Cellular Immunology

1989

DOI: 10.1016/0008-8749(89)90190-1

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Effector and precursor phenotypes of lymphokine-activated killer cells in mice with severe combined immunodeficiency (scid) and athymic (nude) mice

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Yoshiro Saikawa

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Masayoshi Miura

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et al.

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Introduction2

Roles Of Line-1 and Herv-k In Tumorigenesis E Oricchio Et Al1

Discussion1

Characterization Of Cytolytic Effector Cells Generated By Cy1

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Cited by 35 publications

(18 citation statements)

References 30 publications

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“…It has been clearly shown that expression of env, either encoded from infectious retroviruses (Mangeney and Heidmann, 1998;Blaise et al, 2001) or from endogenous retroviral elements (Mangeney et al, , 2005, can subvert the immune surveillance system in mice, thereby eluding the rejection of tumors in immunocompetent animal models. The reduced tumorigenic ability of cells in which HERV-K expression is stably inactivated could be easily explained by envisaging that HERV-K-encoded env protein plays a similar immunosuppressive role, including in nude mice, which do in fact maintain a low level of immunosuppressive activity (Hasui et al, 1989;Farag and Caligiuri, 2006). Our results suggest that L1 expression has a predominant role in early stages of tumorigenesis, possibly exerted by setting up favorable gene expression profiles for tumor growth, whereas HERV-K expression may favor tumor progression by reducing the immune surveillance of mice.…”

Section: Roles Of Line-1 and Herv-k In Tumorigenesis E Oricchio Et Almentioning

confidence: 99%

Distinct roles for LINE-1 and HERV-K retroelements in cell proliferation, differentiation and tumor progression

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et al. 2007

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Transformed cells express high levels of non-telomeric reverse-transcriptase (RT) activity of retrotransposon and endogenous retrovirus origin. We previously reported that RT inhibition, either pharmacological or through transient silencing of RT-encoding LINE-1 (L1) elements by RNA interference (RNAi), reduced proliferation, induced differentiation and reprogrammed gene expression in human tumorigenic cell lines. Moreover, the antiretroviral drug efavirenz antagonized tumor progression in animal models in vivo. To get insight into the role of retroelements in tumorigenesis, we have now produced two cell lines derived from A-375 melanoma, in which the expression of either L1 retrotransposon, or HERV-K endogenous retrovirus, was stably suppressed by RNAi. Compared to the parental A-375 cell line, cells with stably interfered L1 expression show a lower proliferation rate, a differentiated morphology and lower tumorigenicity when inoculated in nude mice. L1 silencing modulates expression of several genes and, unexpectedly, also downregulates HERV-K expression. In HERV-K interfered cells, instead, L1 expression was unaffected, and cell proliferation and differentiation remained unchanged compared to parental A-375 cells. In vivo, however, their tumorigenic potential was found to be reduced after inoculation in nude mice. These results suggest that L1 and HERV-K play specific and distinct roles in cell transformation and tumor progression.

“…It has been clearly shown that expression of env, either encoded from infectious retroviruses (Mangeney and Heidmann, 1998;Blaise et al, 2001) or from endogenous retroviral elements (Mangeney et al, , 2005, can subvert the immune surveillance system in mice, thereby eluding the rejection of tumors in immunocompetent animal models. The reduced tumorigenic ability of cells in which HERV-K expression is stably inactivated could be easily explained by envisaging that HERV-K-encoded env protein plays a similar immunosuppressive role, including in nude mice, which do in fact maintain a low level of immunosuppressive activity (Hasui et al, 1989;Farag and Caligiuri, 2006). Our results suggest that L1 expression has a predominant role in early stages of tumorigenesis, possibly exerted by setting up favorable gene expression profiles for tumor growth, whereas HERV-K expression may favor tumor progression by reducing the immune surveillance of mice.…”

