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Stem Cells, Vol. 14, No. 5, 508-516, September 1996
© 1996 AlphaMed Press

CONCISE REVIEW

The Role of Motility Proteins and Metastasis-Suppressor Genes in Prostate Cancer Progression

Carrie W. Rinker-Schaeffera, Marina A. Chekmarevaa, James L. Mohlerb

a The University of Chicago, Section of Urology, Department of Surgery, Chicago, Illinois, USA;
b Departments of Surgery (Division of Urology) and Pathology, The University of North Carolina, Chapel Hill, North Carolina, USA, and the UNC-Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina, USA

Key Words. Prostate cancer • Metastasis • Motility • Metastasis suppression

Correspondence: Dr. Carrie W. Rinker-Schaeffer, University of Chicago, Section of Urology, MC 6038, 5841 S. Maryland Ave., Chicago, IL 60637, USA.


   Abstract
Top
 Abstract
Introduction
 Prostate Cancer Cell Motility
 The Role of Metastasis...
 Conclusions
 References
 
In 1996, an estimated 317,000 new cases of prostate cancer will be diagnosed in the United States. The incidence of prostate cancer has more than doubled in the past five years; in fact, it is estimated that aggressive screening starting at age 50 could potentially identify 10,000,000 American men with histologically localized prostate cancer. In order to reduce deaths from prostate cancer, it is necessary not only to diagnose but also to accurately predict the clinical course of an individual patient's cancer, thus allowing for more effectively directed treatment.

Acquisition of metastatic ability is a well-recognized criterion for the aggressiveness of prostate cancer. A number of molecular and cellular changes associated with the malignant progression of prostate cancer have been identified. Certain of these changes may potentially be used as markers for metastatic ability of histologically localized prostate cancer cells. This concise review will consider two parameters which are associated with the acquisition of metastatic ability: increased cellular motility and loss of metastasis-suppressor gene function. A link between these two parameters has been demonstrated and may contribute to the development of innovative approaches for predicting the metastatic ability of individual tumors.


   Introduction
Top
 Abstract
 Introduction
Prostate Cancer Cell Motility
 The Role of Metastasis...
 Conclusions
 References
 
In 1996, an estimated 317,000 new cases of prostate cancer will be diagnosed in the United States, making it the most common non-skin malignancy in American men [1]. The incidence of prostate cancer has more than doubled in the past five years [2]. This increase is largely the result of recent public awareness of the disease and the more common use of the prostate-specific antigen (PSA) test for earlier detection. Radical prostatectomy for PSA-detected cancers doubles the chance of treating the disease while it is still organ-confined [3]. In addition, PSA screening appears rarely to detect clinically insignificant cancers [4-6]. Whether treatment of cancers which are detected "earlier" will translate into a significant reduction in prostate-cancer-specific mortality remains controversial. The perceived benefits of early detection and aggressive treatment have resulted in an increase in the number of radical prostatectomies performed over the past decade [7].

In 1996, an estimated 41,000 American men will die of prostate cancer, which represents a small increase in age-adjusted mortality compared to a decade ago [1]. However, a recent study of the Utah Cancer Registry demonstrated a continuous annual decline in cancer-specific mortality in Utah, which was first appreciated in 1992 [8]. In addition, there has been a decline in the number of patients presenting with metastases since 1991 [8]. Aggressive treatment of prostate cancer in older men may not be optimal due to the relatively indolent course of many prostate cancers [9] and the impact of potential side effects of treatment on the patient's quality of life [10]. Early detection and aggressive treatment appear most important in men under the age of 65 and in older men with biologically aggressive and life-threatening cancers. Therefore, to reduce deaths from prostate cancer, it is necessary not only to diagnose but also to accurately predict the clinical course of an individual patient's cancer, thus allowing for more effectively directed treatment.

Among men with clinically localized (potentially curable) prostate cancer, prognosis can be correlated with PSA level and histologic grade. Prostatic cancers are "graded" using the Gleason system, which considers the degree of histologic differentiation of both primary and secondary tumor growth patterns [11]. Gleason grade has been correlated with clinical outcome in large populations of patients, but only at the extremes of grade (i.e., well-differentiated versus poorly differentiated) [12]. Unfortunately, most patients with clinically localized prostate cancer have moderately differentiated tumors, and the behavior of these tumors remains difficult to predict [13]. In similar fashion, PSA levels correlate with tumor volume but cannot predict the extent of cancer in individual patients, even when combined with the results of diagnostic biopsy, Gleason grade and digital rectal examinations [14]. Hence, distinguishing those men who will die with their prostate cancers from those who will die as a result of their prostate cancers requires a more accurate assessment of the biologic aggressiveness of individual prostate cancers than is currently possible.

