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Engineering the pre-metastatic niche

Nature Biomedical Engineering volume 1, Article number: 0077 (2017) Cite this article

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Abstract

The pre-metastatic niche — the accumulation of aberrant immune cells and extracellular-matrix proteins in target organs — primes the initially healthy organ microenvironment and renders it amenable for subsequent colonization by metastatic cancer cells. By attracting metastatic cells, mimics of the pre-metastatic niche offer both diagnostic and therapeutic potential. However, deconstructing the complexity of the niche by identifying the interactions between cell populations as well as the mediatory roles of the immune system, soluble factors, extracellular-matrix proteins and stromal cells has proved challenging. Experimental models are needed to recapitulate niche-population biology in situ and to mediate in vivo tumour-cell homing, colonization and proliferation. In this Review, we outline the biology of the pre-metastatic niche and discuss advances in the engineering of niche-mimicking biomaterials that regulate the behaviour of tumour cells at an implant site. Such ‘oncomaterials’ offer strategies for the early detection of metastatic events, the inhibition of the formation of the pre-metastatic niche and the attenuation of metastatic progression.

The pre-metastatic niche consists of a complex microenvironment that includes inflammatory immune cells, stromal cells, extracellular matrix (ECM) proteins, tumour-secreted exosomes and homing factors. Tumour-secreted factors and tumour-derived exosomes (Fig. 1a) mobilize and recruit bone-marrow-derived cells (BMDCs) to niches in secondary organs (Fig. 1b), where they interact with the local stroma to create permissive and attractive sites for metastatic cells12 (Fig. 1c,d). In fact, the arrival of the vascular endothelial growth factor receptor 1 (VEGFR1)-positive BMDCs to the pre-metastatic site precedes and predicts the arrival of tumour cells13. Tumour-secreted factors also increase the proliferation of fibroblast-like stromal cells, which contribute to the local deposition of fibronectin. VEGFR1+ niche cells express integrin α4β1, which binds to fibronectin and allows the stromal cells to assemble at the site13. Other BMDC populations that have also been implicated in the formation of the pre-metastatic niche include CD11b+ myeloid cells, myeloid-derived suppressor cells (MDSCs), neutrophils, tumour-associated macrophages and regulatory T cells14–21. Tumour-secreted factors and exosomes can also directly modify the host stroma to establish a supportive microenvironment22,23. In addition, fibroblasts, endothelial cells and lung epithelial cells have been associated with the establishment of the pre-metastatic niche via secretion of inflammatory cytokines and chemokines15,18,24. The compelling evidence that pre-metastatic niche formation is required for metastases has prompted biologists and biomedical scientists to elucidate the individual and combinatorial cues that affect cell-niche behaviour, with the ultimate aim of developing effective therapeutic interventions.

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Figure 1: Formation of the pre-metastatic niche.
Figure 2: MDSC and metastatic-cell trafficking in a breast-tumour-bearing mouse implanted with a biomaterial scaffold.
Figure 3: Biomaterials loaded with soluble factors and exosomes mediate tumour-cell homing.
Figure 4: Modelling organotropism by using ECM- or BMSC-functionalized scaffolds.
Figure 5: Proposed use of engineered mimics as oncomaterials.

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Acknowledgements

We thank K. Aguado for figure illustrations. B.A.A. and G.G.B. acknowledge the support of a National Science Foundation Graduate Research Fellowship. Financial support for this work was provided by the National Institutes of Health and the National Cancer Institute (R01 CA173745).

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Author notes

  1. Brian A. Aguado and Grace G. Bushnell: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Engineering, Northwestern University, Evanston, 60208, Illinois, USA

    Brian A. Aguado

  2. Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, 60611, Illinois, USA

    Brian A. Aguado

  3. Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, 48109-2099, Michigan, USA

    Grace G. Bushnell & Lonnie D. Shea

  4. Department of Chemical and Biological Engineering, University of Alabama, Tuscaloosa, 35487, Alabama, USA

    Shreyas S. Rao

  5. Departments of Surgery, Division of Surgical Oncology, Pathology and Biomedical Engineering, University of Michigan, 3303 Cancer Center, 1500 East Medical Center Drive, Ann Arbor, 48105, Michigan, USA

    Jacqueline S. Jeruss

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  1. Brian A. Aguado
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  2. Grace G. Bushnell
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Contributions

B.A.A., G.G.B. and L.D.S. wrote and edited the manuscript. B.A.A. prepared the figures. B.A.A. and G.G.B. prepared the tables. S.S.R. and J.S.J. edited and advised on the manuscript.

Corresponding authors

Correspondence to Jacqueline S. Jeruss or Lonnie D. Shea.

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The authors declare no competing financial interests.

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Aguado, B., Bushnell, G., Rao, S. et al. Engineering the pre-metastatic niche. Nat Biomed Eng 1, 0077 (2017). https://doi.org/10.1038/s41551-017-0077

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