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  • Review Article
  • Published:

Microenvironmental regulation of metastasis

Key Points

  • The tumour microenvironment has a major role in modulating the metastatic capacity of most cancers. Seminal experiments indicated that certain microenvironments can suppress malignancy. However, in most tumours these restraints are overcome such that the tumour now exploits the supporting cells to increase metastatic potential.

  • Primary and metastatic tumours cause systemic perturbations that often involve mobilizing bone marrow-derived cells that home to the tumour and promote tumour progression, malignant cell escape and survival, and growth at the secondary site.

  • Primary tumours recruit macrophages to their microenvironment and these cells increase metastatic potential by increasing tumour cell migration, invasion and intravasation. They also increase angiogenesis and thereby increase the targets for metastatic cell escape.

  • Myeloid cell-derived suppressor cells suppress immune responses to newly displayed tumour antigens and promote the metastatic potential of the tumour.

  • Mesenchymal stem cells can differentiate into many different cell types and are recruited to primary tumours where they enhance metastasis.

  • Tumour cells are protected in their travels through the circulation, particularly by platelets. These platelets together with the tumour cells activate the clotting system such that microthrombi form that help tumour cells lodge in target tissues.

  • The formation of metastases has many rate-limiting steps including survival in the distant organ, extravasation and the establishment of persistent growth. Microenvironmental cues are important at all steps and the recruitment of a variety of bone marrow-derived cells including endothelial progenitors and myeloid cell-derived cells is crucial for these processes.

Abstract

Metastasis is a multistage process that requires cancer cells to escape from the primary tumour, survive in the circulation, seed at distant sites and grow. Each of these processes involves rate-limiting steps that are influenced by non-malignant cells of the tumour microenvironment. Many of these cells are derived from the bone marrow, particularly the myeloid lineage, and are recruited by cancer cells to enhance their survival, growth, invasion and dissemination. This Review describes experimental data demonstrating the role of the microenvironment in metastasis, identifies areas for future research and suggests possible new therapeutic avenues.

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Figure 1: The primary tumour microenvironment.
Figure 2: The invasive microenvironment.
Figure 3: The fate of tumour cells in the metastatic microenvironment.

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Acknowledgements

We apologize to the many authors whose work we could not cite owing to space constraints. Research in the authors' laboratories is supported by the National Cancer Institute (J.A.J. and J.W.P.), the Emerald Foundation, the Sidney Kimmel Foundation and the Rita Allen Foundation (J.A.J.). J.A.J. is a Geoffrey Beene Junior Faculty Chair and J.W.P. is the Louis Goldstein Swan Chair in Women's Cancer Research.

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Glossary

Extracellular matrix

(ECM). The matrix laid down by cells upon which they adhere and move. It consists of many components including laminin and fibronectin, which can influence tumour cell behaviour. ECM is also a rich source of growth factors that can be released upon proteolytic degradation and which in many cases increase metastasis.

Myeloid cell-derived suppressor cell

(MDSC). MDSCs are immature cells of the myeloid lineage that suppress T-cell responses to tumours and also enhance metastasis in the MMTV–PyMT model.

Mesenchymal stem cell

(MSC). MSCs are multipotent cells that differentiate into osteoblasts, chondrocytes adipocytes, and other cells of mesenchymal origin that can be recruited to tumours and increase metastasis.

Tumour-associated macrophage

(TAM). TAMs are cells recruited to the tumour microenvironment where they are educated to perform tasks that enhance metastasis, such as stimulating tumour cell migration, invasion and intravasation.

MMTV–PyMT breast cancer model

Mammary cancers are induced in mice by the mammary-restricted expression of the polyoma virus middle T oncoprotein from the mouse mammary tumour virus (MMTV) long terminal repeat promoter. This model progresses through stereotypical stages of tumour progression and metastasizes to the lung, reminiscent of those seen in human breast cancer.

Immature myeloid cells

(iMC). Myeloid cells without definitive macrophage characteristics (CD11b+CD34+F4/80GR1) that stimulate collective tumour cell invasion in mouse models of colon cancer.

Multiphoton intravital imaging

Visual imaging of tumours in live animals using infrared light and the quantum phenomena of two low energy photons when focused together having sufficient energy to elicit a fluorescent event. This enables imaging in real time of fluorescently tagged cells inside tumours.

Second harmonic resonance

A quantum mechanical phenomena that enables the visualization by multi-photon microscopy of repeating structures such as collagen I in the blue channel. This enables visualization of the tumour microenvironment in real time in live animals.

Pre-metastatic niche

A proposed environment induced by the primary tumour in secondary organs that enhances metastatic cell seeding and that is populated by bone marrow-derived cells.

Experimental metastasis model

This is a xenograft model of metastasis in which malignant cells are introduced into experimental animals usually by intravenous injection but also through the spleen or heart. It is usually used to study lung metastases.

Toll-like receptors

A class of receptors expressed particularly by myeloid cells that recognize foreign substances and have evolved to be a pattern recognition system to detect invading pathogens. Their activation triggers, among others, the NF-κB signalling pathway, which is involved in metastasis in several tumour types.

Endothelial progenitor cell

(EPC). EPCs are bone marrow-derived cells that are recruited to the nascent tumour vasculature, and that have been shown to be important for angiogenesis and metastasis in certain animal cancer models.

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Joyce, J., Pollard, J. Microenvironmental regulation of metastasis. Nat Rev Cancer 9, 239–252 (2009). https://doi.org/10.1038/nrc2618

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