scholarly journals Mouse CD38-Specific Heavy Chain Antibodies Inhibit CD38 GDPR-Cyclase Activity and Mediate Cytotoxicity Against Tumor Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Natalie Baum ◽  
Marie Eggers ◽  
Julia Koenigsdorf ◽  
Stephan Menzel ◽  
Julia Hambach ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Heavy Chain ◽  
Transmembrane Protein ◽  
Cyclase Activity ◽  
Mouse Tumor ◽  
Chimeric Mouse ◽  
Phage Display Technology ◽  
Mediate Cytotoxicity ◽  
Variable Domains

CD38 is the major NAD+-hydrolyzing ecto-enzyme in most mammals. As a type II transmembrane protein, CD38 is also a promising target for the immunotherapy of multiple myeloma (MM). Nanobodies are single immunoglobulin variable domains from heavy chain antibodies that naturally occur in camelids. Using phage display technology, we isolated 13 mouse CD38-specific nanobodies from immunized llamas and produced these as recombinant chimeric mouse IgG2a heavy chain antibodies (hcAbs). Sequence analysis assigned these hcAbs to five distinct families that bind to three non-overlapping epitopes of CD38. Members of families 4 and 5 inhibit the GDPR-cyclase activity of CD38. Members of families 2, 4 and 5 effectively induce complement-dependent cytotoxicity against CD38-expressing tumor cell lines, while all families effectively induce antibody dependent cellular cytotoxicity. Our hcAbs present unique tools to assess cytotoxicity mechanisms of CD38-specific hcAbs in vivo against tumor cells and potential off-target effects on normal cells expressing CD38 in syngeneic mouse tumor models, i.e. in a fully immunocompetent background.

scholarly journals Adenovirus serotype 5 E1A sensitizes tumor cells to NKG2D-dependent NK cell lysis and tumor rejection

2005 ◽  
Vol 202 (11) ◽  
pp. 1477-1482 ◽  
Author(s):  
John M. Routes ◽  
Sharon Ryan ◽  
Kristin Morris ◽  
Rayna Takaki ◽  
Adelheid Cerwenka ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Nk Cell ◽  
Tumor Rejection ◽  
Mouse Tumor ◽  
Mutant Form ◽  
Nkg2d Ligand ◽  
Adenovirus Serotype ◽  
Nkg2d Ligands ◽  
Serotype 5

The expression of the Adenovirus serotype 5 (Ad5) E1A oncogene sensitizes tumor cells to natural killer (NK) cell–mediated killing and tumor rejection in vivo. These effects are dependent on the ability of E1A to bind the transcriptional coadaptor protein p300. To test the hypothesis that E1A up-regulates ligands recognized by the NKG2D-activating receptor, we stably transfected the highly tumorigenic mouse fibrosarcoma cell line MCA-205 with Ad5-E1A or a mutant form of E1A that does not interact with p300 (E1A-Δp300). Ad5-E1A, but not E1A-Δp300, up-regulated the expression of the NKG2D ligand retinoic acid early inducible (RAE)-1, but not murine ULBP-like transcript 1, another NKG2D ligand, in four independently derived MCA-205 transfectants. The up-regulation of RAE-1 by E1A targeted MCA-205 tumor cells to lysis by NK cells, resulting in NKG2D-dependent tumor rejection in vivo. Moreover, the up-regulation of NKG2D ligands by E1A was not limited to mouse tumor cells, as E1A also increased the expression of NKG2D ligands on primary baby mouse kidney cells, human MB435S breast cancer cells, and human H4 fibrosarcoma cells.

scholarly journals siRNAs Targeting Mouse-Specific lncRNA AA388235 Induce Human Tumor Cell Pyroptosis/Apoptosis

2021 ◽  
Vol 11 ◽  
Author(s):  
Yan-Ru Chen ◽  
Wan-Ying Feng ◽  
Yuan-Xiong Cheng ◽  
Hao Zhu ◽  
Hong-Juan Liu ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Large Scale ◽  
Human Tumor ◽  
Mouse Tumor ◽  
Human Tumor Cells ◽  
Human Tumor Cell ◽  
Therapeutic Drugs ◽  
Species Specific

