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10.1245/ASO.2005.08.013
Annals of Surgical Oncology 12:273-281 (2005)
© 2005 Society of Surgical Oncology
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Review

RON, a Tyrosine Kinase Receptor Involved in Tumor Progression and Metastasis

E. Ramsay Camp, MD1, Wenbiao Liu, MD2, Fan Fan, BS2, Anthony Yang, MD1, Ray Somcio, BA2 and Lee M. Ellis, MD1,2

1 Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Unit 444, PO Box 301402, Houston, Texas 77230-1402
2 Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, 7777 Knight Road, Houston, Texas 77054

Correspondence: Address correspondence and reprint requests to: Lee M. Ellis, MD; E-mail: lellis{at}mdanderson.org.

ABSTRACT

Tyrosine kinase receptors mediate many critical cellular functions that contribute to tumor progression and metastasis and thus are potential targets for molecular-based cancer therapy. As has been found for many receptor tyrosine kinases, RON (recepteur d’origine nantais) and its ligand, macrophage-stimulating protein, have recently been implicated in the progression and metastasis of tumors. In in vitro experiments using colon and breast cancer cell lines, overexpression of RON led to increased invasion and migration of cancer cells and prevented apoptosis and anoikis. In addition, transgenic mice engineered to overexpress RON in the lung epithelium developed multiple pulmonary tumors, suggesting a role for RON in tumorigenesis. In human cancer specimens, increased RON expression has been demonstrated in colon, breast, ovarian, and lung tumors. Therefore, therapies designed to inhibit RON activation may hinder critical tumor survival mechanisms and play a role in the treatment of advanced disease.

Key Words: RON • Macrophage-stimulating protein • Cancer • Tyrosine kinase receptor

Elucidation of the molecular mechanisms that contribute to cancer development, progression, and metastasis is essential for the development of molecular-targeted therapies. Tyrosine kinase receptors (RTKs) mediate multiple processes involved in tumor progression and metastasis, thus making them attractive targets for molecular therapy. Therapies targeting such RTKs, such as the epidermal growth factor receptor, have improved the e9cacy of conventional chemotherapy in both preclinical and clinical studies.1,2 A greater understanding of the molecular alterations that facilitate tumor progression and metastasis will provide insight into approaches to optimize targeted therapies. RON (recepteur d’origine nantais), an RTK with homology to c-Met, is implicated in the progression and metastasis of tumors.3,4 Therefore, RON warrants further investigation as a potential antineoplastic target.

THE RTK RON

RON is a member of the MET protooncogene family of RTKs, along with Stk, c-Met, and c-Sea.4 c-Met, the receptor for hepatocyte growth factor (HGF; also known as scatter factor), is associated with many processes related to tumor development and survival (see review4). c-Sea is expressed as a chicken cell–surface receptor, whereas Stk is the murine homolog of RON.5 c-Met and RON are the only MET family members that exist in humans, although RON is evolutionarily conserved in multiple species; this suggests a vital function for the receptor.4

The human RON gene was initially identified and isolated through the screening of complementary DNA (cDNA) libraries prepared from human foreskin keratinocytes.6 This gene was localized to human chromosome region 3p21, which is commonly mutated in small-cell carcinoma of the lung and renal cell carcinoma.6 The ligand for RON, macrophage-stimulating protein (MSP), is also located in the 3p21 region.

RON is a 180-kDa protein formed as a heterodimer of a 40-kDa alpha chain and a 150-kDa beta chain.4 RON is initially created as a single-chain precursor, pro-RON, and is then cleaved into the two active chains. The alpha chain is completely extracellular, whereas the beta chain traverses the cell membrane and contains the intracellular tyrosine kinase and regulatory elements.4 RON and c-Met are the only RTKs that possess a sema domain in the extracellular portion of the protein.7,8 This specialized domain has a conserved pattern of cysteine residues, amino acid sequences, and a potential glycosylation site.7,8 Through experiments using a dominant-negative sema domain sequence, the sema domain of RON was determined to harbor its ligand-binding site.7 For downstream signaling, RON forms either homodimers or heterodimers with other receptors.

