Cancer Letters

Cancer Letters

Volume 198, Issue 1, 30 July 2003, Pages 1-20
Cancer Letters

Mini Review
Metastasis suppressor pathways—an evolving paradigm

https://doi.org/10.1016/S0304-3835(03)00304-5Get rights and content

Abstract

A greater understanding of the processes of tumor invasion and metastasis, the principal cause of death in cancer patients, is essential to determine newer therapeutic targets. Metastasis suppressor genes, by definition, suppress metastasis without affecting tumorigenicity and, hence, present attractive targets as prognostic or therapeutic markers. This short review focuses on those twelve metastasis suppressor genes for which functional data exist. We also outline newly identified genes that bear promising traits of having metastasis suppressor activity, but for which functional data have not been completed. We also summarize the biochemical mechanism(s) of action (where known), and present a working model assembling potential metastasis suppression pathways.

Introduction

Despite better local treatments for cancer using surgery and radiotherapy, the clinical challenge remains combating systemic metastatic disease. Metastasis via the lymphatics, hematogenous system, or through the body cavities results in significant morbidity. Not only must cells leave the primary tumor, but they must also proliferate at the secondary site [1], [2]. Metastasis culminates the evolution of tumor cells whereby a tumor's composition collectively becomes progressively more malignant [3], [4]. Tumor progression results from genetic instability coupled with selection of subpopulations of cells [3]. Eventually some cells accumulate sufficient capacity to dissociate and spread. Depending on whether the mutations occur early or late in tumor progression determines proportions of metastatic cells within tumors of a given size. This conclusion can be appreciated when interpreted in light of classical studies of Luria and Delbrück [5]. Selection of metastatic cells varies with the nature of a tumor as well as between patients. Although it is generally true that larger tumors are more likely to spread, size does not necessarily correlate with metastatic capacity [6], [7]. In addition to accumulating mutations, there are exogenous signals that can influence metastatic efficiency.

Section snippets

Host–tumor interactions in neoplastic advancement

Tumorigenicity and metastasis are distinct, but interrelated phenotypes. Tumorigenicity is necessary, but not sufficient, for metastasis. In part, metastasis is also determined, to a great extent, by tumor–host interactions. That is, the microenvironment participates in the induction and selective proliferation of malignant cells [8].

How does the host environment at the metastatic site affect the metastatic behavior of cells? The relationship is reciprocal, and reflects both host endocrine and

Stochastic and selective aspects of cancer metastasis

In order to metastasize, cells must complete a series of sequential steps, each of which is rate-limiting. Following primary tumor growth (including establishment of neovasculature or primitive vascular channels [12], [13]), tumor cells detach and enter a circulatory compartment. The tumor vasculature is immature and incontinent [14], providing easier access to the vasculature. Once there, tumor cells can remain as single cells or form homo- or hetero-typic emboli but they must survive shear

NM23

By screening cDNA libraries of matched metastatic/non-metastatic K1735 murine melanoma cell lines by differential hybridization, ‘non-metastatic clone 23′ gene, was identified as the first metastasis suppressor gene [71]. Enforced expression in cell lines of diverse cellular origin, suppressed metastasis without altering tumor growth (reviewed in Ref. [72]). The product of the human ortholog, NM23-H1, was identified to be a nucleoside diphosphate kinase (NDPK). NDPKs catalyze the

KAI-1 (CD82)

KAI-1 was identified in prostate cancer cell lines (Dunning rat AT3.1 and AT6.1) that were suppressed for metastasis following introduction of human chromosome 11 [81]. Positional cloning mapped KAI1 to 11p11.2 [82].

KAI-1 is an evolutionarily conserved member of the tetraspanin transmembrane protein family of leukocyte surface glycoproteins. It is the only tetraspanin with an internalization sequence at the C-terminus [83]. Although no allelic losses were seen, expression in the epithelial

KISS-1, TXNIP and CRSP3

KISS-1 was identified as a melanoma metastasis suppressor using subtractive hybridization to compare chromosome 6 metastasis-suppressed melanoma hybrids with metastatic parental cells [68], [95]. Surprisingly, the KISS-1 gene mapped to the long arm of chromosome 1 [68]. Enforced expression of KISS-1 suppressed metastasis of melanoma and breast carcinoma [96]. A deletion variant (neo6qdel; neo6del(q16.3-q23)) of neomycin-tagged human chromosome 6 did not suppress metastasis and did not express

TIMPs

Tissue inhibitors of metalloproteinases (TIMPs) are a family of secreted proteins that selectively, but reversibly, inhibit metalloproteinases (MMPs) with 1:1 stoichiometry [10], [116], [117]. Modulation of MMP and TIMP levels is critical to the control of extravasation and tumor-induced angiogenesis, processes that involve basement membrane degradation. Paradoxically, TIMP-1, 2 and 4 have an anti-apoptotic effect, while TIMP-3 induces apoptosis. TIMP-2, in concert with MT1-MMP can bind to and

