* Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; and
Department of Pathology, University of Western Ontario, London, Ontario, N6A 5C1, Canada
Received August 2, 1999; accepted November 5, 1999
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ABSTRACT |
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Key Words: cadmium; carcinogenesis; rats; sarcoma; tumor progression; tumor invasion; tumor metastasis.
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INTRODUCTION |
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The toxic effects of metals, including Cd, can sometimes be mitigated by prior exposure to low doses of the same metal (Goering et al., 1994; Klaassen et al., 1999
). The acquired self- tolerance to Cd is thought to have some basis in toxicokinetics but primarily concerns specifically modified tissue responses (Goering et al., 1994
; Klaassen et al., 1999
). Induction of the synthesis of metallothionein (MT), a metal-binding protein, after metal exposure is clearly one of the primary modifications in acquired tolerance to Cd (Klaassen et al., 1999
). The carcinogenic effects of Cd can also be modified by low-dose pretreatment, but only for some tissues such as the testes (Waalkes et al., 1988
). At the injection site, a low dose-Cd pretreatment does not block sarcoma formation induced by a subsequent carcinogenic dose of Cd (Waalkes et al., 1988
). On the other hand, zinc treatment can reduce Cd-induction of ISS (Waalkes et al., 1989
) while zinc deficiency states enhance the appearance ISS after Cd injection (Waalkes et al., 1991a
). Generally speaking, the development of tolerance in Cd carcinogenesis is only poorly understood.
Although the carcinogenic mechanism of Cd is not well defined, recent in vitro evidence indicates that this metal may also enhance progression of tumor cells (Abshire et al., 1996; Haga et al., 1996
, 1997
). For instance, when a malignantly transformed rat myoblast cell line is chronically exposed to certain levels of Cd in vitro, and is then inoculated into immunodeficient mice, tumors progress much more rapidly and are highly invasive in comparison to tumors arising from control cells (Abshire et al., 1996
). The enhanced malignant progression seen with in vitro Cd exposure causes increased host lethality after inoculation (Abshire et al., 1996
). This enhancement of progression, based on accumulated in vitro dose of Cd (Abshire et al., 1996
), indicates that repeated or continuous exposures to Cd may modify malignant progression. Similarly, fibrosarcoma cells made resistant to Cd by chronic in vitro exposure showed a much higher invasiveness into recombinant basement membranes than the parent cell line (Haga et al., 1997
). Furthermore, Cd exposure of host-cell monolayer fibroblasts or endothelial cells can enhance invasiveness of a fibrosarcomatous tumor cell line (Haga et al., 1996
). These results indicate that both tumor-cell and host tissue can be altered by Cd exposure in a way that facilitates tumor invasion and presumably metastasis. Such a "progressor" function for Cd could be very important in multiple exposures to this carcinogenic metal or in combination exposures of Cd and other carcinogens, as would occur, for example, in cigarette smoking. However, the effects of Cd on tumor progression or metastasis in vivo are unknown.
Thus, this study was designed to determine the effects of repeated Cd exposures on tumor incidence, progression, and metastasis in vivo. In this regard, two strains of rat were compared: one which is sensitive to acute Cd toxicity (F344) and one which is resistant (Wistar). We selected ISS as the tumor model, which can be induced in F344 and Wistar rats by a single sc injection of Cd (Waalkes et al., 1988, 1991b
). In addition, it can be monitored externally to test the effects of multiple Cd exposures on tumor progression. Since MT is clearly associated with repeated Cd exposure (Klaassen, et al., 1999
) and may be important in enhancing tumor cell invasiveness and metastasis (Haga et al., 1996
, 1997
, 1998
), we carried out additional studies to investigate MT expression in primary and metastatic sarcomas by immunohistochemistry.
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MATERIALS AND METHODS |
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The experimental design of the present study is shown in Table 1. For injection cadmium (CdCl2µ2
H2O; J. T. Baker Co.) solutions were prepared in sterile normal saline. At 8 weeks-of-age, animals were divided into groups as designated in Table 1
and treated subcutaneously (10.0 ml/kg) with 10, 20, or 30 µmol Cd/kg, as CdCl2, once weekly for 18 consecutive weeks. One other group of each strain was given a low loading dose (3 µmol/kg, sc) one week prior to 17 weekly injections of 30 µmol/kg. Controls received vehicle (saline). Injections were given in the dorsal thoracic midline (henceforth referred to as the injection site). Body weights, survival, and clinical signs were recorded throughout the experiment. Body weights were recorded weekly for the first 26 weeks and biweekly thereafter. Clinical signs were checked daily. Animals were killed when significant clinical signs developed or at 104 experimental weeks.
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Metallothionein in primary and metastatic sarcomas.
