Affiliations of authors: B. A. Yoshida, M. M. Sokoloff, C. W. Rinker-Schaeffer, Section of Urology and Genitourinary Oncology Research Program of the University of Chicago, IL; D. R. Welch, The Jake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine, Hershey.
Correspondence to: Carrie W. Rinker-Schaeffer, Ph.D., Section of Urology, Department of Surgery MC6038, The University of Chicago, 5831 S. Maryland Ave., Chicago, IL 60637 (e-mail: crinker{at}surgery.bsd.uchicago.edu).
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ABSTRACT |
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CLINICAL PROBLEM: PREDICTING METASTATIC PROPENSITY |
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The incidence of disease recurrence in surgical patients treated for prostatic and breast cancers illustrates this problem particularly well. Although we have a wealth of clinical and biologic information on these diseases, a large percentage of apparently resectable and theoretically curable lesions is found to be more advanced at the time of resection than envisaged, resulting in a substantial failure rate after attempted curative surgery (68). In studies of prostate cancer patients (911), even when patient selection excludes men with factors predicting poor prognosis (e.g., poorly differentiated histology, high prostate-specific antigen [PSA] levels, and clinical suspicion of local invasion), the relapse rate after radical retroperitoneal prostatectomy has approached 20%30%. Similarly, one third of surgical patients with lymph node-negative breast cancer will develop metastases, while the other two thirds, despite receiving no chemotherapy, will not (12). Even in patients with small tumors and tumor-negative lymph nodes (T1N0), there is a 15%25% likelihood of distant metastases (8).
Since the current staging systems for breast and prostate cancers do not accurately identify those patients curable by regional treatment alone, the evaluation of additional parameters associated with the metastatic phenotype will be very important for the differentiation of patients curable by surgery alone from those requiring systemic therapy. For instance, men at high risk for relapse of prostate cancer can be identified [e.g., serum PSA level >10 ng/mL; clinical stage T1 or T2 with >50% of tissue at Gleason grade 4 (3,4) on biopsy or clinical stage T3 prostate cancer] and would be immediate candidates for adjuvant antimetastatic therapies if they existed (10,11,1316). Likewise, breast cancer patients with particularly poor prognoses can be identified by the detection of high microvessel counts concurrent with low expression of Nm23 and/or E-cadherin in the primary tumor (1217). In fact, these parameters are better prognostic biomarkers than the conventional analysis of tumor size and grade. The information obtained from the simultaneous evaluation of biomarkers such as these have the potential to lead to a reduction in the morbidity among those patients not requiring chemotherapy and possibly identify those patients requiring more aggressive therapies than indicated by current methods.
Overall, it is clear that there is a critical need for markers that will distinguish accurately those histologic lesions and disseminated cells that have a high probability of causing clinically important metastatic disease from those that will remain indolent (5,15). Concerns have been raised that "metastasis" has often occurred by the time of diagnosis of the primary tumor, the implication being that it is then too late for antimetastatic therapy to be of use (18). However, the mere spread of cancer cells into the vasculature or to a secondary site does not constitute metastasis. Development of clinically significant metastases requires that a cancer cell complete a series of well-defined steps, generally referred to as the metastatic cascade (13). If a cell fails to complete any one of these steps, overt metastases will not develop (1315).
The clinical importance of disseminated cancer cells (detected by sensitive methods such as reverse transcriptionpolymerase chain reaction [RTPCR]) has become an issue of considerable interest (19). Several such studies (16,20) have reported the detection of tumor-derived cells in the circulation and bone marrow without future development of disease. Other reports have demonstrated an increased risk of disease recurrence in patients with bone marrow micrometastases both for prostate cancer [by the detection of messenger RNA transcripts for PSA (21)] and breast cancer [by the detection of cytokeratin-positive cells (22)]. Even in these later studies, however, the majority of patients with tumor cell-positive bone marrow samples did not actually develop recurrent disease, although the proportion with recurrence could increase given extended time for patient follow-up. The discrepancy regarding the clinical importance of disseminated cells is likely due to differences in the experimental approaches used to identify cells (i.e., RTPCR versus immunohistochemical detection).
