Resistance to melanoma metastases in mice selected for high acute inflammatory response
Durvanei A. Maria,
Orlando G. Ribeiro,
Kazumi F. Pizzocaro,
Marcelo De Franco,
Wafa K. Cabrera,
Nancy Starobinas,
Valerie Gallois1,
Maria Siqueira,
Michel Seman1 and
Olga M. Ibañez2
Laboratório de Imunogenética, Instituto Butantan, Avenida Vital Brazil 1500, CEP 05503900, São Paulo, SP, Brazil and
1 Laboratoire d'Immunodifferenciation, Université Paris 7, Paris, France
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Abstract
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The role of innate immunity in natural resistance to tumor progression was investigated in two mouse lines, AIRmax and AIRmin, selected by bi-directional selective breeding on the basis of high or low acute inflammatory response. Compared with AIRmin, AIRmax mice were shown to be resistant to 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate-induced skin cancers and here we demonstrate that AIRmax are also able to restrain the development of metastases upon transfer of MHC compatible, incompatible or xenogeneic melanomas. An acute inflammatory response to melanoma cells was observed in AIRmax mice only, although both lines were found to mount similar specific immune responses to melanoma antigens. The genetically selected lines therefore represent a model system to analyze the positive correlation between multiple resistance to tumorigenesis and host inflammatory responsiveness.
Abbreviations: AIR, acute inflammatory response; CSF, colony stimulating factors; DMBA, 7,12-dimethylbenz[a]anthracene; FCS, fetal calf serum; GM, granulocytemacrophage; NSAID, non-steroidal anti-inflammatory drug; PMN, polymorphonuclear leukocytes; TPA, 12-O-tetradecanoylphorbol-13-acetate.
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Introduction
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Chronic inflammation induced by physical, chemical or infectious agents has long been recognized as a risk factor for a variety of human cancers. Tumor infiltration by inflammatory cells is well documented during the precocious host response to gastric neoplasia for instance or in carcinomas of the urinary bladder (1,2). Free reactive oxygen species and nitrogen molecular species produced by inflammatory cells can induce DNA damage in neighboring cells and are thus believed to promote progression to cancer (3). Conversely, various antioxidant and anti-inflammatory substances have been shown to reduce tumor incidence and metastases development in several animal models (46). On the other hand, polymorphonuclear leukocytes (PMN) have the ability to kill tumor targets (7,8). Indeed, alterations in neutrophil or eosinophil functions, such as phagocytosis and cytotoxicity against tumor target cells, have been reported in tumor-bearing patients (911). Moreover, therapeutic benefits have been observed in animals and in cancer patients given recombinant cytokines, such as IL-4, IL-3, granulocyte CSF, granulocytemacrophage (GM) CSF and MCP-3, which stimulate the production, in the bone marrow, of PMN and monocytes (1214), suggesting the involvement of inflammatory cells in disease outcome. In rat and mouse experimental models an implied role of eosinophils and neutrophils in the response to certain types of tumors and lung metastases has also been demonstrated (15,16), although their role in the control of tumor growth is not clear. The role of inflammatory reactions in neoplasic diseases thus remains incompletely understood and controversial.
An appropriate experimental model in which to investigate inflammatory and innate immunity responses to cancer, and to infections as well, is provided by two mouse lines that we have produced by bi-directional selection based on the ability to develop a strong (maximal) or weak (minimal) acute inflammatory response (AIR). This selective breeding was started from a F0 founding population resulting from the intercross of eight inbred strains and AIR was quantified by the number of recruited cells and the concentration of exudated protein at the site of injection of polyacrylamide beads, a chemically inert and non-immunogenic substance (17). After several generations of selective breeding, AIRmax and AIRmin were found to differ mainly in the production and mobilization of neutrophils at the inflammatory focus induced by a variety of agents. This reaction is simultaneous with differential bone marrow activation and production of hematopoietic factors. At selection limit the large interline separation seems to result from accumulation of alleles endowed with opposite coherent additive effects at ~711 independent quantitative trait loci (17).