Localization of MT was examined immunohistochemically in primary ISS and pulmonary metastases. Multiple sections of several sets (WF, 6 primaries and 6 pulmonary metastases; F344, 3 each) were stained for MT. The immunohistochemical localization of MT was performed by the peroxidase-antiperoxidase method using a polyclonal rabbit antibody against rat liver MT (Banerjee et al., 1982). This antibody readily cross-reacts with MT from various species as demonstrated in several previous studies (Banerjee et al., 1982
; Nartey et al., 1987
). In the final reaction, the color was developed with diaminobenzidine in the presence of 0.3% hydrogen peroxide. Hematoxylin was used as a counterstain. The specificity of the antibody for MT was tested with different control experiments as described earlier (Nartey et al., 1987
). Normal rabbit serum was substituted for the primary antibody and used as the negative control, while sections of kidney from rats acutely treated with cadmium, which induces high levels of MT, were used as the positive control.
Data analysis.
In all cases, a one-sided probability level of p 0.05 was considered to indicate a significant difference. In pairwise comparison of lesion incidence, Fisher's exact test was used. Body weight data were examined by Dunnett's t-test after ANOVA. Survival was examined with the Cox test and the generalized Kruskal/Wallis test and was considered significantly different only if so indicated by both tests. In all cases, the number of rats at risk is defined as the number of rats surviving at the time of the appearance of the first tumor of any type (21 weeks). Latency of ISS was defined as the average time in weeks to death or sacrifice with ISS.
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RESULTS |
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DISCUSSION |
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Similar to the results in vivo in the present study, there are several model systems of tumor invasion or progression in which Cd has a striking effect (Haga et al., 1996, 1997
; Abshire et al., 1996
). In this regard, one study has shown that when myoblastic tumor cells are exposed to Cd in vitro, it can markedly enhance tumor growth of the cells upon inoculation into nude mice (Abshire et al., 1996
). Furthermore, the tumors resulting from inoculation of cells exposed to Cd in vitro appeared histologically more malignant, were more invasive, and more readily precipitated host death as a reflection of aggressive behavior than the tumors resulting from inoculation of untreated cells (Abshire et al., 1996
). Another report shows that, when human fibrosarcoma (HT-1080) cells are chronically exposed to Cd in vitro, the exposure promotes tumor cell invasion of reconstituted membranes, indicative of enhanced tumor invasiveness (Haga et al., 1997
). The authors suspect that these characteristics induced by Cd treatment would promote malignancy and tumor metastasis in vivo (Haga et al., 1997
), which is in accord with the present observations. In fact, it is of interest that the malignant potential of both rodent (present study) and human (Haga et al., 1997
) fibrosarcoma cells appear to be enhanced by Cd exposure. Evidence also indicates that Cd, besides having a direct effect on tumors cells, can modify host tissue response resulting in increased tumor invasiveness (Haga et al., 1996
). In this regard, B16 melanoma cells will invade into samples of explanted organs from Cd-treated mice much more readily than similar tissue samples from control mice (Haga et al., 1996
). This includes explanted lung and liver (Haga et al., 1996
), both of which were target tissues for metastasis of ISS in the present study. Additionally, in cell monolayer assays of invasiveness using either human fibroblast (WI-38) or bovine carotid artery endothelial (HH) cells as host monolayers, human HT-1080 fibrosarcoma cells invaded much more readily into host monolayers pretreated with Cd (Haga et al., 1996
). So it appears that, although the precise mechanism cannot be defined in the present study, both tumor cell and host tissue factors may play a role in the enhanced tumor progression and aggressiveness seen with repeated Cd exposures. The long biological half-life of Cd indicates that relatively late, host tissue-mediated effects would be a reasonable possibility.
