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  • Review Article
  • Published:

Targeting metastasis

Nature Reviews Cancer volume 16, pages 201–218 (2016)Cite this article

Subjects

Key Points

  • Metastases, and complications of their treatment, are significant causes of patient morbidity and mortality. Drugging metastasis pathways represents a potential new therapeutic opportunity.

  • Most preclinical experiments demonstrate partial prevention of metastasis rather than shrinkage of existing lesions. These data would apply to the prevention of an initial metastasis in a high-risk patient, or the prevention of additional metastases in patients with treated, limited metastatic disease.

  • Metastatic colonization represents the best 'open' therapeutic window in metastasis. It is the progressive outgrowth of tumour cells in a distant location, influenced by tumour cell signalling and interaction with a modified microenvironment (the formation of a premetastatic niche, alterations in the extracellular matrix and stromal cells, innate and T cell immunity and altered vascular supply).

  • Denosumab, a monoclonal antibody that blocks the receptor activator of NF-κB ligand (RANKL; which is involved in the bone metastatic process), provides evidence that metastasis can be successfully drugged. Denosumab clinical trials used an interesting primary end point — skeletal-related events (SREs).

  • The development of metastasis prevention agents may be hindered by their cytostatic nature, which will not result in shrinkage of established metastatic lesions (responses) in early clinical testing. New clinical trial designs for primary and secondary metastasis prevention are needed to lower the time, cost and cohort sizes of traditional adjuvant trials.

  • It is likely that a single metastasis-preventive agent will not be maximally effective. As for HIV, a combination of distinct classes of drugs, given early and continuously, will be key.

Abstract

Tumour metastasis, the movement of tumour cells from a primary site to progressively colonize distant organs, is a major contributor to the deaths of cancer patients. Therapeutic goals are the prevention of an initial metastasis in high-risk patients, shrinkage of established lesions and prevention of additional metastases in patients with limited disease. Instead of being autonomous, tumour cells engage in bidirectional interactions with metastatic microenvironments to alter antitumour immunity, the extracellular milieu, genomic stability, survival signalling, chemotherapeutic resistance and proliferative cycles. Can targeting of these interactions significantly improve patient outcomes? In this Review preclinical research, combination therapies and clinical trial designs are re-examined.

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Figure 1: Few improvements in 5-year survival for cancer patients initially diagnosed with metastatic disease.
Figure 2: Functional interactions between tumour cells and the metastatic microenvironment in colonization.
Figure 3: A wealth of mechanistic translational targets in metastasis to the brain.
Figure 4: Meaningful incorporation of preclinical metastasis models into drug development.

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Authors and Affiliations

  1. Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, 20892, Maryland, USA

    Patricia S. Steeg

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  1. Patricia S. Steeg
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Correspondence to Patricia S. Steeg.

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The author has received research grants from Sanofi and Genentech.

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Glossary

Standard of care

(SOC). Also known as best practice, treatment for each type and stage of cancer that is accepted in general practice by health care professionals, and iterated in guidelines such as those of the US National Comprehensive Cancer Network.

Metastatic colonization

The progressive growth of a lesion in a foreign location.

Invasion

Cancer cells traverse normal tissues in groups or as single cells, using reversible adhesion, proteolytic destruction and motility.

Genomic instability

A state of high frequency of mutations in a cell, including nucleic acid sequences, chromosomal rearrangements and aneuploidy.

Localized disease

In the clinic, disease that is limited to the tissue or organ in which it began.

Regional disease

Cancer that has grown beyond the original tumour and spread to nearby lymph nodes or tissues.

Overall survival

(OS). The length of time, either from disease diagnosis or the beginning of treatment, until death.

Progression-free survival

(PFS). A metric of patient response to therapy, measured from the time of treatment initiation or clinical trial enrolment until either detectable lesions increase, based on standard measurement criteria, or the patient dies.

Adjuvant trials

Clinical trials to test whether an additional treatment after primary therapy will lower the risk of cancer recurrence.

Pathological complete response

(pCR). The absence of residual invasive tumour cells by microscopic examination of resected tissue after neoadjuvant therapy.

Neoadjuvant trial

In cancer, a trial testing a potential therapy before the 'definitive' treatment, such as primary tumour surgery.

Half-life

In pharmacology, the time it takes for a compound to fall to one-half of its initial steady-state level.

G-protein-coupled receptors

A family of integral membrane receptors that sense extracellular signals and activate intracellular signalling by binding to G proteins.

Focal adhesion kinase

(FAK). Cytosolic non-receptor protein kinase typically linking extracellular matrix with the actin network, regulating cell adhesion, viability and spreading.

Stable disease

A metric of patient response to therapy, in which measurable lesions are neither increasing nor decreasing based on standard measurement criteria.

Maximum tolerated dose

(MTD). The highest dose of a drug or treatment that does not cause unacceptable side effects.

Extravasation

In metastasis, the movement of tumour cells out of the circulatory system into surrounding tissues.

Stem or tumour-initiating cell

A cell found within a cancer that is tumorigenic and can differentiate into one of several cell types found within the tumour.

Anoikis

A form of programmed cell death induced by anchorage-dependent cells detaching from an extracellular matrix.

Neoantigens

Peptides absent from the normal genome, caused by somatic mutations.

Myofibroblasts

Cells with attributes of fibroblasts and smooth muscle cells that are activated to participate in wound repair.

Mismatch repair

A form of DNA repair that corrects erroneous misincorporation of bases during replication, and other insertions, deletions and DNA damage.

Double strand break repair

Repair of hazardous lesions in which both strands of DNA are broken, by non-homologous end joining or homologous recombination repair.

Nonspecific immunity

Also called innate immunity, host responses to pathogens or tumour cells that do not provide long-term memory or protection.

Adaptive immunity

Part of the immune system by which memory is acquired after an initial response to a specific antigen.

Natural killer (NK) cells

Lymphocytes that are cytotoxic for virally infected or tumour cells, without the need for major histocompatibility complex (MHC) and T cell receptor signalling.

Minimal residual disease

In leukaemia, a low level of tumour cells or their products in patients apparently treated successfully, detectable only with molecular markers.

Astrocytes

Star-shaped cells in the brain and spinal cord that maintain the blood–brain barrier, provide nutrients, maintain ion balance and assist in injury repair.

Microglia

Resident macrophage-like cells of the brain and spinal cord.

Neuroinflammatory response

Inflammation of the central nervous system characterized by activation of endothelial and glial cells, cytokines and oedema.

α-particle

A particle for radiation therapy consisting of a helium nucleus with high energy and low penetrance.

Xenografts

In cancer, cells or tissues transplanted from one species to another, often human cancer cells into immunodeficient mice.

Genetically engineered mouse (GEM) models

Mouse models in which the genome has been altered, including transgenes and targeted mutations (knockouts or knockins).

Patient-derived xenografts

(PDXs). Patient tumour tissues implanted directly into immunodeficient mice.

Micrometastases

Metastatic lesions that are too small for conventional detection.

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Steeg, P. Targeting metastasis. Nat Rev Cancer 16, 201–218 (2016). https://doi.org/10.1038/nrc.2016.25

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