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Learning therapeutic lessons from metastasis suppressor proteins

Nature Reviews Cancer volume 9, pages 253–264 (2009)Cite this article

Key Points

  • Metastasis accounts for the preponderance of morbidity and mortality in cancer, and accumulating evidence suggests that dissemination of tumour cells may occur earlier in the development of cancer than previously appreciated.

  • Metastasis is regulated either positively or negatively by proteins that promote steps in the metastatic cascade or those that suppress them.

  • Metastasis suppressor genes encode proteins that prevent or reduce the development of metastases in vivo, without simultaneously affecting primary tumour growth. This is in contrast to tumour suppressors, which affect primary tumorigenesis.

  • Metastasis suppressor proteins are lost primarily during cancer progression and not during transformation.

  • Until recently, relatively few metastasis suppressor genes had been characterized. However, expanding genomic technology has made possible in recent years the description of many metastasis suppressor genes impinging on a wide variety of cellular processes.

  • Although metastasis suppressor genes have been shown to work at multiple steps in the process of metastasis, several have been recently demonstrated to specifically suppress the colonization step of metastasis, the process by which solitary or small clusters of tumour cells living in a second organ site (micrometastases) grow to form clinically apparent and lethal macrometastases.

  • Recent work has shown techniques that restore metastasis suppressor function. These include re-expression of the gene from the endogenous locus or by exogenous gene therapy, direct administration of the protein itself and targeting important metastasis mediators downstream of the suppressor that are reciprocally induced with metastasis suppressor protein losses.

Abstract

Metastasis suppressor proteins regulate multiple steps in the metastatic cascade, including cancer cell invasion, survival in the vascular and lymphatic circulation, and colonization of distant organ sites. Understanding the biology of metastasis suppressors provides valuable mechanistic insights that may translate to therapeutic opportunities. Several reports have explored novel strategies for restoring metastasis suppressor function, including gene transfer, induction of previously suppressed gene expression and exogenous administration of gene product. Pathways activated downstream of metastasis suppressor loss can also be targeted. Although none of these strategies are yet in routine clinical use, several are being tested preclinically and in clinical trials.

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Figure 1: Metastasis suppressor genes and steps in the metastatic cascade in human cancer.
Figure 2: Strategies for restoring metastasis suppressor function.
Figure 3: Targeting key genes downstream of metastasis suppressors.
Figure 4: Targeting metastasis suppressor signatures through the Connectivity Map and COXEN (Coexpression Extrapolation).

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Acknowledgements

Work was supported by National Institutes of Health grant CA075115 to D.T. The authors wish to thank R. Horwitz, M. Schwartz of the University of Virginia, P. Steeg of the National Cancer Institute, and D. Welch of the University of Alabama at Birmingham for their help, suggestions and comments on the manuscript.

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  1. Department of Molecular Physiology and Biological Physics, and The Paul Mellon Urologic Cancer Institute University of Virginia Health System, Charlottesville, 22908, Virginia, USA

    Steven Christopher Smith & Dan Theodorescu

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  1. Steven Christopher Smith
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  2. Dan Theodorescu
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Correspondence to Dan Theodorescu.

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DATABASES

ClinicalTrials.gov

NCT00134056

NCT00577122

National Cancer Institute Drug Dictionary

atrasentan hydrochloride

dexamethasone

etoposide

medroxyprogesterone acetate

MPA

FURTHER INFORMATION

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Glossary

Metastatic colonization

The process by which disseminated tumour cells, present as single or small clusters of cells in a second parenchyma (micrometastasis), grow to form a clinically detectable metastatic nodule (macrometastasis).

Epstein–Barr virus

(EBV). EBV is a herpes family virus that commonly causes infectious mononucleosis in humans. Infection with EBV has been implicated in Burkitt's lymphoma and nasopharyngeal carcinoma, and may also be involved in the pathogenesis of other tumours.

Glucocorticoid response pathway

This nuclear hormone receptor pathway directs the regulation of genes involved in metabolism and immune function. Transcription by the glucocorticoid receptor is ligand-induced by glucocorticoid steroid hormones.

Metronomic chemotherapy

Administration of chemotherapeutic drugs at comparatively low doses on a frequent or continuous schedule, with no extended interruptions, in contrast to traditional maximum tolerated dose chemotherapy.

TRAMP

An autochthonous transgenic mouse model of prostate cancer. Various stages of progressive prostate disease can be observed in TRAMP mice, with focal adenocarcinomas developing between 10 and 20 weeks of age with 100% frequency.

Mediastinal lymph node

Lymphatic tissue occurring in a central region of the chest between the lungs and bordered by the thoracic inlet above and the diaphragm below, where lung and other cancers frequently metastasize.

Orthotopic xenograft

Establishment of a tumour by injecting human cells into the same rodent organ from which the human tumour was derived.

Heterotopic xenograft

Establishment of a tumour by injecting human cells into a different rodent organ than that from which the human tumour was derived, often for technical reasons.

Histone deacetylases

Enzymes that regulate chromatin structure and function through the removal of the acetyl group from the lysine residues of core nucleosomal histones, generally repressing transcription.

DNA methyltransferases

Enzymes that catalyse transfer of a methyl group to cytosines in DNA, generally repressing transcription.

Anoikis

Cell death in response to loss of matrix attachments.

Osmotic pump

Generally small implantable pumps that use a salt concentration gradient to draw in interstitial fluid and generate pressure to expel a drug in a regulated fashion.

Synthetic lethal

Describes a genetic phenomenon in which the combination of two otherwise non-lethal mutations or molecular lesions results in an unviable cell. In the case of drug discovery, the pharmaceutical agent, otherwise non-toxic, substitutes for one of these lesions and becomes lethal only in the presence of the second molecular lesion.

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Smith, S., Theodorescu, D. Learning therapeutic lessons from metastasis suppressor proteins. Nat Rev Cancer 9, 253–264 (2009). https://doi.org/10.1038/nrc2594

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