Section: Roles Of Line-1 and Herv-k In Tumorigenesis E Oricchio Et Almentioning

confidence: 99%

Distinct roles for LINE-1 and HERV-K retroelements in cell proliferation, differentiation and tumor progression

¹

,

²

,

³

et al. 2007

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Transformed cells express high levels of non-telomeric reverse-transcriptase (RT) activity of retrotransposon and endogenous retrovirus origin. We previously reported that RT inhibition, either pharmacological or through transient silencing of RT-encoding LINE-1 (L1) elements by RNA interference (RNAi), reduced proliferation, induced differentiation and reprogrammed gene expression in human tumorigenic cell lines. Moreover, the antiretroviral drug efavirenz antagonized tumor progression in animal models in vivo. To get insight into the role of retroelements in tumorigenesis, we have now produced two cell lines derived from A-375 melanoma, in which the expression of either L1 retrotransposon, or HERV-K endogenous retrovirus, was stably suppressed by RNAi. Compared to the parental A-375 cell line, cells with stably interfered L1 expression show a lower proliferation rate, a differentiated morphology and lower tumorigenicity when inoculated in nude mice. L1 silencing modulates expression of several genes and, unexpectedly, also downregulates HERV-K expression. In HERV-K interfered cells, instead, L1 expression was unaffected, and cell proliferation and differentiation remained unchanged compared to parental A-375 cells. In vivo, however, their tumorigenic potential was found to be reduced after inoculation in nude mice. These results suggest that L1 and HERV-K play specific and distinct roles in cell transformation and tumor progression.

“…The immunodeficient murine model used in these (23)(24)(25)(26)(27). Even though this animal model does not permit the evaluation of a complete host immune response, we believe it is appropriate for the purpose of this study.…”

Section: Discussionmentioning

confidence: 99%

Cryotreatment as a simple method for cell preparation in autologous tumor cell-based vaccination

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et al. 2010

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Abstract. Immunotherapies using autologous whole tumor cell vaccines have great potential in the treatment of cancer. Very few studies report the use of cryotreatment for the preparation of cells in cell-based vaccines. In this study, we demonstrated that a preparation containing cryotreated human breast cancer cells has the same capacity as a preparation containing irradiated human breast cancer cells to induce the activation of immune cells in vivo. The vaccine strategy proposed in this study may provide the experiment basis for the use of autologous or allogeneic breast cancer cells in the cell-based vaccine approach for the treatment of breast cancer and other types of cancer as well. IntroductionBreast cancer is the most frequently occurring malignant disease in women and the second leading cause of cancer deaths in women in many of the regions of the world. According to the World Health Organization, >1.2 million people will be diagnosed with breast cancer this year worldwide. Although tumorectomy, radiotherapy, chemotherapy and hormone replacement therapy have been used successfully for the treatment of breast cancer, the limits of these existing treatment regimes for breast cancer are recognized. There are few effective therapeutic choices for patients with invasive and metastatic breast cancer (1,2). It is evident that novel therapeutic modalities for breast cancer need to be developed in order to eliminate residual circulating cancer cells and micrometastases.New therapies utilizing the immune system have proved effective in treating patients with advanced breast cancer (3-11). Cancer vaccine immunotherapy is certainly one of the most promising methods in cancer immunotherapy (8,12). Vaccination of cancer patients with autologous or allogeneic tumor cell-based vaccines has proved to be safe and elicit anticancer immune responses in clinical trials with patients affected by different types of malignancies (13-17). However some limitations have to be overcome before cell-based vaccine can be accepted as a new treatment for cancer. One of the limitations is the method used to prepare the cells. Irradiation is the common technique used to prepare cells in cancer cell-based vaccines, but its use necessitates expensive equipment and qualified personnel that are not always accessible. Therefore, the aim of this study was to investigate if a simpler, less expensive and faster method could replace irradiation. We investigated whether cells prepared by cryotreatment would be as efficient as cells prepared by the commonly used irradiation technique to induce an immune response in a nude mouse model. Materials and methodsCell lines. The human breast carcinoma cancer cell line MCF-7 was purchased from the American Type Culture Collection. Cells were maintained in Dulbecco's modified Eagle's medium (Gibco-Invitrogen, Grand Island, NY) supplemented with 10% fetal bovine serum (BioMedia, Drummondville, Quebec, Canada), 50 μg/ml gentamycine (Gibco-Invitrogen) and 2 mM L-glutamine (Sigma-Aldrich, St. Louis, MO). The cul...