The strain-related differences seen in the present study with Cd-induced, enhanced tumor progression indicate that genetic factors may well play an important role in this effect of Cd. In fact, it appears that the strain that was most tolerant to the acute toxic effects of Cd (WF) was also the one that was the most sensitive to Cd-induced, enhanced tumor progression. The F344 rat is one of the more sensitive strains of rat with regard to the acute toxicity of Cd, as seen in this and other studies (Kuester et al., 1999; Waalkes et al., 1991b
). This indicates that initial tolerance may actually predispose the animal to Cd induction of the metastatic and/or invasive phenotype. In this regard, it is well recognized that a low loading dose of Cd will make animals or cells tolerant to the effects of subsequent, normally toxic doses of Cd (see Goering et al., 1995 and Klaassen et al., 1999 for review). In the present study, the low loading dose (3 µmol/kg) effectively abolished the high acute lethality (57%) of the highest dose of Cd (30 µmol/kg) in F344 rats, clearly demonstrating this acquired-tolerance phenomenon. Interestingly, it was the groups that received this low loading dose of Cd, and were, therefore, made tolerant to acute effects of Cd, that eventually showed the most aggressive tumors in both strains. This also supports an association between acute tolerance and predisposition to development of aggressive tumors with repeated Cd exposure. This could be due to altered cell-population dynamics in that, with a resistant cell population, more cells, including cells more heavily damaged, would survive the initial Cd exposure. In this regard, the 2 highest weekly doses used in the present study (i.e., 20 and 30 µmol/kg) are in fact often effective in inducing ISS if given as a single dose, although they rarely metastasize (IARC, 1993
). Enhanced survival of cells with more DNA damage would presumably allow tumor progression to occur more rapidly. Recent evidence indicates that at least under some circumstances, Cd can block apoptosis produced by certain DNA damaging agents (Shimada et al., 1998
; Yuan et al., 1999
). Thus, if the first several doses of Cd were effective in tumor initiation, subsequent doses, by blocking apoptosis, may allow survival of genetically damaged cells. In any event, it appears cellular survival of the initial Cd exposure, for whatever reasons, is a key in the development of these Cd-induced aggressive tumors.
Initial tolerance also appears to affect ISS incidence as well as latency, at least in Wistar rats. In Wistar rats given a single injection of 30 µmol/kg, the average latency (time to death with tumor) of ISS was over 20 weeks longer (87.0 ± 4.3 weeks) (Waalkes et al., 1991b, 1989
) than latency of ISS in rats given repeated injections of the same dose in the present study (65.7 ± 5.3). Similarly, the incidence of ISS (40%) in Wistar rats given a single dose of 30 µmol/kg (Waalkes et al., 1991a
, 1989
) appeared higher in rats given the same dosage, only repeatedly, in the present study (67%). These comparisons may not be totally valid as they compare outbred Wistar [Crl:(WI)BR] rats used in the prior study (Waalkes et al., 1989
) and inbred WF rats in the present study. However, both these Wistar substrains are certainly resistant to the acute toxic effects of Cd when compared to the F344 rat. Furthermore, with F344 rats a prior study showed that a single sc dose of 30 µmol/kg produced a 66% incidence and a 65.3 ± 2.9 week latency of ISS (Waalkes et al., 1991b
), which is remarkably similar to the incidence (67%) and latency (67.0 ± 7.6 weeks) in the present study. Based on these results, it appears that the strain generally less sensitive to acute Cd toxicity (Wistar) is more sensitive to the enhancing effects of repeated Cd exposure on tumor progression. Thus, again it appears that initial tolerance allows the more rapid formation of more highly aggressive tumors with repeated Cd exposure. The observation that acute tolerance to Cd toxicity does not translate into tolerance to the carcinogenic effects of Cd, at least with regard to Cd-induced enhanced tumor progression and metastasis, is both counter-intuitive and surprising.
Tolerance to acute Cd toxicity can be induced by a variety of substances, including other metals, and is generally associated with induction of MT synthesis (Goering et al., 1995; Klaassen et al., 1999). However, tolerance to Cd does not, in all cases, require MT and can be induced in cells through means that involve reduced uptake of the toxic metal ion (Takiguchi and Waalkes, 1999
). In the present study, the primary sarcomas showed high levels of MT. The staining for MT in the primary ISS was frequently most intense in the nucleus, a characteristic thought to be associated with rapid proliferation (Cherian, 1993
). Therefore, the expression of MT in the ISS of the present study could be a reflection of their rapid proliferative growth. In fact, many tumors show intense staining for MT, but others are heterogenous or show minimal staining (Cherian, 1993
;Waalkes and Perez-Ollie, 1999
). Given the long residence time of Cd at the injection site (Kasprzak and Poirier, 1985
), the MT in the ISS could also represent a response to residual Cd, as Cd is one of the better MT-inducing agents (Klaassen et al., 1999
). Alternatively, this heightened MT expression in ISS could be a genotypic response affording tolerance to the repeated Cd exposure, as seen in vitro or in vivo with acquired self tolerance to Cd (Klaassen et al., 1999
). In any event, there is some evidence that MT may be important to invasion and metastasis (Haga et al., 1998
). When HT-1080 fibrosarcoma cells are treated with propargylglycine (PPG) to deplete cellular MT, the ability of these cells to invade a reconstituted basement membrane is significantly reduced (Haga et al., 1998
). The authors hypothesize that increased MT levels correlate with invasiveness and metastatic potential (Haga et al., 1998
), which would be consistent with the metastatic potential and high MT levels in the primary ISS in both F344 and WF rats from the present study. PPG can have many effects beyond a simple depletion of MT, so this cannot be considered conclusive evidence of a role of MT in progression. In a study which used antisense MT and found suppression of leukemia P388 cell growth, the authors concluded that the growth of neoplastic cells depends on expression of the MT gene (Takeda et al., 1999
). However, tumors and tumor cell lines show a great diversity of MT expression from minimal to high (Waalkes and Perez-Ollie, 1999
Woo et al., 1997
) and the role of MT in tumor cell pathobiology and growth is, at best, complex and poorly defined.