AIRmax and AIRmin mice were also shown to differ in natural resistance to various bacterial infections, independently of their genotypes at the already known susceptibility loci and of the specific immune responses to the pathogens (18). Importantly too, AIRmax mice proved to be highly resistant and AIRmin susceptible to two-step skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) (19) and the genetic association of these phenotypes with AIR could be demonstrated in F2 segregants.
Two basic protocols are used for studying in vivo carcinogenesis in mice: tumor induction by chemical or physical agents and metastatic spreading of transferred tumor cells. The main difference between the two models is that in the first both susceptibility to mutagenic agents and/or DNA repair mechanism efficiency are involved and immunosurveillance is tested at each step of tumor development, whereas in the second the host defences are confronted with a considerable load of transformed cells. Knowing that AIRmax and AIRmin mice differ in their resistance to chemically induced skin tumors, we investigated metastatic dissemination following s.c. transplantation of syngeneic, allogeneic and xenogeneic tumor cells. The results in this article show metastases incidence and host immunological and inflammatory responses to the tumor cells. In contrast to AIRmin and other lines of mice, AIRmax could control the metastatic propensity of implanted melanomas. This striking difference between AIRmax and AIRmin was found to be independent of the specific cellular or humoral immunoresponsiveness to tumor cells, which were similar in the two lines. Resistance to metastases is therefore genetically associated with the strong AIR capacity of AIRmax mice.
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Materials and methods
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Mice
AIRmax and AIRmin mice from generations 2426 of selective breeding were produced at the Laboratory of Immunogenetics of the Instituto Butantan (Sao Paulo, Brazil). A/J, DBA/2 and C57BL/6 mice were purchased from the central animal care unit at Instituto Butantan. Males and females 812 weeks old were used in all experiments.
Melanoma cell lines
Murine B16F10 and S91 and human SKMel-28 melanoma cell lines were obtained from the American Type Culture Collection. Cells were cultured in RPMI-1640 medium (Gibco) supplemented with 10% fetal calf serum (FCS), 2 mM L-glutamine (Sigma), 1 mM sodium pyruvate (Sigma) and antibiotics. Cell suspensions were detached from plates with trypsin and 0.2% versene. Upon trypsin inactivation with 10% FCS, viable cells were counted. For tumor transfer 5x104 B16F10, S91 or SKMel-28 cells suspended in 0.1 ml of phosphate-buffered saline were injected s.c. into the flank regions of mice. Tumor development was monitored twice a week. A tumor mass exceeding 3 mm in diameter was recorded as a positive take. Groups of mice were killed at different times after injection to search for metastases in internal organs. Macroscopically detected lesions were considered as metastases after histopathological confirmation.
Immune response to melanoma cells
Antibodies directed to melanoma cells were titrated by ELISA. Melanoma cells were cultured in flat-bottomed plates (105 cells/0.2 ml) for 24 h at 37°C in a 5% CO2 atmosphere. Cells were fixed with 0.1% glutaraldehyde in saline. After blockade, serial dilutions of pooled sera collected from mice at 7, 21 and 90 days after injection of 5x104 melanoma cells were distributed in triplicate. Isotype-specific goat anti-mouse IgG1 or IgG2a antibodies and peroxidase-conjugated rabbit anti-goat Ig antibodies (all from Bio-Rad) were successively used for antibody titration. The proliferative response of LN cells to melanoma cell extract (sonicated cells) was tested by thymidine incorporation in cultures (5x105 cells/0.2 ml) in Click's medium containing 2% normal mouse serum, with increasing concentrations of cell extract, for 96 h at 37°C in a 5% CO2 atmosphere, with 0.25 µCi [3H]thymidine (28 Ci/mmol; CEA, France) being added to each well 18 h before cell harvest.
Treatment with non-steroidal anti-inflammatory drugs (NSAIDs)
Powdered food containing 300 p.p.m. aspirin (Bayer) and 250 p.p.m. nimesulide (Asta Medica) were given ad libitum to mice 14 days, in the case of aspirin, or 1 day, in the case of nimesulide, before tumor injection. The NSAID diet was maintained until the mice were killed.