Cadherins

Cadherins are transmembrane glycoproteins responsible for Ca+2-dependent cell adhesion. Although the family is widely expressed, E-cadherin (gene designation CAD1) is expressed on epithelial cells. A precursor protein (135 kDa) is processed to a mature 120 kDa form. The extracellular N-terminus is critical for homophilic Ca+2-dependent cell–cell adhesion. The C-terminus interacts with β-catenin to mediate actin binding. E-cadherin/β-catenin binding sequesters the latter, blocking nuclear

MKK4

MKK4/JNKK1/SEK1 is a mitogen-activated protein kinase, which transduces signals from MEKK1 to stress-activated protein kinase/JNK1 and p38MAPK [59]. MKK4 transmits stress signals to nuclear transcription factors that mediate proliferation, apoptosis and differentiation. Portions of the MKK4 gene (on chromosome 17) were deleted or altered in cancer cell lines that displayed defects in signal transduction from MEKK1 [141]. Suppression of prostate cancer cell metastasis was brought about by

BRMS1

Following upon MMCT studies, Seraj et al., performed differential display to identify the gene(s) responsible for chromosome 11 suppression of breast cancer metastasis. Three novel cDNAs were identified. BRMS1 suppressed metastasis in MDA-MB-231 and MDA-MB-435 [145] breast carcinomas in addition to two human melanoma (C8161 and MelJuSo, [146]) and two murine mammary carcinoma cell lines (4T1 and 66cl4 [147]). BRMS1 transfectants were not suppressed for growth in vitro or in vivo; adhesion to

SSeCKS

SSeCKS (pronounced essex) for Src-suppressed C kinase substrate expression is down-regulated in src-and ras-transformed rodent fibroblasts [155], [156]. It is the likely rodent ortholog of human Gravin/AKAP12, a cytoplasmic scaffolding protein for protein kinases A and C [157], concentrating at the cell edge and podosomes. In response to phorbol esters, SSeCKS controls elaboration of a cortical cytoskeletal matrix. Over-expression suppresses v-src-induced morphological transformation and

RhoGDI2

Rho GTPases are guanine nucleotide binding proteins, which cycle between active GTP-bound state and inactive GDP-bound state. RhoGDI (Rho GDP dissociation inhibitors) stabilize the GDP-bound form and sequester them in an inactive non-membrane localized, cytoplasmic compartment [161]. In an earlier bladder carcinoma study, RNA expression of RhoGDI2 was associated with decreased metastatic potential [151]. Transfection and enforced expression suppressed metastasis of T24 human bladder carcinoma

Drg-1

Drg-1 (a.k.a. RTP, cap43 and rit42) was identified as a differentiation-associated gene in colon carcinomas by differential display [163]. It is orthologous to mouse TDD45 and Ndr1 and rat Bdm1. Kurdistani and colleagues showed that introduction of Drg-1 cDNA suppressed tumorigenicity of human bladder carcinoma cells, suggesting that Drg-1 is a tumor suppressor gene [164]. However, in vitro invasion and liver metastases are inhibited from colorectal carcinomas when expression is restored either

Metastasis suppressors without functional portfolio

The above genes have functional evidence supporting classification as metastasis suppressors. We will briefly describe below several others whose evidence is suggestive, but the data are deficient with regard to classification as metastasis suppressors for two reasons. First, the data are at this time correlative, not functional. Second, functional suppression of metastasis occurs concurrent with diminished tumorigenicity. In the absence of experimental arms to accommodate differential growth

Remaining questions and perspectives

The critical clinical threshold for any cancer is development of metastasis. Diagnosis occurring prior to the establishment of secondary lesions means favorable prognosis and more effective treatment. As a result, earlier, more effective diagnosis has been instrumental in improving cure rates for cancer.

Unfortunately, there are many cases in which there is no evidence of cancer spread at the time of diagnosis. Treatment plans are usually based upon somewhat subjective morphologic criteria in

Acknowledgements

Work from the Welch lab has been supported by grants from the NIH (CA62168; CA88728, and CA89109), the US Department of Defense Medical Research and Materiel Command (DAMD-17-96-1-6152 and DAMD17-02-1-0541) and the National Foundation for Cancer Research Center for Metastasis Research. L.R.S. is the recipient of a Susan G. Komen Postdoctoral Fellowship (PDF-2000-218). We also appreciate our colleagues Pat Steeg, Carrie Rinker-Schaeffer and Kent Hunter for stimulating conversations and

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