The function of RON has been shown to be important for embryological development, a characteristic common to many RTKs involved in cancer progression. The function of RON during development was established by the use of RON homozygous and heterozygous knock-out mice. Homozygous loss of RON(–/–) was embryonically lethal by day 6.5 during the peri-implantation stage of development. Failure of the RON–/– mice to survive at such an early stage emphasizes the critical role of RON in embryonic development.9,10 In contrast to RON–/– mice, heterozygous (RON+/–) mice mature normally to adulthood, except for an inappropriate inflammatory response. The altered inflammatory response was associated with impaired regulation of nitric oxide.9,10 When wild-type mice were injected with lipopolysaccharide, 87.5% of these mice survived, compared with only 12.5% of the heterozygous mice.9 This outcome was attributed to defects in the immune system of RON+/– mice. In addition to demonstrating RON’s critical role in embryonic development, the studies in RON knock-out mice also suggest that RON may regulate nitric oxide expression and the inflammatory response.

RON is expressed in multiple epithelial cell types, including both nonmalignant and malignant epithelium from the colon and breast. RON has also been identified on macrophages, bone marrow stem cells, and osteoclasts.11,12 In addition to activation of RON by its ligand MSP, ß1 integrins can phosphorylate RON through a Src-dependent pathway. RON activation can enhance signaling through other RTKs such as c-Met and epidermal growth factor receptor.13–15 RON-Met heterodimers have been observed in gastric cancer (GTL-16) cells that express high levels of both receptors.4 These heterodimers may allow for signaling through the receptors without the presence of the receptor’s associated ligand.

RON mediates multiple signaling cascades that involve cell motility, adhesion, proliferation, and apoptosis (Fig. 1Go). The signaling pathways activated downstream of RON include the ras/mitogen-activated protein kinase (MAPK), phosphatidyl inositol-3 kinase (PI-3K)/Akt, and focal adhesion kinase (FAK) pathways. RON activation can also significantly increase c-Src activity, a signaling intermediate involved in cell-cycle progression, motility, angiogenesis, and survival.



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  		FIG. 1. Oncogenic signaling pathways activated downstream of RON (recepteur d’origine nantais). EMT, epithelial to mesenchymal transition.

 
Recently, a truncated RON receptor (short-form RON; sf-RON) lacking most of the extracellular domain has been observed in both normal and malignant human tissues.16 By reverse transcriptase-polymerase chain reaction (RT-PCR), the truncated RON was found to be highly expressed in both human ovarian and breast cancer specimens.16 sf-RON demonstrated increased intrinsic kinase activity and was constitutively phosphorylated in epithelial cells engineered to overexpress sf-RON.17

MACROPHAGE-STIMULATING PROTEIN

The ligand for RON is MSP. MSP was originally identified as a serum protein that stimulated murine resident peritoneal macrophage chemotaxis in response to complement factor C5a.18,19 MSP is an 80-kDa heterodimer composed of a 53-kDa alpha chain and a 30-kDa beta chain linked by a disulfide bond.4 MSP, also known as HGF-like protein or scatter factor 2, belongs to the plasminogen-prothrombin gene family that includes plasminogen and HGF, among others. The plasminogen-prothrombin family is characterized by multiple kringle domains that are identified by triple disulfide loop structures in the N-terminal domain.5 Unlike other members in the family, MSP and HGF have no proteolytic activity. MSP and HGF also perform similar functions and have a 45% sequence homology.20

Hepatocytes are the major source of MSP, which is secreted as biologically inactive pro-MSP.21 To become active, pro-MSP must diffuse into tissues and be proteolytically cleaved at Arg483-Val484.22 Many enzymes can cleave pro-MSP, including several coagulation cascade enzymes such as factors XIa, XIIa, and kallikrein. Pro-MSP convertase, a proteolytic enzyme that cleaves pro-MSP, has been found in wound fluid exudates and on the cell surface of macrophages.21,23

BIOLOGICAL FUNCTIONS OF RON

Activation of RON by MSP can initiate signaling through many pathways implicated in tumor progression and metastasis, such as adhesion, invasion, motility, proliferation, and inhibition of apoptosis. Furthermore, overexpression and mutations of RON have demonstrated its potential role in tumorigenesis and metastasis formation.3,24