Statistical analysis
The significance of interline differences in locally infiltrated cell numbers were calculated by Student's t-test. The significance of tumor incidence differences in control versus NSAID-treated groups was checked by the
2 test. Differences were considered significant at P < 0.05.
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Results
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AIRmax mice are resistant to metastatic development of compatible, incompatible and xenogeneic melanomas
The interference of AIR genetic control with susceptibility to cancer spread was explored by analyzing the development of metastases after transplantation of melanoma cells. The B16F10 (H2b) variant of the B16 melanoma cell line, originating from B6 (20), and the S91 (H2d) melanoma, originating from DBA/2, were selected for these experiments because of their high metastatic potential and their H2 haplotypes. Indeed, most AIRmax mice are H2b, whereas AIRmin mice are H2d or H2k/d. B6 and DBA/2 mice were used as control histocompatible hosts for each tumor cell.
Tumoral pigmented dorsal masses with ulceration and necrosis were observed in all AIRmax animals 15 and 30 days after inoculation of B16F10 cells. However, metastases were not found in abdominal or thoracic organs of these mice (Table I
). As expected, due to histo-incompatibility, no dorsal tumors appeared in AIRmin mice during the same observation period, but surprisingly 80% of the mice had multiple pulmonary or hepatic metastases as soon as 15 days after tumor injection. Both dorsal tumors and metastases were found in almost all control B6 mice tested.
Table I
also shows the results observed with S91 melanoma implants. These tumor cells were unable to grow locally in AIRmax mice, only one of 10 of which had pulmonary metastases 30 days after injection. A low incidence of dorsal tumors was also observed in AIRmin as well as the isogeneic DBA/2 mice, likely due to poor growth rate. However, most AIRmin and DBA/2 mice (90100%) had histologically identified metastatic tumors in the lung and some had tumors in the kidney. Spontaneous tumors were never observed in untreated mice until the age of 10 months.
Metastatic melanoma cells are known to reduce MHC class I expression as a mechanism of immune evasion to prevent CTL induction (21). Consistently, an absence of MHC class I expression was demonstrated in B16F10 metastases by immunohistochemical staining of lung lesions with H2b-specific mAb (not shown). In the complex hosttumor relationship involved in the model, our results indicate that primary tumor intake followed the MHC compatibility rules of specific immunity whereas metastases development was dependent on host inflammatory reactivity.
To confirm this hypothesis under similar hosttumor incompatibility conditions, AIRmax and AIRmin mice were grafted with the human malignant melanoma SKMel-28. In all mice the incidence of dorsal tumors was low. However, metastases were firstly observed in the lung then in the liver and kidneys in 100% of AIRmin mice starting 30 days after tumor implantation (Table II
). In contrast, the incidence of metastases was very low in AIRmax mice (1/28). Histopathological analysis of dorsal tumors and pulmonary metastases revealed neoplastic cells with melanic pigmentation and discrete inflammatory infiltrates. Staining of metastases with anti-GD3, a specific tumor marker, confirmed the human origin of these lesions (not shown).
The results in DBA/2 and A/J mice and in two mouse lines, CarR and CarS, genetically selected (from the same F0 founding population as AIRmax and AIRmin mice) for resistance or susceptibility to chemically induced skin carcinogenesis (22) revealed that resistance to primary tumors is a general rule and that the incidence of metastases is close to 50% in all strains. This emphasizes that resistance to the metastatic propensity of human melanoma cells is restricted to AIRmax mice and is likely related to their genetically determined high acute inflammatory responsiveness. In fact, previous results have shown that the inflammatory response to polyacrylamide beads of these other lines of mice is significantly lower than that of AIRmax.