Tumor cell growth at the site of metastasis is an important clinical target, since cells must survive and proliferate to grow into overt, macroscopic metastases. The first step toward developing effective therapies to inhibit such growth is to identify the genes/proteins that regulate metastatic colonization. To this end, a growing number of laboratories are focusing translational research efforts on the discovery of genes that specifically regulate the metastatic ability of cancer cells. For example, several metastasis-promoting genesincluding WDNM-1, WDNM-2, MMP11 (stromelysin-3), MTA1, and ERBB2have been identified in association with the development of metastatic breast cancer (2327). One must keep in mind, however, that it takes the coordinated expression of many genes to allow the development of metastases (28,29). Thus, while it is relatively easy to demonstrate an association for a given gene with metastatic ability, it is difficult to prove that a particular gene is essential. On the other hand, it only takes one gene to block metastasis, since inability to complete any step of the metastatic cascade renders a cell nonmetastatic. Metastasis-suppressor genes suppress the formation of spontaneous, macroscopic metastases without affecting the growth rate of the primary tumor. It has now been more than 10 years since the discovery of the first metastasis-suppressor gene nm23 (NME1) (30). Since then, both in vitro and in vivo (e.g., animal) studies (15,3032) have documented the important role of the loss of metastasis-suppressor gene function in the acquisition of metastatic ability.
While the initial motivation for these studies was the development of new diagnostic markers of metastasis, the biologic approach used to identify metastasis-suppressor genes has provided surprising insights into the in vivo mechanisms regulating the formation of metastases. We anticipate that identifying the molecular pathways that regulate metastatic colonization and growth control at the secondary site will provide additional, potentially novel therapeutic targets for the treatment of metastatic disease. The purpose of this review is 1) to present the evolving view of the mechanisms that regulate metastasis, 2) to describe the functional strategy used to identify metastasis-suppressor genes and discuss important principles learned from these studies, 3) to document the known metastasis-suppressor genes and report new evidence that supports their role in the regulation of growth control at the secondary site, and 4) to discuss the multidisciplinary approach needed to translate metastasis-suppressor genes into clinical tools.
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REGULATION OF METASTATIC PROPENSITYEVOLVING PARADIGMS |
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Cancer metastasis, both clinically and experimentally, is known to be inefficient (36). In experimental models, fewer than 0.1% of cells injected into the circulation go on to form secondary tumors (15,37). While many factors contribute to the observed inefficiency of metastasis formation, those considered to be most important include the low survival rates of cells in the circulation and the low percentage of cells that successfully escape from the vasculature into surrounding tissues (18). At this time, there is some question as to whether postextravasational growth control or growth within a vessel are more predominant (38). This process has, for the most part, been studied using assays in which the number and kind of cells injected are known and the numbers and sizes of metastases formed are assessed (18,39). The processes that are responsible for metastatic efficiency in vivo remain hidden; thus, mechanistic paradigms have largely been based on logical inference rather than on direct observation. The development of new technologies has enabled researchers to test the possibility that cancer cell dissemination, arrest (nonspecific arrest and/or specific adhesion events), and growth at the secondary site are critical determinants in metastasis formation.
The ability to observe single cells in vivo has been greatly enhanced by improvements in intravital microscopy and the use of vital fluorescent dyes like green fluorescent protein (GFP) (18,40). Studies that couple these two powerful techniques have added greatly to our knowledge of the metastatic processes following tumor cell entry into circulatory compartments. The use of in vivo video microscopy allows for the direct observation of experimental metastasis over time (39). Cancer cells can be fluorescently labeled in vitro and then injected into an animal. The cells can then be viewed at different time points, by both fluorescence and oblique transillumination, in thin tissues or superficial (50 µm) regions of thick tissues in vivo (39). Experiments using this technology have demonstrated that, in contrast to the long-held belief, the vast majority of cancer cells in the microcirculation manage not only to survive there but also to extravasate into the surrounding tissue within 12 days (41,42). Such studies have translated well into the clinical arena. Specifically, the vast majority of clinical studies using RTPCR to detect prostate tumor cells in the peripheral circulation and bone marrow found no association between the detection of disseminated cells and treatment failure (16,20). Of interest, in a recent study of breast cancer patients (22), detection of cytokeratin-positive cancer cells in the bone marrow was associated with the development of overt metastases and death. The apparent difference between these two findings may be due to differences in study design (e.g., detection methods and markers used) or in factors that influence the growth of disseminated cancer cells at the metastatic site. Additional studies will be necessary to distinguish between these possibilities. Taken together, the clinical and experimental evidence supports the observation that dissemination from the primary tumor site is a frequent event. Furthermore, these independent and complementary studies strongly suggest that growth control of individual disseminated cells determines the efficiency of metastatic colonization.
