum, which are the membranes of the bowels.

Neutrophils

Also known as polymorphonuclear leukocytes. Mature granular white blood cells with a multilobular nucleus and cytoplasm containing very fine granules. They are typically the first responders to acute inflammation, such as bacterial infection, injury or certain cancers.

Exosomes

Extracellular vesicles (typically 30–150 nm in diameter) of endocytic origin, released into the extracellular space by all cell types through the fusion of multivesicular bodies with the plasma membrane.

Kupffer cells

Specialized liver-resident phagocytic macrophages that line the walls of the liver sinusoid blood vessels.

Stellate cells

Pericytes that reside in the area between liver sinusoid blood vessels and hepatocytes. They play a prominent role in liver fibrosis and may function as liver-resident antigen-presenting cells.

Blood–brain barrier

(BBB). A complex structure formed by the tight interactions between the brain endothelium, surrounded by the basal lamina and stabilized by pericytes, glial cells and neurons.

Micrometastasis

The formation of a microscopic metastasis, usually defined as a cluster of 10–12 cells in mouse models of metastasis.

Cancer stem cells

A subset of cancer cells that share features of normal stem cells, such as self-renewal and differentiation and that can regenerate the tumour.

Fenestrated vasculature

A permeable type of vasculature that contains ultramicroscopic pores of variable sizes, usually found in kidneys and glands as well as in the circumventricular organs of the brain.

Venous thromboembolism

(VTE). Refers to either of two blood clot-related conditions: deep vein thrombosis (DVT) or pulmonary embolism (PE). DVT occurs when a blood clot forms in a deep vein whereas a PE occurs when a blood clot breaks off and circulates to the lung.

Disseminated intravascular coagulation

Systemic activation of blood coagulation, leading to fibrin accumulation, which in turn results in the formation of microvascular thrombi in vital organs.

T helper 1 (TH1) cell

Member of a subset of CD4+ T cells that can activate macrophages and mediate cellular immunity through secretion of interferon-γ (IFNγ), interleukin-2 (IL-2) and tumour necrosis factor-α (TNFα).

Metastasis-initiating cells

Rare tumour cells that have the capacity to survive and proliferate in distant metastatic sites.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of myeloid-derived immunosuppresive and pro-tumorigenic cells that suppress T cell function. They expand in number in pathological conditions and interact with other innate and adaptive immune cells to modulate their function. They universally express CD11b, but can be further categorized in both mice and humans on the basis of expression of additional markers into granulocytic and monocytic lineages.

Macrometastases

The outgrowth of micrometastases that are histologically or radiologically detectable.

Type I interferon

A class II α-helical cytokine essential for protection against viral infections that also plays important roles in bacterial infections, shock, autoimmunity and cancer.

Leukotrienes

Products of the eicosanoid metabolism of leukocytes that mediate inflammation and allergic reactions.

Dormancy

A latent state in which individual tumour cells are quiescent and reversibly arrested in G0 phase of the cell cycle.

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Peinado, H., Zhang, H., Matei, I. et al. Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer 17, 302–317 (2017). https://doi.org/10.1038/nrc.2017.6

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