Adhesion
A prominent function of RON is its involvement in cellular adhesion. MSP increased cell adhesion to human fibronectin only in cells expressing RON.25 In both transformed human kidney epithelial cell line 293, which expresses endogenous RON, and RE7 cells, which are Martin-Darby canine kidney (MDCK) cells engineered to overexpress RON, MSP enhanced cell adhesion in a dose-dependent manner.25 Parental MDCK cells display no enhanced cell adhesion with the addition of MSP.25 A synthetic peptide containing the arginine-glycine-aspartate (RGD) sequence motif that blocks integrin binding to fibronectin was able to completely inhibit MSP-mediated adhesion. This blocking ability of the RGD peptide verified that increased cell adhesion requires integrin function.25 Furthermore, MSP was able to enhance the integrin’s affinity for the extracellular matrix rather than augment the number of integrins to increase adhesion.25 This observation was confirmed by demonstration of an unchanged level of ß1 integrin expression with MSP stimulation. The MSP-dependent adhesion required PI-3K activation and was blocked by wortmannin, a PI-3K inhibitor, in a concentration-dependent manner.25 RON activation also resulted in FAK phosphorylation through PI-3K signaling and increased FAK-associated kinase activity.25 However, inhibition of FAK did not affect the MSP-enhanced adhesion, and this implies that FAK phosphorylation is not critical in RON-mediated adhesion.25

The functional interaction between RON and integrins is further supported by studies using RE7 cells (RON-overexpressing MDCK cells). In RE7 cells, RON was coimmunoprecipitated with ß1 integrin in both MSP-stimulated and MSP-unstimulated RE7 cells, thus suggesting both a functional and a physical relationship.25 Furthermore, in RE7 cells adherent to collagen, RON remained constitutively phosphorylated, and the degree of phosphorylation was further enhanced by the addition of MSP.26 This functional interaction with the extracellular matrix was inhibited by antibodies to ß1 integrin.26 Similar to the interactions between integrins and other RTKs, both FAK and Src mediate signaling between RON and integrins.26–29 Dominant-negative forms of both FAK and Src decreased the level of integrin-mediated RON phosphorylation.

Invasion and Motility
Studies have also demonstrated that RON is involved in invasion and cell motility. Normal colonic epithelial cells (CoTr) transfected with RON cDNA demonstrate increased migration and invasion after MSP treatment in a dose-dependent manner.3 In contrast to the RON-transfected CoTr cells, mock-transfected cells exhibited no migration or invasion in response to MSP. In addition, the human colon cancer cell line HCT116, which endogenously expresses RON, exhibited increased migration and invasion after stimulation with MSP.3

Increased migration and invasion have also been demonstrated in human breast carcinoma cells that overexpress RON.24 In ZR75.1 human breast cancer cells, which endogenously overexpress RON relative to normal breast epithelial cells, MSP causes a 12-fold increase in migration compared with unstimulated cells. Enhanced ZR75.1 migration and invasion in response to MSP were confirmed in a wound-scratch assay.24 This ability of RON overexpression to enhance cellular invasion and migration supports the role of RON in cancer progression and metastasis.

RON Mediation of Epithelial to Mesenchymal Transition
Epithelial to mesenchymal transition (EMT) is a unique process observed in embryonic development and tumorigenesis in which cells lose epithelial characteristics and gain mesenchymal properties.30 EMT is characterized by a loss of cellular adhesions and normal cytoskeletal arrangements.30 Morphologically, epithelial cells undergoing EMT change conformation from a cuboidal appearance to a spindle form. This morphological transformation is associated with loss of E-cadherin and increased expression of vimentin and {alpha}-smooth muscle actin ({alpha}-SMA). The altered expressions of E-cadherin, vimentin, and {alpha}-SMA are more characteristic of mesenchymal cells and are not usually observed in unstimulated epithelial cells. When epithelial cells display EMT alterations, presumably a transformation has occurred from an epithelial phenotype to a more motile mesenchymal type of cell. These phenotypical changes of EMT correlate with increased motility and invasion.30 In addition to demonstrating functional significance, EMT is also associated with tumor progression and a worse clinical prognosis.31–33 Transforming growth factor (TGF)-ß1 and HGF are two cytokines that have been shown to induce EMT.30