Metastatic colonization is the lodging and subsequent growth of disseminated cancer cells to form clinically significant metastases (Fig. 1, B). To proliferate, surviving disseminated tumor cell(s) must be able to initiate cell-appropriate, context-dependent signaling cascades, which enable them to survive, enter the cell cycle, and divide. While disseminated cells are likely to be present in numerous organs, only certain environment(s) appear to allow their survival and subsequent growth (37,43,44). Intercellular interactions with the stroma and with other tumor cells are critical for tumor cell survival and involve the activation of adhesion-dependent survival pathways, such as those described for E-cadherin (45,46) and integrin molecules (47). Clusters of proliferating cells grow into lesions consisting of a few hundred that can be detected reliably by histologic methods. Cells within such microscopic lesions can receive oxygen and nutrients by diffusion. Progressive growth of microscopic lesions into overt or macroscopic metastases (>1 mm in diameter) requires that the fraction of proliferating cells exceed the fraction that are quiescent or apoptotic. This transition from microscopic to macroscopic metastasis has often been referred to as the switch to an angiogenic phenotype or the angiogenic switch (48). This terminology implies that microscopic metastases exist in one of two states: Either the lesion is angiogenic (forming new blood vessels), or it is not. However, the progression from a "microscopic lesion" to an overt metastasis is more accurately described in terms of growth control. Indeed, the interchangeable use of "angiogenesis" and "growth" has been a source of confusion. This progression may occur over a period of months or even years and is not necessarily dependent on new blood vessel formation. Vascularization is, in fact, a late step in metastatic colonization (49). Recent studies have shown that, in addition to the induction of classical neovascularization via endothelial cell recruitment, tumor cell masses can develop a blood supply by alternative means, such as the cooption of pre-existing host vessels (49) or by the formation of tumor channels, a process referred to as vascular mimicry (50). As we will describe in the following paragraphs, recent data from our laboratories suggest that a subset of metastasis-suppressor genes inhibits early steps in metastatic colonization, prior to the need for development or recruitment of vessels.
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IDENTIFICATION OF METASTASIS-SUPPRESSOR ACTIVITY: A FUNCTIONAL APPROACH |
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Studies using highly metastatic Dunning rat prostatic cells as the recipients for chromosomal transfer (63,64) showed that chromosomes 12 and 17 specifically suppressed the metastatic ability of these cells. The observed metastasis suppression had no effect on tumor growth rate. Of interest, in analogous studies of human prostate cancer cell lines, transfer of these chromosomes suppressed the cells' tumorigenicity (69,70). These findings could result from at least three alternative mechanisms. First, a given chromosomal region may encode a number of different genes, one or more of which may be active as a tumor-suppressor gene in human prostate cancer cells but be inactive or not expressed in rat prostate cancer cells. Second, genes may function as metastasis-suppressor genes when expressed in rat prostate cancer cells but may be inactive or not expressed in human prostate cancer cell lines. Third, gene(s) that lie in the same chromosomal region may have different functions, depending on the context (i.e., cell type) in which they are expressed.
In the third scenario, the effect of the gene product may be limited or determined by the recipient cells. We refer to this scenario as the "cellular hard-wiring" hypothesis.1 For example, human prostate cancer cell lines compared with Dunning rat prostate cancer cell lines are weakly metastatic in spontaneous metastasis assays (62). These differences in their in vivo biologic activities could be the result of genetic differences between the tumor cells, or they could result from an epigenetic mechanism, such as differential tumorstromal interactions. The nature of cellular interactions with the extracellular matrix can regulate tissue-specific gene expression, since cells form an elaborate three-dimensional network composed of the nuclear, cytoskeletal, and extracellular matrices (27,71). Thus, the differential effects of a given chromosome transferred into different cell types can be the result of differential expression of the genes on the chromosome as determined by the way a cell responds to its environment.