Acquisition of metastatic ability is a well-recognized criterion for the aggressiveness of prostate cancer. A number of genetic and epigenetic changes have been associated with the initiation and progression of prostate cancer [15]. Some of these changes, such as increased allelic imbalance, are highlighted in Figure 1Go. Once identified, the presence of molecular and/or cellular markers for metastatic ability of prostate cancer cells could potentially be used to determine the clinical course and optimal therapy for individual patients [16]. In addition, the identification of cellular pathways or activities which render a cell metastatic might be used as targets for therapies to suppress metastatic growth. This concise review will consider two parameters which are associated with the acquisition of metastatic ability: increased cellular motility and loss of metastasis-suppressor gene function. Increased cellular motility has been correlated with increased metastatic potential. Loss of metastasis-suppressor gene function may provide a mechanism by which cells acquire metastatic ability. A relationship between these two parameters has been demonstrated in experiments where introduction of metastasis-suppressor genes into metastatic cell lines resulted in decreased cellular motility in vitro as well as reduced metastatic ability in vivo [17-19].



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  		Figure 1. Selected genetic and epigenetic changes associated with the malignant progression of prostatic cancers. Changes which are the subject of this review are indicated with *.

 

   Prostate Cancer Cell Motility
Top
 Abstract
 Introduction
 Prostate Cancer Cell Motility
The Role of Metastasis...
 Conclusions
 References
 
Many grading systems, both architectural and cytological, have been developed to assess the metastatic potential of prostate cancers. These quantitative techniques have been applied to the prediction of prognosis based on the study of fixed (i.e., dead) cancer cells. Until recently, methods did not exist for study of the dynamic biological properties of living cancer cells. Enhanced motility in cancer cells was suggested in 1863 by Rudolph Virchow but was first documented in vitro by George Gey [20] and in vivo by Sumner Wood et al. [21]. A correlation between cellular motility and a tumor's invasive and metastatic abilities has been reported in a number of model systems [22]. The development of time-lapse videomicroscopy has allowed an accurate and practical method of recording and analyzing the motility of individual cells. Discrete types of cellular motion have been characterized and their effect on metastatic potential suggested.

Studies of prostate cancer cells were conducted using the Dunning R3327 rat prostatic adenocarcinoma model [23]. A significant advantage of this model is that it is comprised of a spectrum of sublines that differ widely in their histology, growth rate, androgen sensitivity and metastatic ability [23, 24]. The sublines have been extensively characterized both in vitro and in vivo. Using a variety of Dunning sublines, distinct types of cell motility were observed, including cell membrane ruffling, lamellapodal extension, cell membrane undulation and total and vectoral translation [25]. In these studies cell motility was graded visually with intra-assay, intra-observer and inter-observer reproducibilities of greater than 75%. Among the parameters of motility examined, membrane ruffling, lamellapodal extension and vectoral translation provided the nonredundant information necessary for optimal characterization of cellular motility (Fig. 2Go). Motility was sufficiently characteristic of the various sublines so that the subline of origin of 59% of unknown cells was identified correctly by blinded examination of videomicroscopic recordings, compared to an expected 17% correct by chance assignment [25].



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  		Figure 2. Parameters used for characterization of cellular motility. Membrane ruffling, lamellapodal extension, and vectoral translation provided the information necessary to accurately identify Dunning sublines.

 
Dunning sublines were separated perfectly by motility into four nonmetastatic and three highly metastatic sublines [26]. Single cells were classified correctly in 96% of cases. When 11 sublines were tested prospectively using classification parameters determined previously, the metastatic potential of the subline from which single cells were studied was assigned correctly in only 70% of the cells studied. Highly metastatic sublines were all highly motile, but two sublines of high motility had low metastatic potential [27]. To investigate this paradox further, the substrate dependence of motility and attachment were investigated in serum-free media. No consistent substrate-dependent differences were observed across sublines [28]. Furthermore, motility was independent of cell procurement method [29, 30] or cell culture conditions [31]. Thus, motility appeared to be required but not sufficient for metastasis.

Promoters of cell motility have been described in many tumor systems since the description by Liotta et al. of autocrine motility factor [32]. However, inhibition of cell motility with concomitant suppression of metastatic potential has greater clinical relevance. Two groups of investigators were among the first to demonstrate inhibition of metastasis-associated properties that might modulate metastatic potential in malignant cells. Hendrix et al. demonstrated that retinoic acid inhibited the production of proteolytic enzymes and autocrine motility factor receptors in invasive human melanoma cells [33]. Yu et al. found that introduction of the adenovirus E1A gene into c-erbB2/neu-transformed 3T3 cells reduced the formation of experimental metastases and inhibited cell adhesion to endothelial cells, migration through reconstituted basement membranes and secretion of proteolytic enzymes [34]. Direct motility inhibition, to our knowledge, has only been demonstrated in normal cells in which fibro-blast growth factor decreased the motility of retinal pigment epithelial cells [35].