RON’s role in EMT was investigated in MDCK cells transfected with RON cDNA (RE7 cells). The RE7 cells stimulated with MSP had increased cell scattering. By immunofluorescent techniques, MSP-treated RE7 cells displayed redistribution of E-cadherins, ß-catenin, and actin. After 48 hours of MSP exposure, the level of E-cadherin was reduced by 50%.34 EMT due to either TGF-ß1 or MSP was successfully blocked by PD98059 (a MEK MAPK inhibitor); this suggests a similar pathway for mediation of EMT.34 PD98059 was able to maintain the epithelial characteristics of the RE7 cells, with increased E-cadherin expression and inhibition of vimentin and {alpha}-SMA in the presence of MSP, TGF-ß1, or both. The changes associated with EMT because of RON activation further support the ability of RON to increase cellular migration and invasion. Moreover, these EMT phenotypic changes observed with MSP may also implicate RON in tumor progression and metastasis.

RON Inhibition of Apoptosis and Anoikis
RON expression and activation by MSP can enhance the ability of cells to avoid apoptosis. These antiapoptotic properties of RON have been investigated in nonmalignant and malignant colon epithelial cells.3 Normal colon epithelial cells (CoTr) and CoTr cells engineered to overexpress RON were treated with Fas-activating monoclonal antibody (Fas Ab) to induce apoptosis. With the addition of Fas Ab, both wild-type CoTr and the engineered CoTr cells underwent equivalent DNA ladder formation, thus signifying apoptosis.3 With the addition of MSP, however, the apoptotic effect observed in the RON-overexpressing cells was reduced by 50%.3 Parental CoTr cells demonstrated a similar apoptotic response to Fas Ab with or without the addition of MSP. Thus, overexpression and ligand activation of RON were necessary to inhibit Fas-mediated apoptosis.

The antiapoptotic signaling pathways downstream of RON were demonstrated in serum-starved MDCK and RE7 cells.35,36 Initially, adherent cells avoided apoptosis from serum starvation through activation of both the MAPK and PI-3K/Akt pathways. In cells that express RON, MSP can activate both signaling pathways to enhance the antiapoptotic effect. When either pathway was inhibited, MSP could activate signaling through the alternative pathway to prevent apoptosis.35

Detachment of cells from the basement membrane or matrix normally leads to cell death (anoikis). In contrast to normal epithelial cells, which undergo anoikis upon detachment, cancer cells may avoid anoikis. Metastatic cancer cells must survive in circulation; therefore, avoiding anoikis is a critical property in cancer progression. In RE7 cells (MDCK cells engineered to overexpress RON), anoikis is prevented by the addition of MSP.35,36 This antianoikis property of RON requires the activation of the PI-3K/Akt pathway and can be completely inhibited by the transfection of a dominant-negative Akt construct.35,36 Unlike the antiapoptotic effects of RON that may be governed by two separate pathways, anoikis was avoided only through activation of the PI-3K/Akt pathway.35,36 The MAPK-mediated antiapoptotic properties of RON possibly require cell adhesion to function. This pathway could potentially involve translocation of MAPK from the cytoplasm to the nucleus, and this has been observed only in adherent cells treated with MSP.35

RON as an Oncogene
Cell transformation as a result of RON overexpression has been elegantly demonstrated in transgenic mouse models. Transgenic mice were engineered to express RON only in distal lung epithelium by using a surfactant protein C promoter—a promoter specific for lung epithelium.37 These transgenic mice seemed normal at birth but developed multiple pulmonary adenomas at 2 months of age. After 4 months, multiple tumor nodules developed and led to respiratory failure by 14 months secondary to tumor progression from adenoma to adenocarcinoma.37 No tumors were identified in any other organ or in the littermate control mice. Immunohistochemical analysis confirmed that RON was highly expressed in the tumors and was constitutively phosphorylated.37 By selective upregulation of RON expression in the lung epithelial cells of the transgenic mice, overexpression of RON was demonstrated to be oncogenic.

sf-RON may also have the capability to transform cells, thus leading to the development of malignant tumors. T74D epithelial cells transfected with sf-RON constructs displayed altered morphology and an altered phenotype, with a loss of E-cadherin expression.16 Furthermore, the presence of sf-stk (the mouse homolog to sf-RON) in mice erythroid cells enhances susceptibility to erythroleukemia induced by the Friend leukemia virus.17

