Review
Roles of fascin in human carcinoma motility and signaling: Prospects for a novel biomarker?

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Abstract

Fascin is a globular actin cross-linking protein that has a major function in forming parallel actin bundles in cell protrusions that are key specialisations of the plasma membrane for environmental guidance and cell migration. Fascin is widely expressed in mesenchymal tissues and the nervous system and is low or absent in adult epithelia. Recent data from a number of laboratories have highlighted that fascin is up-regulated in many human carcinomas and, in individual tissues, correlates with the clinical aggressiveness of tumours and poor patient survival. In cell culture, over-expression or depletion of fascin modulates cell migration and alters cytoskeletal organisation. The identification of biomarkers to provide more effective early diagnosis of potentially aggressive tumours, or identify tumours susceptible to targeted therapies, is an important goal in clinical research. Here, we discuss the evidence that fascin is upregulated in carcinomas, its contributions to carcinoma cell behaviour and its potential as a candidate novel biomarker or therapeutic target.

Introduction

Malignant neoplasms, termed cancer, are one of the most common causes of death and constitute a major public health problem. In 2002 there were more than 10,000,000 new cases of cancer diagnosed worldwide and 555,000 deaths from cancer in the United States, making it the second most common cause of death in the USA (American Cancer Society, http://www.cancer.org).

Among the malignant neoplasms, 85% are carcinomas that develop from the epithelial tissues that cover the external and internal surfaces of the body. The most frequent carcinoma in the USA population is lung carcinoma: in women the next most common are breast and colorectal carcinomas and in men the next most common are prostate and colorectal carcinomas (American Cancer Society). Despite major improvements in diagnosis, surgical techniques, patient care, and adjuvant therapy in recent years, all aimed at decreasing cancer mortality (Stewart, King, Thompson, Friedman, & Wingo, 2004), carcinomas remain a major cause of death. Most of these deaths do not result directly from the primary tumour, but are caused by secondary, metastatic tumours that are resistant to conventional therapies. Therefore, a major current focus in cancer research is to understand the early event by which carcinoma cells escape from the primary tumour, invade local tissue and disseminate through the blood or lymphatic systems to colonise remote body sites. There is also an increasing awareness that individuals differ in the molecular processes that underlie disease pathogenesis, progression and the response to therapeutics. Therefore identification of molecular markers that could provide more effective early diagnosis of potentially aggressive tumours, or identify tumours for particular therapies (“personalised medicine”), is also an important goal (Carr, Rosenblatt, Petricoin, & Liotta, 2004).

With regard to the mechanisms by which cells become competent to move out from the primary tumour, changes in cell–cell and cell–ECM (extracellular matrix) adhesion properties are of particular interest. Epithelial tissues form as contiguous sheets or layers in which adjacent cells are firmly connected to each other by cadherin-based cell–cell adhesions and other junctions and to the basement membrane by integrin-mediated cell–ECM adhesions. Under normal physiological conditions, the movement of epithelial cells is limited either to upward movement during the terminal differentiation of stratified epithelial cells, or lateral migration of groups of cells that repair wounds in the epithelial layer (reviewed by Gumbiner, 1996, Watt, 2002).

For carcinoma cells to invade adjacent tissues, they must acquire the ability to cross the basement membrane and also an increased capacity to migrate as single cells. Increased production of ECM proteases, reduced cell–cell adhesion and altered expression of cell–ECM adhesion receptors have all been implicated in these processes (reviewed by Gumbiner, 1996, Friedl and Wolf, 2003; Mott & Werb, 2004; Guo & Giancotti, 2004). Changes in the organisation of the actin cytoskeleton are also important for the function of cell–cell and cell–ECM adhesion receptors and the migratory capacity of epithelial cells (Carragher & Frame, 2004). Certain cytoskeletal components of normal epithelial cells such as ezrin and α-actinin are up-regulated in carcinoma cells and contribute to metastasis (Curto & McClatchey, 2004; Nestl et al., 2001). However, from the perspectives of prognosis or treatment, the most interesting changes are those involving the expression of a protein that is not present in the normal epithelium. In this regard, an exciting recent development has been the realisation that many forms of human carcinoma express the actin-bundling protein, fascin. Fascin is a globular actin-cross-linking protein that is normally expressed in mesenchymal tissues and the nervous system. It has a major function in forming the parallel actin bundles that support lamellipodial and filopodial cell protrusions that are key cellular structures for environmental guidance and cell migration (reviewed by Kureishy, Sapountzi, Prag, Anilkumar, & Adams, 2002; Adams, 2004). In intact cells, the actin-binding activity of fascin is under complex molecular regulation in response to extracellular cues that is mediated through the activities of protein kinase Cα and small GTPases. Fascin has emerged as a very interesting candidate, either as a potential early prognostic marker, or as a candidate target for possible therapeutic intervention to block initial carcinoma cell migration and invasion.

In this review, we discuss the evidence that fascin is upregulated in carcinomas, the meaning of fascin expression for carcinoma cell behaviour, and assess the potential of fascin as a novel prognostic biomarker or target for novel therapeutic treatments.