Species-specific lncRNAs significantly determine species-specific functions through various ways, such as epigenetic regulation. However, there has been no study focusing on the role of species-specific lncRNAs in other species yet. Here, we found that siRNAs targeting mouse-specific lncRNA AA388235 could significantly induce death of human tumor cells, although it has no effect on mouse tumor cells and normal human cells. The mechanism studies showed that these siRNAs could activate the response of human tumor cells to exogenous nucleic acids, induce pyroptosis and apoptosis in the presence of GSDME, but induce apoptosis in the absence of GSDME. They also significantly inhibited the growth of human tumor cells in vivo. 17 siRNAs were designed for seven more mouse-specific lncRNAs selected randomly, among which 12 siRNAs targeting five lncRNAs induced death in human tumor cell. Our study not only demonstrates that the siRNAs designed for knocking down mouse-specific lncRNA AA388235 can be potential tumor therapeutic drugs, but also suggests that non-human species-specific lncRNAs are a huge potential library that can be used to design siRNAs for tumor treatment. Large-scale screening based on this is promising.

scholarly journals P. aeruginosa Mediated Necroptosis in Mouse Tumor Cells Induces Long-Lasting Systemic Antitumor Immunity

2021 ◽  
Vol 10 ◽  
Author(s):  
Jia-long Qi ◽  
Jin-rong He ◽  
Shu-mei Jin ◽  
Xu Yang ◽  
Hong-mei Bai ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Tumor Response ◽  
Necrotic Cell Death ◽  
Immunogenic Cell Death ◽  
Mouse Tumor ◽  
Necrotic Cell ◽  
Tumor Cell Death

Necroptosis is a form of programmed cell death (PCD) characterized by RIP3 mediated MLKL activation and increased membrane permeability via MLKL oligomerization. Tumor cell immunogenic cell death (ICD) has been considered to be essential for the anti-tumor response, which is associated with DC recruitment, activation, and maturation. In this study, we found that P. aeruginosa showed its potential to suppress tumor growth and enable long-lasting anti-tumor immunity in vivo. What’s more, phosphorylation- RIP3 and MLKL activation induced by P. aeruginosa infection resulted in tumor cell necrotic cell death and HMGB1 production, indicating that P. aeruginosa can cause immunogenic cell death. The necrotic cell death can further drive a robust anti-tumor response via promoting tumor cell death, inhibiting tumor cell proliferation, and modulating systemic immune responses and local immune microenvironment in tumor. Moreover, dying tumor cells killed by P. aeruginosa can catalyze DC maturation, which enhanced the antigen-presenting ability of DC cells. These findings demonstrate that P. aeruginosa can induce immunogenic cell death and trigger a robust long-lasting anti-tumor response along with reshaping tumor microenvironment.

scholarly journals PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity

2017 ◽  
Vol 214 (4) ◽  
pp. 895-904 ◽  
Author(s):  
Vikram R. Juneja ◽  
Kathleen A. McGuire ◽  
Robert T. Manguso ◽  
Martin W. LaFleur ◽  
Natalie Collins ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cells ◽  
Immune Evasion ◽  
Antitumor Immunity ◽  
Cd8 T Cell ◽  
Genetically Engineered ◽  
Mouse Tumor ◽  
Cell Cytotoxicity ◽  
T Cell Cytotoxicity

It is unclear whether PD-L1 on tumor cells is sufficient for tumor immune evasion or simply correlates with an inflamed tumor microenvironment. We used three mouse tumor models sensitive to PD-1 blockade to evaluate the significance of PD-L1 on tumor versus nontumor cells. PD-L1 on nontumor cells is critical for inhibiting antitumor immunity in B16 melanoma and a genetically engineered melanoma. In contrast, PD-L1 on MC38 colorectal adenocarcinoma cells is sufficient to suppress antitumor immunity, as deletion of PD-L1 on highly immunogenic MC38 tumor cells allows effective antitumor immunity. MC38-derived PD-L1 potently inhibited CD8+ T cell cytotoxicity. Wild-type MC38 cells outcompeted PD-L1–deleted MC38 cells in vivo, demonstrating tumor PD-L1 confers a selective advantage. Thus, both tumor- and host-derived PD-L1 can play critical roles in immunosuppression. Differences in tumor immunogenicity appear to underlie their relative importance. Our findings establish reduced cytotoxicity as a key mechanism by which tumor PD-L1 suppresses antitumor immunity and demonstrate that tumor PD-L1 is not just a marker of suppressed antitumor immunity.