During the past decade, several human chromosomes have been functionally tested through the use of MMCT, and metastasis-suppressor activities have been reported on chromosomes 1, 6, 7, 8, 10, 11, 12, 16, and 17 (63,64,7282) (Table 1). Such functional studies, combined with positional and expression-based gene cloning techniques, have enabled the identification of KAI1, KISS-1, MKK4/SEK1, and BRMS1 as metastasis-suppressor genes.
Metastasis-Suppressor Genes
As discussed earlier, metastasis-suppressor genes suppress the formation of spontaneous, macroscopic metastases without affecting the growth rate of the primary tumor. To date, five genes, nm23 (NME1), KAI1, KiSS1, BrMS1, and MKK4 (MAP2K4), have been shown to meet the criteria of a metastasis-suppressor gene [see Table 2; (31,32,83119)]. The role of other genes, such as CD44 and maspin/PI5, in metastasis suppression is less well defined (102,120131). The potential mechanism of action of all of these genes has been inferred by analogy to other family members and observations in model systems. How these genes and their protein products function to suppress metastasis in vivo is the subject of enthusiastic study. Decreased expression of the suppressor gene is the key parameter determining metastatic potential and may occur by a variety of mechanisms, not necessarily LOH (32,91). To date, nm23 (NME1) and KAI1 are the best-characterized metastasis-suppressor genes.
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The prototypical metastasis-suppressor gene, nm23, was identified in the murine K1735 melanoma by use of subtractive hybridization (a method to identify genes differentially expressed between two cell lines), and six human homologues have been identified (90). Loss of Nm23-H1 expression is associated with metastatic potential in many, but not all, late-stage tumors (91). Transfection of nm23-H1 cDNA into highly metastatic murine melanoma, rat mammary adenocarcinoma, and human breast cancer and melanoma cells reduces their invasiveness and metastatic ability in vivo (91). In cancers, such as lung, colon, prostate, etc. [reviewed in (87)], where no alterations in the expression pattern of Nm23-H1 are evident, it is possible that the biologic function of Nm23-H1 does not influence malignant progression in these cell types. Alternatively, its effects may be inhibited by alternate mechanisms. The mechanism of action for metastasis suppression by Nm23 still remains unknown; however, evidence suggests that it is phosphorylated and may be involved in a novel signaling pathway that, in turn, controls cell motility (84,87).
KAI1
The localization of metastasis-suppressor activity to rat chromosome 2 in the cell fusion experiments by Ichikawa et al. (57) prompted the search for homologous metastasis-suppressor genes for human prostate cancer. The first of such genes identified was KAI1. MMCT was used to transfer human chromosome 11 into Dunning AT6.1 and AT3.1 rat prostate cancer cells, and the resulting microcell hybrids were assayed for metastasis suppression in immunodeficient mice (81). These studies led to the identification of the metastasis-suppressor gene KAI1, which maps to 11p11.2p13 (101). The metastasis-suppressor activity of KAI1 was subsequently demonstrated by transfecting it into AT6.1 cells and assaying the metastatic ability of individual transfected control cell lines in severe combined immunodeficient (SCID) mice (101). Reports (101,110) suggest that expression of KAI1 decreases both the invasiveness and motility of cells in vitro. Additional studies show that KAI1 transfectants exhibit enhanced Ca2+-independent aggregation, indicating that KAI1 expression alters cellcell interactions (109). The metastasis-suppressor activity of KAI1 was subsequently demonstrated by its transfection into AT6.1 cells and assaying the metastatic ability of individual transfected control cell lines in SCID mice (101). Lowered expression of KAI1 has also been associated with progression in a wide variety of cancers, including pancreatic, hepatocellular, bladder, breast, and non-small-cell lung cancers (31,133136), as well as esophageal cell carcinomas (137) and squamous and lymphoid neoplasms (138). These data suggest that KAI1 has a conserved metastasis-suppressor function. Furthermore, these studies demonstrate that metastasis-suppressor genes can be developed as clinical markers even before their biochemical mechanism of action has been elucidated.