Fascins are evolutionarily conserved actin-binding proteins that are present in both invertebrate and vertebrate animals. Fascins are c. 493 amino acid polypeptides that are distinct in sequence from all other actin-bundling proteins (reviewed by Kureishy et al., 2002). Sequence pattern analysis and a crystal structure of fascin-1 uncovered that fascins are members of the beta-trefoil fold family of proteins and therefore related in structure to an actin-binding protein of Dictyostelium, hisactophilin (Ponting & Russell, 2000). However, whereas hisactophilin consists of a single beta-trefoil domain, fascins contain four beta-trefoil domains (Fig. 1). Drosophila melanogaster and other insects have single forms of fascin (Paterson & O’Hare, 1991; Adams et al., 2000; Holt, Subramanian, & Halpern, 2002). Mammalian genomes encode a small gene family consisting of fascin-1 (also known as fascin), fascin-2 and fascin-3. In humans, the gene encoding fascin-1 is located at chromosome 7p22; the gene for fascin-2 is at 17q25, and the fascin-3 gene is located at 7q31 (Tubb, Bardien-Kruger, & Kashork, 2000; Tubb et al., 2002, Duh et al., 1994). Fascin-1 is widely expressed in mesenchymal tissues and in the nervous system, whereas fascin-2 and fascin-3 are specifically expressed in retinal photoreceptor cells and the testis, respectively (Edwards & Bryan, 1995; De Arcangelis, Georges-Labouesse, & Adams, 2004; Saishin et al., 1997, Tubb et al., 2002). The focus of this article is on fascin-1.

To bundle F-actin, fascin-1 must contain two actin-binding sites. One site is located at the amino terminus, in the first beta-trefoil domain between amino acids (aa) 33–47, and the other has been deduced by limited proteolysis to lie between aa 277–493 (Fig. 1) (reviewed by Kureishy et al., 2002). Fascin-1 also binds to non-cytoskeletal proteins. Fascin-1 is a substrate of protein kinase C alpha (PKCα) in vitro and in intact cells (Ono et al., 1997, Adams et al., 1999). The highly-conserved site of phosphorylation, Ser-39, is located within actin-binding site 1 (Fig. 1) and phosphorylation of fascin at Ser-39 inhibits the actin-bundling activity of fascin and confers an additional activity, binding of the regulatory domain of active PKCα. The latter interaction has been mapped to the C1 domain of PKCα (Anilkumar, Parsons, Monk, Ng, & Adams, 2003). A third interaction of fascin-1 is with the cytoplasmic domain of the p75 neurotrophin receptor (p75NTR) (Shonukan, Bagayogo, McCrea, Chao, & Hempstead, 2003). This binding depends on the third and fourth beta-trefoil domains (Fig. 1).

Section snippets

Fascin-1 expression in normal mammals

During mouse embryogenesis from E8.0 to E16.5, fascin-1 transcripts are expressed principally in the developing nervous system, developing somites and other mesoderm-derived tissues such as mesenchyme and limbs (De Arcangelis et al., 2004). As early as E8.0, fascin-1 is expressed in the neural epithelium along the whole antero-posterior axis of the embryo. Later in development, many domains of the central nervous system including the brain and spinal cord and the dorsal root ganglia of the

Emerging information on the expression of fascin protein by human carcinomas

The absence or low expression of fascin in normal epithelia is dramatically altered in many human carcinomas. As summarised in Table 1A, among the carcinomas examined to date a proportion of the primary tumours in all of the tissues tested express fascin. Although it is tempting to speculate that a common mechanism for up-regulation of fascin protein might be involved, it appears more likely that there are tissue-specific mechanisms, because of the wide variation in the proportion of

How is fascin up-regulated in carcinoma cells?

It is not yet known whether the molecular basis for increased fascin protein expression by carcinomas is transcriptional or post-transcriptional, or whether the same mechanism is involved in carcinomas of different origins. Because of the different frequencies with which fascin-positive tumours have been detected in different tissues (see Table 1A and Section 3), we suspect that there could be several mechanisms for fascin up-regulation.

In this regard, chromosomal aberrations are a

What are the functional consequences of fascin up-regulation in carcinoma cells?

Compared with normal epithelial cells, carcinoma cells are more proliferative, less terminally differentiated and more motile. These properties arise during the process of malignant transformation as a result of chromosomal aberrations, gene mutations and altered patterns of gene expression. Many oncogenes and tumour suppressors are known to affect the proliferation, survival and cell motility of tumour cells. How does fascin link functionally to these well-established molecular alterations and

Future prospects: potential of fascin as a biomarker or therapeutic target?

Targeted therapy is a major goal of personalized medicine and has emerged in new cancer treatment strategies, for example, the use of herceptin, a humanized monoclonal antibody against human epidermal growth factor receptor 2, to treat HER2-positive breast carcinomas (Menard et al., 2004). The ideal anti-cancer target should be crucial for the malignant phenotype, not significantly expressed in the corresponding normal tissue, and clearly correlated with clinical outcome. Is fascin

Acknowledgements

We thank our collaborators in Department of Anatomic Pathology, Mary Bronner and David Hicks, for stimulating discussions. Research in the Adams’ Laboratory is supported by NIH grant GM68073 and grant 04-330 from the Association for International Cancer Research.

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