Whatever the basis for the high levels of MT in the primary ISS, our results show that the ISS cells, once having metastasized, are essentially devoid of MT in both the WF and F344 rats. This argues against a major role for MT in metastasis, although very early metastases were not observed and the stimulus for MT may be lost because of the new tissue environment of the metastatic tumor. Alternatively, the metastatic cells may originate from the least well-differentiated subpopulation in the primary tumor and hence the associated loss of MT expression. In this scenario, the cells most prone to metastasis may be the cells expressing the least MT out of the primary ISS cell population. In this regard, the work of Rossman et al. (1997) indicates that suppression of MT expression results in increased spontaneous mutations, indicating that MT may act as an antimutagen, and the loss of MT expression could create a less differentiated state. In fact, it is not infrequent that tumors develop distinctive subpopulations (Cherian, 1993). Our previous studies have shown that MT cannot be detected in the metastatic adenocarcinoma of human liver but the metastases have a greatly increased number of apoptotic bodies (Deng, et al., 1998
). These results suggest that MT may also have an anti-apoptotic effect in human liver (Deng, et al., 1998
). Additionally, in patients with metastatic colorectal cancers, the metastatic lesion contains very little MT (Mulder et al., 1992
). Likewise in lymph node metastases of breast cancers in humans, there is typically minimal evidence of MT expression (Haerslev et al., 1994
) although some breast carcinomas prominently express MT (Cherian, 1993
; Douglas-Jones et al., 1997
). Based on limited available data, it appears that MT is often expressed to a much lesser extent in metastatic tumors when compared to the primary tumor. Further study will be required to define the role of MT in tumor-cell progression and metastasis. Perhaps the use of MT-null mice in assays of tumor cell metastasis would be appropriate.
The observation that repeated exposures to Cd has an impact on tumor progression could have important implications in humans exposed to Cd. Industrial Cd exposures are undoubtedly multiple events over many years. Furthermore, it is estimated that cigarette smoking will double the total lifetime body burden of Cd, because of the Cd content in tobacco (Elinder, 1985). So, in this case there would be repeated exposures to Cd along with all the other organic carcinogens contained in tobacco smoke and a role of progressor for Cd could be quite important. In this regard, smoking cessation can reduce cancer deaths even after diagnosis of a primary lung cancer, although it is very premature to attribute any such effect to Cd.
Repeated Cd exposures, with the consequent high accumulated doses, and associated body-weight suppression and reduced survival, suppressed a variety of spontaneously occurring tumors in the present study. This included suppression of leukemias, pituitary adenomas, testicular interstitial-cell tumors, and adrenal pheochromocytomas. The suppression of these common spontaneous tumors is not unusual under such circumstances and is likely due to a combination of reduced body weight, reduced survival, and/or enhanced cytotoxicity. With the testicular tumors in WF rats, Cd at lower doses first increased tumor incidence; then, at higher doses, caused tumor suppression. Cd induction of testicular interstitial cell tumors has been widely reported after single systemic exposures (IARC, 1993; Waalkes et al., 1997
). Cd causes acute testicular necrosis and subsequent atrophy and loss of testicular function, including androgen production (Waalkes et al., 1997
). After this acute phase reaction, it is likely that the remnant interstitial cell population, which has largely lost its androgen production capacity, is chronically overstimulated by gonadotropin, resulting in a proliferative response and hence, tumor formation (Waalkes et al., 1997
). The loss of tumor response in the testes, at the highest accumulated doses of Cd in the present study, may well be due to a more complete destruction of the interstitial cell population, allowing the survival of remnant cells in sub-minimal numbers to eventually form tumors.
In summary, the present results indicate that repeated exposures to the carcinogenic, inorganic Cd can result in the more rapid onset of more highly aggressive tumors. The mechanism of this effect is yet undefined, but this could have an important impact on hazards posed by multiple Cd exposures alone or in combination with exposure to other carcinogens. Finally, acute tolerance to Cd toxicity does not appear to translate into tolerance to the carcinogenic effects of Cd, at least with regard to Cd-induced enhanced tumor progression and metastasis.
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ACKNOWLEDGMENTS |
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NOTES |
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2 Present address: SmithKline Beecham, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406.
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