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EMERGING ROLE OF METASTASIS-SUPPRESSOR GENES IN THE REGULATION OF METASTATIC GROWTH |
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Chromosome 17
We have reported the identification of discontinuous portions of human chromosome 17 (D17S952 D17S805, D17S930
D17S797, and D17S944
qter) that together suppress the metastatic ability of AT6.1 Dunning rat prostatic cancer cells when introduced via MMCT (63,80). PCR and Southern blot analyses demonstrated that three of the four markers on 17p13, including HIC1 and TP53, and 12 of the 13 markers in 17q21-23, including BRCA1 and the metastasis-suppressor gene NME1 (nm23), were not retained in this region (63). AT6.1 microcell hybrids containing this portion of chromosome 17 were tested in vivo in spontaneous metastasis assays. Spontaneous metastasis is measured by the ability of tumor cells to form a locally growing tumor at the site of injection and disseminate and grow at to secondary sites thereafter.
At the experimental end point, the number of overt surface metastases observed in the lungs from mice with AT6.117 tumors was reduced 15- to 30-fold compared with lungs from mice bearing parental AT6.1 tumors (63). This suppression could be due to the inhibition of any step within the metastatic cascade. We reasoned that examination of the biology of metastasis suppression would provide clues to the identity of genes responsible for suppression of metastatic growth. A series of in vivo experiments were conducted, and no evidence was found to suggest that there is a decrease in the number and/or viability of tumor cells colonizing the lung (80).
On the basis of these findings, we hypothesized that a gene or genes encoded by the suppressor region of chromosome 17 function by inhibiting the growth of metastases in the lung (139). To test this possibility, AT6.117 cells were transduced with a ß-galactosidase reporter gene construct (AT6.117Tßgal cells) and tested in spontaneous metastasis assays (2). At the experimental end point, animals were killed and the excised lungs were stained for ß-galactosidase expression. This approach allowed the visualization of microscopic AT6.117ßgal surface metastases. Subcutaneous injection of AT6.1 parental cells resulted in the formation of a mean number of 97 overt surface metastases (detected using Bouin's fixation) per lung (Fig. 3, A; left). As expected, the number of overt macroscopic metastases after the subcutaneous injection of AT6.117-Tßgal cells was greatly reduced (Fig. 3
, A; middle). In contrast, when lungs removed from the mice carrying AT6.117-Tßgal tumors were stained for ß-galactosidase activity, numerous blue-staining microscopic metastases were observed (Fig. 3
, A; right). Of interest, the mean number of AT6.117-Tßgal micrometastases (i.e., 62 ± 12 standard error [SE]) detected by this method is on the same order of magnitude as the mean number of macroscopic AT6.1 metastases (i.e., 97 ± 6 SE). These results demonstrate that AT6.117 cells do escape from the primary tumor and arrive in the lungs but do not form large metastatic foci (139). Development of overt metastases was associated with loss of the metastasis-suppressor region of chromosome 17 (139).
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Taken together, our data suggested that AT6.117 cells escape from the primary tumor but are growth inhibited at the secondary site (139). If this is an early event, we predicted that viable, disseminated AT6.1 and AT6.117 cells should be present in the lung at very early time points. We found that viable cells could be harvested from the lungs of both AT6.1 and AT6.117 tumor bearers as early as 18 days after injection (Fig. 3, B). Our preliminary time-course data show that AT6.117 cells disseminate and lodge in the lungs but have an extended latent period as compared with AT6.1 parental cells.
Chromosome 6
On the basis of the high incidence of chromosome 6 abnormalities in late-stage human melanoma (141), we introduced an intact chromosome 6 into the highly metastatic C8161 human melanoma cells by MMCT. Parental cells formed tumors in every mouse given an intradermal injection of 1 x 106 cells, and more than 90% of the mice developed regional lymph node and lung metastases. In contrast, chromosome 6-C8161 hybrids (neo6/C8161) were still tumorigenic but completely suppressed for metastasis (142). Intravenous injection of neo6/C8161 cells also did not produce metastases. In a recent study (143), introduction of a version of a chromosome 6 with deletions on the long arm allowed refinement of the metastasis-suppressor locus to a 40-megabase (Mb) region represented by chromosomal bands 6q16.3q23.
The mechanism of action for the metastasis-suppressor protein from the gene on chromosome 6 was studied using a variety of in vitro and in vivo techniques. The neo6/C8161 cells were still locally invasive, and cells were even detected in efferent vessels. This finding implied that the step(s) in the metastatic cascade inhibited by introduction of chromosome 6 occurred subsequent to intravasation. The identity of those steps was not further elucidated using in vitro assays mimicking adhesion, invasion, motility, or growth. No important differences between the metastatic and nonmetastatic cells were observed using the many in vitro assays (72,73,141,142).
