Enhancement of 3-methylcholanthrene-induced neoplastic transformation by 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5 H )-furanone in the two-stage transformation assay in C3H 10T1/2 cells

Laaksonen, Mariitta; Mäki‐Paakkanen, Jorma; Komulainen, Hannu

doi:10.1007/s00204-001-0285-7

Cited by 10 publications

(2 citation statements)

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“…In vitro systems of MCA induced cellular transformation have shown that 3-8 weeks are required to yield transformed cells (32)(33)(34). If this were the case in vivo, e.g., first tumor cells appear at 3 weeks, it would then take 2 23 to 2 26 cell doublings to establish a detectable tumor mass (Ͼ5 mm in diameter) containing 10 7 to 10 8 cells.…”

Section: Discussionmentioning

confidence: 99%

Accelerated chemically induced tumor development mediated by CD4 ⁺ CD25 ⁺ regulatory T cells in wild-type hosts

Nishikawa

Kato²,

Tawara³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

104

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We examined the role of CD4 ؉ CD25 ؉ regulatory T cells in the development of 3-methylcholanthrene (MCA)-induced tumors. Immunization of wild-type BALB͞c mice with a series of SEREX (serological identification of antigens by recombinant expression cloning)-defined broadly expressed self-antigens results in the development of highly active CD4 ؉ CD25 ؉ regulatory T cells. Accelerated tumor development was observed in mice immunized with self-antigens and was abolished by antibody-mediated depletion of CD4 ؉ T cells or CD25 ؉ T cells. A similar acceleration of tumorigenesis was also observed in mice adoptively transferred 2 or 4 weeks after MCA injection with CD4 ؉ CD25 ؉ T cells derived from mice immunized with DnaJ-like 2, one of these self-antigens. Experiments with J␣281 ؊/؊ mice lacking invariant natural killer (iNK) T cells indicated that iNK T cells, known for their protective role in the development of MCAinduced tumors, were suppressed in immunized hosts. NK cells, also known to play a protective role in MCA induced-tumorigenesis, were also suppressed in mice immunized with serologically defined selfantigens in a CD4 ؉ CD25 ؉ T cell-dependent manner. We propose that CD4 ؉ CD25 ؉ regulatory T cells generated by immunization with these self-antigens enhance susceptibility to MCA induced-tumorigenesis by down-regulating iNK T and NK reactivity, and suggest that these observations provide direct evidence for the existence of cancer immunosurveillance in this system of chemical carcinogenesis.immunosurveillance ͉ self-antigen immunization W e have recently reported that immunization with serologically defined self-antigens leads to heightened susceptibility to challenge with syngeneic tumor lines observed as enhancement of pulmonary metastasis (1). These broadly expressed self-antigens have been identified by serological identification of antigens by recombinant expression cloning (SEREX), a serological expression cloning method that has been widely used to identify immunogenic molecules in murine and human tumors (2-4). Using sera of animals bearing 3-methylcholanthrene (MCA)-induced sarcoma lines of BALB͞c origin, four of the most frequently detected gene products were selected and used as immunogenic self-antigens after verifying the lack of gene mutations based on the registered sequences in GenBank (4).Although these self-antigens were identified by IgG type antibodies and thus considered to be recognized by CD4 ϩ helper T cells, immunization with these SEREX-defined self-antigens surprisingly enhanced pulmonary metastasis via elicitation of self-antigen-specific regulatory CD4 ϩ CD25 ϩ T cells with strong suppressive activity on CD4 ϩ T and CD8 ϩ T cell activity (1, 4, 5). In mice immunized with one of the SEREX-defined selfantigens, DnaJ-like 2, the number of ␣-galactosylceramide (GalCer)͞CD1d tetramer ϩ CD3 ϩ T cells [representing invariant natural killer T (iNKT) cells] was reduced in the pulmonary compartment, whereas no evident change in the number of other T cell subsets was observed. Experiments w...

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Section: Discussionmentioning

confidence: 99%

Accelerated chemically induced tumor development mediated by CD4 ⁺ CD25 ⁺ regulatory T cells in wild-type hosts

Nishikawa

Kato²,

Tawara³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

104

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“…Exposure to MX as the initiator slightly enhanced the development of foci, suggesting that MX may rather act via promoting tumour development (Laaksonen et al, 2001). formation (Hakulinen et al, 2004).…”

Section: Potassiummentioning

confidence: 99%

In vitro studies on the tumorigenic potential of the halonitromethanes trichloronitromethane and bromonitromethane

