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  • Review Article
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Metastasis suppressors alter the signal transduction of cancer cells

Nature Reviews Cancer volume 3, pages 55–63 (2003)Cite this article

Key Points

  • Metastasis-suppressor genes are identified by their reduced expression in highly metastatic, compared with tumorigenic but poorly or non-metastatic, tumour cells. Following re-expression of a metastasis-suppressor gene in a tumour cell line, in vivo metastasis is inhibited, without a significant reduction in tumorigenicity.

  • Eight metastasis-suppressor genes have been confirmed so far. They affect many aspects of signal transduction, including pathways that are involved in invasion, growth-factor-receptor signalling, the mitogen-activated protein kinase pathway, cell–cell communication and transcription.

  • Many metastasis suppressors affect metastatic colonization — the final outgrowth of tumour cells after they have arrived at a distant site — by non-angiogenic means. Re-expression of metastasis-suppressor expression in micrometastatic tumour cells might halt their further progression with a clinical benefit.

  • The loss of metastasis-suppressor expression in metastatic lesions indicates that several aspects of signal transduction are compromised, compared with non-metastatic tumour cells. Preclinical drug testing based on primary tumour size in mice might not reflect these important differences, and metastatically competent model systems might predict clinical efficacy more accurately.

Abstract

Tumour metastasis is a significant contributor to death in cancer patients. Eight metastasis-suppressor genes that reduce the metastatic propensity of a cancer cell line in vivo without affecting its tumorigenicity have been identified. These affect important signal-transduction pathways, including mitogen-activated protein kinases, RHO, RAC and G-protein-coupled and tyrosine-kinase receptors. So how might we use this knowledge to improve the treatment of patients with cancer?

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Figure 1: Metastasis is a complex, multistep process.
Figure 2: Metastasis suppressors affect all three arms of the MAPK signalling pathway.
Figure 3: The therapeutic window in antimetastasis drug development.

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  1. Women's Cancers Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, 20892, Maryland, USA

    Patricia S. Steeg

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DATABASES

LocusLink

BRMS1

CRMP1

CRSP3

EGF

EGFR

hOT7T175

KAI1

KiSS1

MAPK

MEK

MKK4

MYC

NM23

RAS

RB

TGF-β

VDUP1

Glossary

METASTASIS ASSAYS

In spontaneous metastasis assays, the tumour cells are inoculated either subcutaneously or orthotopically in animals, and spontaneous metastases from this primary site to distant locations are monitored. In experimental metastasis assays, tumour cells are injected into the bloodstream (for example, intravenously for lung metastasis, into the left heart ventricle for bone metastases and into the portal vein for liver metastases), thereby circumventing the first steps in the metastatic process.

EXTRACELLULAR MATRIX

A complex, three-dimensional network of very large macromolecules that provides contextual information and an architectural scaffold for cellular adhesion and migration.

EXTRAVASATION

The passage from blood or lymph vessel into tissue.

DIFFERENTIAL DISPLAY

A gel-based technique that is used to survey genome-wide levels of transcription.

SUBTRACTIVE HYBRIDIZATION

A technique that is used for identifying differentially expressed transcripts between two sources. cDNA from one source is hybridized to mRNA from another source to remove comparably expressed transcripts, and the resulting differentially expressed cDNAs are separated by chromatography.

MICROARRAY

An array of polymerase chain reaction products (corresponding to either genomic or cDNA sequence) that is deposited onto solid glass slides.

SERIAL ANALYSIS OF GENE EXPRESSION

(SAGE). A technique for the identification and quantitation of transcripts from two sources, including differentially expressed genes. SAGE is based on the isolation of short tags from a defined location within a transcript, which are sequenced as concademers and quantitated.

SCAFFOLD PROTEIN

Scaffolds are thought to provide docking sites for pathway proteins, to participate in intracellular re-localization, and to influence the specificity and duration of signalling.

EPITHELIAL–MESENCHYMAL TRANSITION

The conversion from an epithelial to a mesenchymal phenotype, which is a normal component of embryonic development. In carcinomas, this transformation results in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.

GLEASON GRADE

The 'gold standard' for grading prostate cancer, which is used by pathologists worldwide. This system involves assessing both the predominant and secondary pattern of gland formation within a prostate sample. The sample is scored to create a Gleason 'sum', ranging from 2 to 10, with the highest number indicating the most aggressive cancer. Patients with a Gleason sum of less than 6 typically respond well to therapy, whereas patients with a Gleason sum of greater than 7 usually have poor outcomes.

INTEGRINS

A family of more than 20 heterodimeric cell-surface extracellular-matrix receptors. They connect the structure of the extracellular matrix with the cytoskeleton and can transmit signalling information bidirectionally.

GAP JUNCTIONS

Gap junctions are membrane-spanning channels that are composed of connexin (Cx) proteins that allow the passage of small (1,000 molecular weight) signalling molecules between cells. Homotypic gap junctions exist between the same cell type and heterotypic gap junctions exist between distinct cell types.

LAMELLIPODIA

Thin, sheet-like cell extensions that are found at the leading edge of crawling cells or growth cones.

PARACRINE FACTORS

A form of bioregulation in which a secretion produced by one cell type in a tissue diffuses through the tissue and affects another cell type in the same tissue.

PHARMACOKINETIC

The study of the time course of a drug and its metabolites in the body after administration by any route.

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Steeg, P. Metastasis suppressors alter the signal transduction of cancer cells. Nat Rev Cancer 3, 55–63 (2003). https://doi.org/10.1038/nrc967

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