Since Mohler et al. demonstrated the strong correlation between metastatic potential and motility in the Dunning R3327 prostatic adenocarcinoma model, several groups of investigators have attempted to impair motility with the goal of developing novel methods of inhibiting metastatic potential. Alteration of cell culture conditions, such as electrolyte composition, calcium concentration, pH and temperature, failed to alter motility until the conditions became so severe that cell injury occurred [31]. In MAT-LyLu cells and the human prostate cancer cell line LNCaP, suramin reduced motility in vitro, an effect that was reversed upon addition of basic fibroblast growth factor to the cell culture media [36]. A novel chemotherapeutic agent, pentosan, interrupted cellular contacts with the extracellular matrix, both inhibiting cell motility in vitro and prolonging survival of rats injected with Dunning MAT-LyLu cells by 25% [37]. In an effort to identify factors which might regulate cellular motility, Mohler et al. examined the ability of the nonmotile, nonmetastatic Dunning G subline to secrete factors which would inhibit the motility of the highly motile, highly metastatic MAT-LyLu cell line.

Initially, these studies found that G cells secreted a heat- and protease-labile substance into serum-free medium that inhibited the motility of MAT-LyLu cells [38]. Motility was inhibited by conditioned medium dialysates of molecular weights (Mr) 50-100 kDa. Time-lapse videomicroscopy revealed the preservation of membrane ruffling, undulation and lamellapodal activity, suggesting that the proteins identified were pure translational inhibitors and not nonspecific cell membrane agents. Analysis of G-cell-conditioned serum-free medium by SDS-PAGE revealed several discrete bands of Mr ranging from 53 to 116 kDa that were not present in media conditioned by MAT-LyLu cells. G-conditioned serum-free medium was separated by DEAE-cellulose chromatography and the fractions that inhibited motility subjected to two-dimensional gel electrophoresis. Five protein families with a total of 12 proteins of Mr ranging from 34 to 66 kDa were not present or were present in reduced quantities in column fractions that did not inhibit motility [39]. This protein, termed "motility inhibitory protein," is apparently a novel paracrine factor capable of inhibiting the motility of highly-metastatic cells. Identification of the interaction, or paracrine signaling, between tumor subpopulations is an exciting new area of tumor cell biology. However, paracrine signaling proteins occur biologically at low concentrations, which makes their isolation difficult. The search for motility inhibitory protein was facilitated by the use of the Dunning system of rat prostatic cancers. The candidate proteins are currently being further purified, biochemically characterized and assayed for biological activity.


   The Role of Metastasis-Suppressor Genes
Top
 Abstract
 Introduction
 Prostate Cancer Cell Motility
 The Role of Metastasis...
Conclusions
 References
 
Changes in cellular motility represent a phenotypic alteration associated with the acquisition of metastatic ability. Such phenotypic changes may be due to a variety of genetic or epigenetic alterations. The potential roles of numerous genetic changes, including oncogene activation and tumor-suppressor gene loss, have been studied in the malignant progression of prostate cancer [15]. These changes appear to be associated with, but not sufficient for, acquisition of metastatic ability. In contrast, genes which encode proteins that regulate a tumor's transition from a benign to a metastatic phenotype may serve as useful markers in predicting a tumor's malignant potential. These genes, termed "metastasis-suppressor" genes, encode products that normally function to suppress metastasis. They are distinct from oncogenes, which promote cellular transformation, and tumor-suppressor genes, which suppress tumor growth. Thus, it was hypothesized that the loss of putative metastasis-suppressor genes would allow primary tumor cells to become metastatic. The recent identification of novel metastasis-suppressor genes supports this hypothesis.

Approximately six years ago, studies to identify chromosomal regions and genes involved in the suppression of prostate cancer metastasis were initiated. Initially, these studies consisted of fusing nonmetastatic and highly metastatic Dunning rat prostatic cells. The hypothesis was that if the loss or inactivation of metastasis-suppressor genes is involved in malignant progression, the somatic cell hybrids from such fusion would be nonmetastatic, since chromosomes from the nonmetastatic parental cell would supply the lost suppressor gene functions. Ichikawa et al. found that the tumorigenicity and in vivo growth rates of the hybrid clones, which contained a full complement of parental chromosomes, were not affected [40]. In contrast, none of the animals bearing hybrid tumors developed distant metastases. When these nonmetastatic primary tumors were passaged in vivo, animals occasionally developed distant metastases. Cytogenetic analysis of eight of these metastatic revertants resulted in consistent loss of a copy of normal rat chromosome 2 [40]. This study demonstrated that prostatic cancer metastasis is associated with the loss of specific chromosomes which do not affect the growth rate or tumorigenicity — only the metastatic ability.

