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Metastasis

Dissemination and growth of cancer cells in metastatic sites

Key Points

  • Metastasis consists of a series of sequential steps, all of which must be successfully completed. These include shedding of cells from a primary tumour into the circulation, survival of the cells in the circulation, arrest in a new organ, extravasation into the surrounding tissue, initiation and maintenance of growth, and vascularization of the metastatic tumour.

  • Some types of tumour show an organ-specific pattern of metastasis. Both 'seed' (the cancer cell) and 'soil' (factors in the organ environment) contribute to this organ specificity.

  • Mechanical factors influence the initial fate of cancer cells after they have left a primary tumour. Blood-flow patterns from the primary tumour determine which organ the cells travel to first. There, the relative sizes of cancer cells and capillaries lead to the efficient arrest of most circulating cancer cells in the first capillary bed that they encounter.

  • After cells have arrested in an organ, their ability to grow is dictated by molecular interactions of the cells with the environment in the organ.

  • Metastasis is an inefficient process. In vivo videomicroscopy and cell-fate analysis have led to the conclusion that early steps in metastasis are completed very efficiently. By contrast, later steps in the process are inefficient. Metastatic inefficiency is due primarily to the regulation of cancer-cell growth in secondary sites.

  • Metastases can occur many years after primary cancer treatment. Tumour dormancy might be due to pre-angiogenic micrometastases that subsequently acquire the ability to become vascularized, or solitary cells that persist for an extended period of time without division in a secondary site. These cells would be resistant to current cancer therapies that target actively dividing cells.

  • Because growth of metastases is a primary determinant of metastatic outcome, the growth phase of the metastatic process is a promising therapeutic target. Treatments that target the specific 'seed–soil' compatibility that results in organ-specific metastatic growth would be especially useful.

Abstract

Metastases, rather than primary tumours, are responsible for most cancer deaths. To prevent these deaths, improved ways to treat metastatic disease are needed. Blood flow and other mechanical factors influence the delivery of cancer cells to specific organs, whereas molecular interactions between the cancer cells and the new organ influence the probability that the cells will grow there. Inhibition of the growth of metastases in secondary sites offers a promising approach for cancer therapy.

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Figure 1: The metastatic process.
Figure 2: Vascular flow patterns and corresponding movement of cancer cells arising in different organs.
Figure 3: Cancer and normal cells arrest in the circulation.
Figure 4: Chemokines can influence organ-specific metastatic growth of cancer cells.
Figure 5: Activation of RAS signalling pathways can protect small metastases and promote their early growth.

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Acknowledgements

We apologize to those authors whose work we could not cite directly due to space constraints. The authors acknowledge the contributions of current and former laboratory members to the work discussed in this review. We thank especially G. Naumov and H. Varghese for their creativity and expertise in helping to develop the figures. The authors' research summarized here is supported by the Canadian Institutes of Health Research, the US Department of Defense Breast Cancer Research Program and the Lloyd Carr–Harris Foundation.

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Correspondence to Ann F. Chambers.

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DATABASES

Cancer.gov

bone cancer

brain cancer

breast cancer

colorectal cancer

liver cancer

lung cancer

melanoma

prostate cancer

stomach cancer

testicular cancer

LocusLink

actin

BRMS1

CCL21

CCL27

CCR7

CCR10

CXCR4

epidermal growth-factor receptor

HRAS

IL-1α

IL-6

insulin-like growth-factor 1

MAPK

MMPs

parathyroid hormone-related protein

RAS

TGF-α

TGF-β

TIMP1

Medscape DrugInfo

Glivec

Herceptin

FURTHER INFORMATION

Ann Chambers' lab

PBS Nova show 'Cancer Warrior'

Glossary

ANGIOGENESIS

The formation of new blood vessels that are needed for growth of primary tumours and metastases that are beyond a minimal size.

ORTHOTOPIC INJECTION

Injection of cancer cells into the 'correct' anatomical site for primary tumour growth — for example, mammary fat pad for breast cancer cells.

HAEMATOGENOUS METASTASIS

Metastasis via the bloodstream.

ISCHAEMIA

A reduction in local tissue oxygen levels due to inadequate blood supply.

VASCULAR MIMICRY

The formation of blood-flow channels that lack an endothelium, which might be formed by tumour cells in some tumours.

TRASTUZUMAB

(Herceptin). A humanized monoclonal antibody against the ERBB2 receptor that is used to treat breast cancers that are shown to be positive for this receptor.

IMATINIB

(Glivec). A small-molecule therapy that targets the Abelson leukaemia (ABL) kinase. It is used to treat patients with chronic myelogenous leukaemia.

FARNESYLTRANSFERASE INHIBITORS

Therapeutic agents that target a specific post-translational modification — farnesylation — which allows the RAS protein to attach to the inner cell membrane and which is necessary for RAS-mediated signalling.

BISPHOSPHONATES

A class of compounds that inhibit the bone-resorptive activity of osteoclasts, and are used to treat osteoporosis. They might also be useful in the treatment and prevention of metastases growing in the bone.

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Chambers, A., Groom, A. & MacDonald, I. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2, 563–572 (2002). https://doi.org/10.1038/nrc865

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