RON Mediation of Metastasis
Wild-type and activating mutations in RON have been associated with the mediation of metastasis formation. NIH3T3 cells transfected with either wild-type RON or three mutated variants of RON with single amino acid substitutions were studied to evaluate the role of RON in mediating cell transformation and metastasis. The engineered mutations of RON were homologous to well-described mutations in its related family member c-Met. These transfected cell lines were injected subcutaneously or into the tail vein to assess their metastatic potential in vivo. After subcutaneous injection of parental NIH3T3 cells, tumors developed in only 25% (1 of 4) of the mice, whereas subcutaneous injection of the transfected cell lines generated tumors in 88% (22 of 25) of the mice.38 One engineered mutation (L1176V) generated tumors in 58% of the mice injected, whereas the wild-type RON and the other two mutations generated tumors in 100% of the mice injected. The M1231T mutation in the RON kinase domain developed tumors with a significantly higher growth rate and an increased mitotic index relative to the other mutated RON-transfected cell lines.38 In contrast to subcutaneous injection, tail vein injection significantly increased the number of lung metastases with two of the mutated forms of RON. No lung metastases were generated from tail vein injection of the nontransfected cells or the cells transfected with wild-type RON.

Summary of RON-Mediated Cell Functions
RON overexpression and activation mediate many properties associated with cancer development and progression. Increased adhesion, motility, and invasion are demonstrated with RON overexpression and activation. RON overexpression can also lead to increased tumorigenesis and the characteristic cellular alterations associated with EMT. Although RON is present on many normal epithelial cells, these altered properties are elicited only with RON overexpression. Furthermore, the oncogenic characteristics of RON can also be enhanced by specific activating mutations in the RON kinase domain. These observations imply that altered RON expression is required for RON to have a tumor-enhancing eLect. As will be discussed next, both overexpression and mutations of RON are exactly what is observed in human epithelial malignancies.

EXPRESSION OF RON IN CANCER

The previously described studies indicate that RON has the potential to play a prominent role in tumor progression and metastasis. To support this hypothesis, it is important to determine whether RON or its ligand is overexpressed in epithelial malignancies13,14,16,24,39–42 (Table 1Go). RON overexpression was first observed in 1998 in breast cancer.24 In an immunohistochemical analysis of human breast cancer specimens, approximately 50% of the tumors overexpressed RON, and, in 16% of the tumors, a >20-fold increase in expression was observed compared with normal epithelium.24 An equivalent degree of RON overexpression was observed in both lobular and ductal carcinomas. In a subset analysis, breast cancers from postmenopausal women had significantly higher levels of RON expression compared with both normal tissue and cancers from premenopausal patients.24 The significance of RON overexpression in tumors from postmenopausal women is uncertain, especially because no correlation was found between RON expression and hormone receptor status.24 Southern blot analysis of the breast cancer specimens revealed no genomic alterations or amplifications, thus suggesting that RON overexpression results from enhanced gene transcription.24 This initial demonstration of RON overexpression in human tumors directed attention toward the role of this RTK in the development of cancer.


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  		TABLE 1. RON expression in human epithelial malignancies
 
In colorectal carcinoma, adenocarcinomas demonstrated overexpression of RON compared with normal colon mucosa. By immunohistochemical analysis, 29 (59.2%) of 49 cancer specimens overexpressed RON relative to a panel of normal colon mucosa specimens.42 It is interesting to note that RON was diffusely present in the cytoplasm of cancer cells, whereas in normal epithelial cells, RON is located on the cell surface and in cytoplasmic granules.42 No correlation was observed between RON expression and characteristics of advanced colorectal carcinoma, such as depth of invasion and vascular involvement.42 In vitro experiments analyzing colon cancer cell lines demonstrated constitutive phosphorylation of RON with increased constitutive kinase activity relative to normal colon epithelial cells.3 The in vitro data suggest that in addition to RON overexpression in colorectal carcinoma, constitutive activation of the receptor occurs that also may lead to altered cellular function. Although overexpression of RON leads to increased invasion and metastatic potential in multiple preclinical studies, RON overexpression did not correlate with aggressive tumor characteristics in colorectal carcinoma or breast cancer.3,24

