Research review
The role of Osteopontin in tumor metastasis

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Osteopontin (OPN) is a glyco-phosphoprotein that is expressed and secreted by numerous human cancers. OPN functions in cell adhesion, chemotaxis, macrophage-directed interleukin-10 (IL-10) suppression, stress-dependent angiogenesis, prevention of apoptosis, and anchorage-independent growth of tumor cells by regulating cell-matrix interactions and cellular signaling through binding with integrin and CD44 receptors. While constitutive expression of OPN exists in several cell types, induced expression has been detected in T-lymphocytes, epidermal cells, bone cells, macrophages, and tumor cells in remodeling processes such as inflammation, ischemia-reperfusion, bone resorption, and tumor progression. Recently, substantial evidence has linked OPN with the regulation of metastatic spread by tumor cells. However, the molecular mechanisms that define the role of OPN in tumor metastasis are incompletely understood. Transcriptional regulators that contribute to the induction of OPN expression have received significant attention as potential modulators of the OPN-mediated metastatic phenotype. The following review will discuss the molecular structure of OPN, the evidence for its functional role in tumor cell metastasis, the downstream signals that activate invasive mechanisms, and the recent reports concerning regulation of OPN transcription.

Introduction

Osteopontin (OPN) was first described by Senger in 1979 as a phosphoprotein secreted by transformed, malignant epithelial cells [1]. Investigators studying various cell models have since independently detected this molecule as bone sialoprotein I, secreted phosphoprotein I (Spp1), 2ar, uropontin, and early T-lymphocyte activation-1 (Eta-1) [2, 3, 4, 5, 6, 7, 8, 9, 10]. OPN is a secreted glycoprotein that is rich in aspartate and sialic acid residues and contains several functional domains [11]. OPN functions by mediating cell-matrix interactions and cellular signaling through binding with integrin and CD44 receptors [12].

OPN is expressed in multiple species, including humans and rodents [10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25]. Cell types which express OPN include osteoclasts, osteoblasts, epithelial cells of the breast, kidney, and skin, nerve cells, vascular smooth muscle cells, and endothelialcells [10, 11, 26, 27, 28]. Activated immune cells such as T cells, natural killer (NK) cells, macrophages, and Kupffer cells also express OPN. The secreted OPN protein is widely distributed in plasma, urine, milk, and bile [29, 30, 31]. Constitutive expression of OPN exists in several cell types but induced expression has been detected in T lymphocytes, epidermal cells, bone cells, macrophages, and tumor cells in remodeling processes such as inflammation, ischemia-reperfusion, bone resorption, and tumor progression [26, 27, 28]. A variety of stimuli including phorbol-12-myristate 13-acetate (PMA), 1,25-dihydroxyvitamin D, basic fibroblast growth factor (bFGF), tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interferon-gamma (IFN-γ), and lipopolysaccharide (LPS) up-regulate OPN expression [25, 26, 27, 28]. Functionally, OPN mediates cell adhesion, chemotaxis, macrophage-directed interleukin-10 (IL-10) suppression, stress-dependent angiogenesis, prevention of apoptosis, and anchorage-independent growth of tumor cells [25, 26, 27, 28].

Recently, substantial data have linked OPN with the regulation of metastatic spread by tumor cells. However, the molecular mechanisms which define the role of OPN in tumor metastasis are incompletely understood. The following focused review will discuss the molecular structure of OPN, the evidence for its functional role in tumor cell metastasis, the downstream signals that activate invasive mechanisms, and the recent reports concerning regulation of OPN transcription.

Section snippets

Molecular structure of OPN

Comparative analysis of OPN cDNA from human, mouse, rat, pig, bovine, and chicken samples reveals a high degree of sequence homology [11]. The single-copy OPN gene maps to chromosome 4q13 in humans and to the ricr locus on chromosome 5 in mice [4, 27, 32]. The human and mouse genes consist of seven exons and extend over 8 and 7 kb, respectively [4, 10, 11, 25, 33, 34]. Analysis of human OPN cDNA suggests that alternative RNA splicing of OPN exists with at least three OPN cDNAs identified [27].

OPN receptors: meditators of cell-matrix interactions and cellular signaling

OPN is a ligand for the αvβ integrin and CD44 families of receptors. Efficient ligation involves both RGD-dependent and RGD-independent interactions. Receptor binding allows OPN to mediate adhesive cell-matrix interactions and activate cellular second messengers in signal transduction pathways.

CD44

The CD44 glycoproteins are ubiquitously expressed, cell-surface adhesion molecules that mediate cell-matrix and cell-cell interactions [71]. The principal ligand for CD44 is hyaluronic acid (HA) but other extracellular-matrix (ECM) proteins including serglycin, collagen, fibronectin, chondroitin sulfate, laminin, and OPN also bind CD44. OPN-CD44 interactions appear to be RGD independent [72, 73].

Standard CD44 (CD44s) aids in maintenance of the three-dimensional structure of tissue. However, the

OPN and the metastatic phenotype

Cumulative evidence suggests that OPN functions in the regulation of tumor metastasis. Investigators have established a correlation between high levels of OPN protein expression and malignant invasion by demonstrating OPN expression within tumor cells and in the surrounding stroma of numerous human cancers [29, 85, 86, 87, 88, 89, 90, 91]. In addition, the plasma concentration of OPN in patients with metastatic disease is significantly increased in comparison with normal sera [29, 88, 92].

Transcriptional regulation of OPN

Since induced OPN mediates tumor progression, regulators of OPN expression represent potential targets for modulation of tumor phenotype. The remainder of this discussion will describe transcriptional regulators that target OPN. Selected regulatory molecules are summarized in Table 2.

The wide variety of stimuli involved in the regulation of OPN expression suggests that OPN expression is controlled by complex regulatory pathways [25, 26, 27, 28]. The human, porcine, and murine OPN promoters have

Summary

OPN is a secreted phosphoprotein that is expressed at high levels by T-lymphocytes, epidermal cells, bone cells, macrophages, endothelial cells, and tumor cells in remodeling processes such as inflammation, ischemia-reperfusion, bone resorption, arteriosclerosis, and tumor progression. The OPN DNA sequence is highly conserved among species and the protein contains several important functional domains including the αvβ integrin and CD44 binding sites. High levels of OPN expression correlate with

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