The localization of one or more metastasis-suppressor genes to rat chromosome 2 prompted the search for the locations of homologous metastasis-suppressor genes in the human genome. At approximately the same time, NM23, the first such gene whose expression is decreased in metastatic melanoma and breast cancer cells, was identified by Steeg et al. [41]. Several studies have demonstrated that the decreased expression of NM23 protein and RNA expression in human prostate cancers and model systems is not required for the progression of human prostatic cancers [15, 42].

In an attempt to identify other genes involved in the suppression of prostatic cancer metastasis, a panel of highly metastatic Dunning rat prostatic cancer sublines which contain defined portions of individual human chromosomes was constructed. Metastatic Dunning sublines (i.e., AT6.1 and AT3.1) have the advantages of being genetically and phenotypically stable and highly metastatic, yielding >=100 lung metastases/animal in spontaneous lung metastasis assays [15]. The number of lung metastases per animal is also highly reproducible, which is essential for studies of metastasis-suppression. At this time, there is no analogous human model for the study of prostate cancer metastasis. The approach currently being used to identify these genes is the microcell-mediated chromosomal transfer of individual human chromosomes into highly metastatic Dunning prostate cancer cells [15, 43].

Briefly, mouse fibrosarcoma cells containing normal human chromosomes tagged with a drug-resistance gene (i.e., neoR, hygroR, etc.) are sequentially treated with colcemid to depolymerize microtubules and cytochalasin B to depolymerize actin bundles. The treated cells are then centrifuged and the resulting pellet contains the microcells. Microcells are, in effect, micelles which contain single or multiple chromosomes. To enrich for those containing single chromosomes, the microcells are sized by sequential filtration through polycarbonate membranes of decreasing pore size. The purified microcells are fused to the recipient cells by incubation with polyethylene glycol. Recipient cells containing human chromosomes are selected in antibiotic-containing media and then characterized by fluorescence in situ hybridization (FISH), classical cytogenetic methods and molecular mapping techniques. The growth rate and metastatic ability of the resulting microcell hybrids is tested by the s.c. injection of cells into immunodeficient mice. After 40 to 60 days, animals injected with the control cells have numerous macroscopic metastases per lung. If the human chromosome being tested encodes a metastasis-suppressor gene which is expressed and functional in the AT6.1 or AT3.1 cells, the microcell hybrids are suppressed for metastasis as evidenced by a decrease in the number of macroscopic metastases at the experimental endpoint.

Using this method, several human chromosomes have been introduced into highly metastatic rat prostatic cancer cell lines. The effects of human chromosomes on the tumorigenic and metastatic potential of the aforementioned lines are being tested. By comparing the results in each of these systems, both general and specific mediators of metastasis are being identified. Introduction of human chromosome 11 into highly metastatic, androgen-independent, rat prostatic cancer cells results in suppression of metastatic ability without suppression of in vivo growth rate or tumorigenicity [44]. These results demonstrate that there are genetic alterations which are uniquely required for acquisition of metastatic ability of tumorigenic prostatic cancer cells. Furthermore, these findings support a model in which tumorigenicity and metastatic ability are distinct properties of cancer cells, requiring both common and unique genetic alterations.

Spontaneous deletion of portions of human chromosome 11 in some of these clones revealed that the minimal portion of this chromosome capable of suppressing prostatic cancer metastasis involves a region between 11p11.2-13, not including the Wilms tumor-1 locus [44]. In contrast, transfer of human chromosome 11 into highly metastatic, estrogen-independent rat mammary cancer cells had no effect on the tumor growth rate or metastatic ability [42]. This result indicates that the metastatic-suppressor gene on human chromosome 11p11.2-13 may be prostate cancer-specific. Using these methods, a novel prostate cancer metastasis-suppressor gene, KAI 1, was recently identified [18]. The KAI 1 gene maps to the 11p11.2-p13 region, is strongly expressed in normal human prostatic tissues and is downregulated in human prostatic cancer cell lines derived from metastases. The ability of KAI 1 to function as a metastasis suppressor in vivo was tested, and it was demonstrated that KAI 1 expression suppressed metastasis to the same extent as the 11p11.2-p13 region [18]. The utility of KAI 1 in the molecular substaging of prostatic cancers is currently under way.