In addition to the demonstration of RON overexpression in colorectal carcinoma, mutations of RON have been detected in this disease. Three splice variants in the extracellular portion of RON’s beta chain have been identified in colorectal carcinoma specimens and evaluated by RT-PCR42,43 (Fig. 2Go). These splice variants were identified and sequenced in 2 of 11 primary colorectal carcinoma specimens.42 The first variant (RON{Delta}165) resulted from a deletion of 49 amino acids in exon 11. The second identified variant (RON{Delta}160) resulted from a deletion of 109 amino acids in exons 5 and 6 and corresponded to the mutation previously discovered in the HT29 colon cancer cell line.3 The third variant (RON{Delta}155) resulted from a deletion of 158 amino acids from a combination of exons 5, 6, and 11. Further analysis revealed that all three identified mutations were located in the extracellular portion of RON. The biological significance of the splice variants was investigated by transfecting mouse fibroblasts (NIH3T3 cells) with cDNA constructs of the RON mutations. In both in vivo and in vitro models, the expressions of two of the splice variants of RON (RON{Delta}160 and RON{Delta}155) were biologically active, and this led to increased migration, invasion, and metastatic potential relative to control cells and cells transfected with wild-type RON.42 Identifying activating RON mutations in human colorectal carcinoma specimens reveals another mechanism (in addition to receptor overexpression) that may contribute to the progression of cancer.



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  		FIG. 2. Schematic of the RON (recepteur d’origine nantais) splice variants observed in colorectal cancer. The first model demonstrates the structure of wild-type RON with the alpha and beta chains. In the schematic of the RON splice variants, the shaded areas represent the deleted sequences in RON. bp, base pair.

 
The presence and function of RON and MSP have been investigated in non–small-cell lung cancer (NSCLC).40 In NSCLC specimens, MSP messenger RNA (mRNA) is expressed in two different patterns. First, normal lung epithelium can express high levels of MSP mRNA (evaluated by RT-PCR) adjacent to the malignant tissue. This relationship was demonstrated in three of eight analyzed NSCLC specimens, thus suggesting a possible paracrine relationship between adjacent normal tissue and the tumor.40 Second, enhanced MSP mRNA expression can also be displayed by the neoplastic cell lines. In approximately 3% of the lung cancer cell lines, cancer cells demonstrated high MSP mRNA levels. Overall, RON was present in 62% (10 of 16) of the cancer cell lines as assessed by RT-PCR.40 In 5 of 16 NSCLC cell lines, RT-PCR detected coexpression of both RON and MSP mRNA, and this supported the possibility of autocrine signaling.40 As demonstrated in the studies investigating RON’s biological function, the combination of RON overexpression and activation by the addition of MSP leads to increased invasion and resistance to apoptosis. These tumors supported by either autocrine or paracrine stimulation may have a survival advantage due to increased activation of the RON receptor by the local secretion of MSP.

RON has also been observed to be overexpressed in human ovarian cancer. In 55% (29 of 53) of the ovarian cancer specimens investigated, RON overexpression was identified by RT-PCR.13 Faint expression of RON by RT-PCR was noted in only two of eight normal ovarian epithelium specimens.13 However, in contrast to the results for colorectal carcinoma, no mutations in RON were noted in the ovarian cancer specimens analyzed.13 RON was identified by immunohistochemical analysis in both the cytoplasm and cell membrane in the cancer specimens, similar to the location of RON in colorectal carcinomas.13 No correlation was observed between the presence of RON and disease progression.13

CONCLUSIONS

As is true for other cell-surface RTKs, RON influences the function of multiple downstream pathways mediating various steps in tumor progression and metastasis. RON overexpression and mutations are identified in cancers involving various organ systems. Therefore, novel antineoplastic therapies designed to inhibit RON may hinder critical tumor-survival mechanisms and enhance the e9cacy of future therapeutic regimens. Ultimately, expanding our knowledge of the molecular alterations that contribute to the process of tumor progression and metastasis will provide insight into methods to optimize targeted therapies.

ACKNOWLEDGMENTS

Supported by National Institutes of Health (NIH) T32 Grant CA-09599 (E.R.C. and A.Y.), NIH 5 U54 CA90810 02 (L.M.E.), The Lockton Fund for Pancreatic Cancer Research (L.M.E.), and NIH Cancer Center Support Grant CA-16672. The authors thank Chrisine Wogan from Scientific Publishing and Rita Hernandez from Surgical Oncology, M. D. Anderson Cancer Center, for editorial assistance.

Received for publication August 12, 2004. Accepted for publication November 29, 2004.

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