“…Since NK ceils lack memory and are functional in SCID mice [10,19,20,24,26], the possibility that cells of this lineage contribute to the IL-2-dependent effector cell pool was evaluated. This initially was addressed by depleting SCID and SCID-beige mice (the latter having diminished NK cell activity) of NK cells by the repeated administration of anti-asialo-GM1 antibody prior to and following subcutaneous inoculation of the IL-2-secreting N2A/IL2/CMS5 tumor.…”

Section: Characterization Of Cytolytic Effector Cells Generated By Cymentioning

confidence: 99%

“…Mice homozygous for the SCID mutation are deficient in mature T and B cells [4], but have normal levels of T-cell-independent macrophage function [2] and normal NK activity [10,19,26]. Cells that are cytotoxic for tumors have been generated from SCID mouse spleen cells cultivated in IL-2 [20]. Spleen cells from SCID-beige mice, which have reduced splenic NK cell activity compared to SCID mice, produce less tumor killing activity when cultivated with IL-2 [24].…”

Section: Introductionmentioning

confidence: 99%

Antitumor response independent of functional B or T lymphocytes induced by the local and sustained release of interleukin-2 by the tumor cells

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et al. 1993

Cancer Immunol Immunother

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Transfection of tumor cells with a vector containing the entire coding sequence of human interleukin-2 (hIL-2) was previously shown to convert the tumorigenic murine fibrosarcoma line CMS-5 into a non-tumorigenic line. The failure of the IL-2-secreting tumor to grow in conventional (immunocompetent) mice was attributed to the activation of CD8+ T cells that exhibited tumor specificity and memory. In order to determine whether or not the IL-2 produced by the tumor may be activating tumor cytotoxic effector cells other than B or T cells we have repeated this study using immunodeficient SCID and SCID-beige mice as syngeneic tumor recipients. In contrast to the rapid growth of the wild-type tumor, the hIL-2-transfected cells (N2A/IL2/CMS5) did not grow, or grew more slowly and regressed, in the mice that lack functional B and T cells. The inhibition of tumor growth associated with the local release of IL-2 was reversed in mice treated with antiasialo-GM1 antibodies specific for natural killer (NK) lineage cells. In contrast to the studies with conventional mice, the IL-2-dependent effector cells in the immunodeficient mice exhibited no evidence of memory. In vitro analysis of spleen cells from tumor-bearing mice revealed the presence of effector cells able to lyse YAC-1 target cells as well as the wild-type CMS-5 and the IL-2-transfected variant tumor lines but unable to lyse P815 cells. The pattern of selective target cell killing and the kinetics of killing were indistinguishable from those observed using tumor necrosis factor alpha (TNF alpha) the mediator associated with natural cytotoxicity cell killing of tumor cells. Histopathology of the IL-2-secreting tumors in SCID mice reveals the presence of infiltrating lymphoid cells and macrophages that were not observed in the CMS-5 tumors. Consistent with the notion that the tumor killing in the SCID mice was mediated by TNF alpha, mice bearing IL-2-secreting tumors had elevated levels of serum TNF alpha and little or no effector cell activity, or TNF alpha was found in tumor-bearing mice treated with anti-asialo-GM1 antibody. The results indicate that the cytokine-induced tumor regression observed in the IL-2-transfected tumors is a more complex phenomenon than previously recognized and one that is mediated by effector cells of the NK cell and/or monocyte/macrophage lineages, in addition to CD8+ T cells.

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