Additional efforts to map metastasis-suppressor activities on human chromosome 8, 10, 16 and 17 are currently under way [19]. Clinically, chromosome 17 is a logical candidate for these studies since its loss has been associated with prostate cancers [45, 46]. In addition, Gao et al. have recently reported loss of heterozygosity on chromosome 17 in a region near the familial breast cancer gene (BRCA1) at 17q21 [47]. More recently, Murakami et al. have also reported a tumor-suppressor gene for prostate cancer near the BRCA1 locus [48]. Initial studies demonstrated that chromosome 17 encodes one or more genes which specifically suppress the metastatic ability of prostate and mammary cancer cells [42]. These studies found no apparent correlation between the level of NM23 protein and metastatic ability in the AT6.1-17 microcell hybrids and control cells, suggesting that chromosome 17 encodes additional metastasis-suppressor activities. More recently, four microcell hybrids which had lost regions of human chromosome 17 were identified by cytogenetic techniques using G-banding and FISH analysis with chromosome 17-specific paints [49]. The region of chromosome 17 retained in these "deletion" microcell hybrids was determined with polymerase chain reaction analysis using primers for markers which had been mapped by physical, molecular or linkage techniques. The minimal region retained in these hybrids did not include the TP53, NM23 or BRCA1 loci. These cells were still suppressed for metastasis when injected into severe combined immunodeficiency mice, supporting a role for novel genes in the observed metastasis suppression. High-density maps of the "minimal metastasis-suppressor" region are now being generated using the sequence-tagged sites mapped and reported in the MIT Whitehead database [50]. A combination of physical and candidate gene approaches, as well as functional assays, are being employed to identify the novel genes encoded by this region [Chekmareva MA, Wharam JF, Rinker-Schaeffer CW, unpublished data].

The metastasis-suppressor genes encoded by chromosomes 11, 17, 8 and 16 specifically block the process of tumor metastasis, apparently by complementing a function that is lost in metastatic cells. Currently it is not known whether the activities encoded by these chromosomes represent separate "brakes" for metastasis, or if they possibly function in the same biochemical pathways. By studying a combination of cell panels containing individual human chromosomes, it should be possible to construct a molecular map of chromosomes specifically involved in prostatic cancer metastasis, and to use this information for positional cloning of genes involved in this process.


   Conclusions
Top
 Abstract
 Introduction
 Prostate Cancer Cell Motility
 The Role of Metastasis...
 Conclusions
References
 
There has been a recent emphasis on the early detection and screening of men for prostate cancer. Enhanced screening has already resulted in a significant increase in the number of pathologically organ-confined prostate cancers detected each year. However, the relatively indolent course of many prostate cancers and the advanced age at diagnosis suggest that many men may be managed expectantly. It is a difficult clinical decision to ascertain which patients should be followed conservatively and which should undergo immediate therapy. In addition, if surgical therapy is chosen, it must be determined which of these patients should be given adjuvant therapy in addition to definitive local treatment. Cellular and molecular markers for biological aggressiveness, especially the acquisition of metastatic ability, may allow for the development of a more accurate method for predicting the outcome of individual patients with prostate cancer.

Innovative approaches which can ultimately substage individual tumors and perhaps even control their metastatic ability are currently being pursued. The finding that increased cellular motility is strongly associated with metastatic ability provides both a potential prognostic factor and a therapeutic target. In contrast, the loss of metastasis-suppressor functions may provide a sensitive marker for specifically predicting the metastatic potential of clinically localized prostate cancer. Since aggressive screening for prostate cancer could potentially identify 10,000,000 American men with histological prostate cancer, the need for tools to characterize prostate cancer beyond a simple diagnosis is needed. A clearer understanding of the cellular and molecular events involved in the progression of prostate cancer may include insights gained from the study of cancer cell motility and metastasis-suppressor genes.


   Acknowledgments
 
We would like to thank Ms. Carol L. Kelly and Mrs. Patricia McQueen for their assistance and in the preparation of this manuscript. We also wish to acknowledge the editorial efforts of Mr. Edwin F. Schaeffer III.

This work is supported in part by American Cancer Society Institutional Grant IGR41-35-3 and Council for Tobacco Research Grant 4225.


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Top
 Abstract
 Introduction
 Prostate Cancer Cell Motility
 The Role of Metastasis...
 Conclusions
 References
 

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  50. http://www–genome.wi.mit.edu/cgi–bin/contig/phys_map

accepted for publication May 9, 1996.




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