For a better definition of the step(s) in metastasis blocked by addition of chromosome 6, cells that constitutively express GFP were engineered. GFP-tagged C8161 and neo6/C8161 cells were injected intravenously into athymic mice. C8161, as expected, formed overt metastases, but neo6/C8161 cells did not. Microscopic metastases (single cells or clusters of <10 cells) were observed in the lungs following neo6/C8161 cell injection, suggesting that these cells lodged in the lungs but failed to proliferate (144). For the determination of whether the fluorescing cells were viable, they were isolated from the lung up to 60 days after injection and grown in culture. On injection into the skin of athymic mice, the neo6/C8161 cells isolated from the lung grew at rates similar to those of previously injected neo6/C8161 cells. This result implies that the gene or genes on chromosome 6 interfere specifically with growth-regulatory responses in the lung but not in the skin.
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FROM GENE DISCOVERY TO CLINICAL UTILITY |
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Technologic advances are enabling us to examine the metastatic process and the genes that regulate it in new ways. This ability has led us to re-evaluate fundamental concepts concerning the determinants of metastatic propensity. In the past, the escape of cells from the primary site was viewed as the rate-limiting step for the development of metastases. The clinical implication was that disseminated cancer cells were destined to grow into lethal metastases; thus, they were not a target for therapeutic intervention (18). Findings from clinical studies and basic research from several independent laboratories have shown that survival and subsequent growth of extravasated cancer cells at the secondary site may determine metastatic efficacy. These observations are driving our laboratories and others to reconsider the role of endothelial celltumor cell interactions in survival, signaling, and growth control cascades to develop new strategies for controlling the growth of disseminated cancer cells (39,45,156).
As metastasis researchers, we find ourselves in the midst of a revolution. In preparing this review, we considered the parallels between recent developments in our field and the development of the field of molecular biology. Much of early molecular biology was pursued by individuals who were not trained as biologists, but as physicists, such as Max Delbrück (157). We are respectful of the observations of Erwin Schrödinger, the father of statistical mechanics, who observed that, "all of the physical and chemical laws that are known to play an important part in the life of organisms are of the statistical kind. The behavior of such systems depends entirely on a large number of molecules that cooperate to form the observed function or phenotype" (158). Although this comment was made in regard to normal biologic processes, it is equally applicable to the multiple genetic changes that are required for the acquisition of metastatic ability. Metastasis is a complex, multigenic phenotype. As such, multiple markers will be needed for the accurate assessment of the metastatic ability of tumors and tumor cells. This need is highlighted by the tremendous impact of seemingly trivial experimental manipulations on the outcome of metastasis assays (155). Parallels have been drawn between the behavior of cancer cells and complex adaptive systems (159,160). As such, very small changes in initial conditions may produce an outcome of such great diversity as to appear random (159). Ultimately, we believe that, to translate our molecular findings into meaningful markers, we will have to go beyond our traditional areas of expertise and work with mathematicians, computational biologists, and others to take this revolution from bench to bedside.
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NOTES |
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Supported by Public Health Service (PHS) grant CA62168 (D. R. Welch) from the National Cancer Institute (NCI), National Institutes of Health (NIH), Department of Health and Human Services (DHHS); by DAMD1-96-6152 (D. R. Welch) from the Army Medical Research and Materiel Fund; by The National Foundation for Cancer Research (D. R. Welch); by The Jake Gittlen Memorial Golf Tournament (D. R. Welch); by PHS grants P20CA66132 and R29CA6948702 (C. W. Rinker-Schaeffer) from the NCI, NIH, DHHS; by Cancer Research Foundation Young Investigator Award (C. W. Rinker-Schaeffer); by the American Foundation for Urologic Disease (B. A. Yoshida and C. W. Rinker-Schaeffer), and by the University of Chicago RESCUE Fund (B. A. Yoshida, C. W. Rinker-Schaeffer).
We thank Ms. Zita Dubauskas and Mr. Edwin F. Schaeffer III for their editorial efforts. We also thank Dr. Charles Brendler of the University of Chicago for his enthusiastic support of this research.
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Manuscript received January 7, 2000; revised August 15, 2000; accepted August 29, 2000.
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