AIRmax and AIRmin mount similar specific immune responses to SKMel-28 human melanoma cells
In man, early melanoma evokes a specific T cell response which is impaired with disease progression. In our experiments the two murine melanomas induced only low antibody production in AIRmax and AIRmin mice. The more immunogenic SKMel-28 human cell line induced similar antibody titers of all IgG isotypes in the two lines (Figure 1
). Interestingly, hypopigmentation was observed in melanoma-transplanted mice, similar to the vitiligo lesions found in patients suffering from melanoma and possibly due to anti-melanoma antibodies (23). Lymph node cell proliferation in response to a range of doses of SKMel-28 protein extract was also found to be similar in AIRmax and AIRmin and was inhibited by anti-CD4 mAb in both cases. These results demonstrated that humoral and cellular specific immune responses did not account for the huge difference in metastases incidence observed between the two mouse lines.

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Fig. 1. Specific immune responses of AIRmax and AIRmin mice to human melanoma cells. (a) Kinetics of specific IgG1 and (b) IgG2a Ab titers in pools from 10 mice after s.c. injection of 5x104 SKMel-28 cells. (c) Specific in vitro lymph node cell proliferation in response to melanoma proteins. Lymph node cells were collected 10 days after s.c. injection with 5x104 SKMel-28 cells. Proliferation was assessed on day 4 by measuring [3H]thymidine uptake. Results represent the mean of c.p.m./culture ± SE in triplicates from four individual mice.
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High inflammatory response to melanoma cells in AIRmax
As shown in Table III
, injection of 5x104 SKMel-28 human cells into the dorsal air chamber induced, after 24 h, a significant inflammatory response in AIRmax but not in AIRmin mice. Similar results were obtained after injection of 5x104 murine B16F10 cells (data not shown). At a higher dose (106 cells) B16F10 cells induced a significant reaction in both lines, the number of infiltrated cells being higher in AIRmax than in AIRmin or in control mice. The interline difference in the response to SKMel-28 and B16F10 cells was essentially due to the higher number of neutrophils and eosinophils found in AIRmax exudates.
We have recently shown that s.c. injection of Biogel beads stimulates a strong and rapid GM CFU response to exogenous colony stimulating factors (CSF) in the bone marrow of AIRmax mice (to be published). The local inflammatory stimulus induced by tumor cells is much weaker than that induced by Biogel, however, preliminary results indicate that 48 h after melanoma cell injection AIRmax bone marrow develops colonies of GM CFU type (5867%), whereas macrophage CFU colonies largely predominate in the case of AIRmin and control mice.
Altogether, these results are consistent with the main phenotypic character resulting from selection. The inflammatory response to low numbers of melanoma cells in AIRmax, but not AIRmin mice, should be taken into account to explain their resistance to metastases.
Resistance modulation by NSAID
If resistance to the development of melanoma metastases in AIRmax mice depends on the intensity of the AIR to tumor cells, inhibition of this response by anti-inflammatory drugs should render the mice prone to metastases development. This was tested by treating mice with two cyclooxygenase inhibitors, namely aspirin and nimesulide, at doses comparable to the maximal doses recommended for humans (5,24). The two NSAIDs were given in powdered food before tumor implantation (5x104 B16F10 cells) and for the next 30 days. Treatment efficiency was assessed by reduced prostaglandin level in the stomach (data not shown). In neither line did treatment with aspirin or nimesulide have a significant effect on the incidence or size of dorsal tumors (Table IV
). Yet, in AIRmax mice the incidence of metastases increased from 21% in untreated mice to ~80% in aspirin- and nimesulide-treated animals as early as 30 days after tumor injection. Metastases multiplicity was also 10-fold higher in NSAID-treated mice. No drug effect was observed in AIRmin or B6, neither on dorsal tumors nor on metastases. This directly demonstrated that inflammatory mechanisms, related to innate immunity, participate in the resistance to tumor development observed in AIRmax mice.