Marsà

Cortés

Teixidó

et al. 2017

Toxicology in Vitro

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Epidemiological data indicate that chronic exposure to water disinfection by-products (DBPs) may result in increased risk of cancer. However, the real carcinogenic potential of individual DBPs is not well known. In this study, we assessed the in vitro carcinogenic potential of trichloronitromethane (TCNM) and bromonitromethane (BNM), two halonitromethanes (HNMs) commonly found in DBPs' mixtures at comparably high concentrations. Human lung BEAS-2B cells were exposed for 8weeks to TCNM and BNM, and the acquisition of different in vitro cancer-like features was evaluated. The results indicate that long-term exposure to non-cytotoxic doses of TCNM and BNM did not cause carcinogenic transformation as indicated by the absence of morphological changes, no effects on cell growth, no changes in the level of matrix metalloproteinases (MMPs) secretion, and no increased anchorage-independent cell growth capacity. Furthermore, TCNM- and BNM-exposed BEAS-2B cells were unable to enhance tumour growth directly or by indirect influence of the surrounding stroma. Our results indicate that the carcinogenic effects of DBP mixtures cannot be attributed to the evaluated HNMs. This is the first study evaluating the cell transformation effects of TCNM and BNM under a long-term exposure scenario using suitable hallmarks of the cancer process.

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Effects of chlorohydroxyfuranones on 3-methylcholanthrene-induced neoplastic transformation in the two-stage transformation assay in C3H�10T1/2 cells

Laaksonen¹,

Mäki‐Paakkanen²,

Krönberg

et al. 2003

Archives of Toxicology

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3-Chloro-4-(chloromethyl)-5-hydroxy-2(5 H)-furanone (CMCF), 3-chloro-4-methyl-5-hydroxy-2(5 H)-furanone (MCF) and 3,4-dichloro-5-hydroxy-2(5 H)-furanone (MCA) are chlorination byproducts in disinfected drinking water. These compounds are positive in genotoxicity tests in vitro. We have previously shown that 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5 H)-furanone (MX) can induce malignant transformed foci in the two-stage cell transformation assay in C3H 10T1/2 cells in vitro in both the initiation and promotion phases. In the present study we compared the effects of CMCF, MCF and MCA in the same assay. C3H 10T1/2 mouse embryonic fibroblasts were exposed to these chlorohydroxyfuranones (CHFs) at three different concentrations in the initiation phase or the promotion phase of the assay. In the latter experiments 3-methylcholanthrene (MC, 5 micro g/ml) was used as the initiating chemical. The phorbol ester 12- O-tetradecanoylphorbol-13-acetate (TPA, 0.3 micro g/ml) was used as a positive control promoter. At the end of the assay (6 weeks from the start), the transformation foci were counted and scored after fixation and staining of the cells. When added at the initiation phase of the assay on their own, CMCF and MCF, but not MCA, increased the transformation foci formation. TPA added in the promotion phase did not modify the responses of CMCF and MCF but TPA increased the number of foci in MCA-treated cells. When CHFs were added during the promotion phase to the MC-initiated cells, MCF and MCA enhanced the development of the transformation foci. The effect of CMCF was equivocal since at higher concentrations CMCF actually decreased the number of the MC-induced foci. Including the previous data for MX in this assay and considering the lowest active concentrations, the initiation activity of the foci formation decreased in the order MX >CMCF >MCF, i.e. with the decreasing number of chlorine atoms of the methyl group in the 4-position of the CHF molecule (two, one, and zero, respectively). In contrast, the activity in the promotion phase did not follow the same pattern. MX, MCF and MCA were all active over the same concentration range. Hence, in addition to MX, MCF and MCA may also possess some potential to promote tumor development.

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Enhancement of 3-methylcholanthrene-induced neoplastic transformation by 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5 H )-furanone in the two-stage transformation assay in C3H 10T1/2 cells

Cited by 10 publications

References 24 publications

Accelerated chemically induced tumor development mediated by CD4 ⁺ CD25 ⁺ regulatory T cells in wild-type hosts

Accelerated chemically induced tumor development mediated by CD4 ⁺ CD25 ⁺ regulatory T cells in wild-type hosts

In vitro studies on the tumorigenic potential of the halonitromethanes trichloronitromethane and bromonitromethane

Effects of chlorohydroxyfuranones on 3-methylcholanthrene-induced neoplastic transformation in the two-stage transformation assay in C3H�10T1/2 cells

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Enhancement of 3-methylcholanthrene-induced neoplastic transformation by 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5 H )-furanone in the two-stage transformation assay in C3H 10T1/2 cells

Cited by 10 publications

References 24 publications

Accelerated chemically induced tumor development mediated by CD4 + CD25 + regulatory T cells in wild-type hosts

Accelerated chemically induced tumor development mediated by CD4 + CD25 + regulatory T cells in wild-type hosts

In vitro studies on the tumorigenic potential of the halonitromethanes trichloronitromethane and bromonitromethane

Effects of chlorohydroxyfuranones on 3-methylcholanthrene-induced neoplastic transformation in the two-stage transformation assay in C3H�10T1/2 cells

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Accelerated chemically induced tumor development mediated by CD4 ⁺ CD25 ⁺ regulatory T cells in wild-type hosts

Accelerated chemically induced tumor development mediated by CD4 ⁺ CD25 ⁺ regulatory T cells in wild-type hosts