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Table IV. Effect of aspirin and nimesulide on the development of B16F10 melanomas implanted in the AIR lines and B6 mice
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Discussion
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The present results demonstrate that the multigenic regulation leading to a high acute inflammatory response capacity has dramatic consequences not only as regards the host defences against infectious diseases and chemical tumor induction (18,19), but also against cancer metastases. Indeed, the AIRmax genotype, previously shown to be associated with resistance to DMBA/TPA-induced skin carcinogenesis and more recently to urethane induction of lung tumors (to be published), is now found to be associated with resistance to melanoma metastases development after s.c. transplantation. AIRmax and AIRmin thus have coherent opposite phenotypes in the two different tumorigenesis conditions evoked. This strongly suggests that AIRmax animals have a multifactorial resistance pattern to tumorigenesis which operates at the level of the innate inflammatory response. Keeping in mind that AIR selection was based on the non-specific inflammatory response to acrylamide, it can be hypothesized that the selected genes modulate the defensive inflammatory responses through production and chemoattraction of PMNs, two major target mechanisms of the selection. The finding that the number of locally infiltrated granulocytes at the site of injection of tumor cells is much higher in AIRmax than in AIRmin mice whereas the specific immune response to melanoma antigens is similar in the two lines is consistent with this view. The therapeutic efficacy of GM CSF and other hematopoietic cytokines in tumors and infections in mouse and man further supports this conclusion. GM CSF and IL-3, in addition to their effect on myeloid cell differentiation, increase neutrophil migration, enhance phagocytosis and stimulate macrophages to produce IL-1 and TNF
. TNF
-dependent neutrophil activation and attraction involving chemokines and IL-1 has also been described (25). Consistently, we observed that higher numbers of leukocytes, mainly neutrophils, infiltrated the dorsal air pouches of AIRmax mice compared with AIRmin (4.3 ± 0.9x106/ml and 1.6 ± 0.5x106/ml, respectively, P < 0.02) 4 h after 10
g TNF
inoculation, demonstrating that the neutrophil activation pathway was also differentially modified by the genetic selection. Furthermore, the anti-inflammatory properties of nimesulide have been attributed to its inhibitory effect on TNF
production (26). Regarding other mediators of inflammation, several prostaglandins, like those of the A and J series, also display anti-tumoral activities (27,28) and treatment of B16 tumor-bearing C57BL/6 mice with indomethacin and an antibody specific to IL-4 was reported to increase both the incidence and multiplicity of metastases (29). Again, the prostaglandin content of local inflammatory exudate induced by Biogel was shown to be significantly higher in AIRmax mice compared with AIRmin (17). The aggravation of melanoma metastases incidence and multiplicity observed in AIRmax mice treated with NSAIDs described in this article gives additional support to the impact of the inflammatory reaction on tumorigenesis. Finally, administration to normal mice of proteins isolated from the exudate of chronic granulomas induced by acrylamide was shown to increase resistance to infections and to various tumors (30). These proteins have not been fully characterized but their overproduction in AIRmax mice might help to explain their remarkable phenotype and their broad resistance to major experimental diseases.
The AIRmax and AIRmin phenotypes result from accumulation, during the selection, of genes endowed with opposite additive effects. Even if the intensity of the acute inflammatory response to acrylamide beads varies among inbred mice, none of them displays a phenotype similar to either of the two AIR lines (31). Many candidate genes could participate in these phenotypes, including cytokines, cytokine receptors and adhesion molecules, which are currently under investigation in our laboratory. Similar gene combinations might exist among the human population, which could have major effects on the susceptibility to infectious diseases and cancer or on the outcome of these diseases. Identification of the chromosome regions involved in the AIRmax and AIRmin divergent inflammatory phenotypes should provide important clues in this area.
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Notes
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2 To whom correspondence should be addressed Email: olgaibanez{at}originet.com.br 
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Acknowledgments
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We thank Dr Denise Mouton for helpful discussions and critically reading the manuscript. M.De Franco, N.Starobinas, M.Siqueira and O.M.Ibañez were supported in part by CNPq. The study was supported by FAPESP and CAPES/COFECUB.
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Received July 27, 2000;
accepted October 18, 2000.