scholarly journals Radiosensitizing Effect of Bromelain Using Tumor Mice Model via Ki-67 and PARP-1 Inhibition

2021 ◽  
Vol 20 ◽  
pp. 153473542110603
Author(s):  
Mai H. Mekkawy ◽  
Hanan A. Fahmy ◽  
Ahmed S. Nada ◽  
Ola S. Ali
Keyword(s):  
Tumor Cells ◽  
Tumor Model ◽  
Mouse Tumor ◽  
Mice Model ◽  
Ki 67 ◽  
Radiosensitizing Effect ◽  
Treatment And Prevention ◽  
Parp 1

Recent reports have shown that bromelain (BL), a pineapple extract, acts as an adjuvant therapy in cancer treatment and prevention of carcinogenesis. The present study was designed to investigate the possible mechanisms by which BL could radiosensitize tumor cells in vitro and in a mouse tumor model. BL has shown a significant reduction in the viability of the radioresistant human breast carcinoma (MCF-7) cell line using cell proliferation assay. The in vivo study was designed using the Ehrlich model in female albino mice, treated with BL (6 mg/kg b. wt., intraperitoneal, once daily for 10 days) 1 hour before exposure to a fractionated dose of gamma radiation (5 Gy, 1 Gy for 5 subsequent days). The radiosensitizing effect of BL was evident in terms of a significant reduction in tumor volume, poly ADP ribose polymerase-1 (PARP-1), the proliferation marker Ki-67 and nuclear factor kappa activated B cells (NF-κB) with a significant elevation in the reactive oxygen species (ROS) content and lipid peroxidation (LPO) in tumor cells. The present findings offer a novel insight into the radiosensitizing effect of BL and its potential application in the radiotherapy course.

scholarly journals Optimization of a Luciferase-Expressing Non-Invasive Intrapleural Model of Malignant Mesothelioma in Immunocompetent Mice

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2136
Author(s):  
Elisabeth Digifico ◽  
Marco Erreni ◽  
Federico Simone Colombo ◽  
Camilla Recordati ◽  
Roberta Migliore ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Human Disease ◽  
Invasive Procedure ◽  
Tumor Burden ◽  
In Vivo Model ◽  
Mouse Tumor ◽  
Non Invasive ◽  
Set Up ◽  
Immunocompetent Mice

Malignant Pleural Mesothelioma (MPM) is an aggressive tumor of the pleural lining that is usually identified at advanced stages and resistant to current therapies. Appropriate pre-clinical mouse tumor models are of pivotal importance to study its biology. Usually, tumor cells have been injected intraperitoneally or subcutaneously. Using three available murine mesothelioma cell lines with different histotypes (sarcomatoid, biphasic, epithelioid), we have set up a simplified model of in vivo growth orthotopically by inoculating tumor cells directly in the thorax with a minimally invasive procedure. Mesothelioma tumors grew along the pleura and spread on the superficial areas of the lungs, but no masses were found outside the thoracic cavity. As observed in human MPM, tumors were highly infiltrated by macrophages and T cells. The luciferase-expressing cells can be visualized in vivo by bioluminescent optical imaging to precisely quantify tumor growth over time. Notably, the bioluminescence signal detected in vivo correctly matched the tumor burden quantified with classical histology. In contrast, the subcutaneous or intraperitoneal growth of these mesothelioma cells was considered either non-representative of the human disease or unreliable to precisely quantify tumor load. Our non-invasive in vivo model of mesothelioma is simple and reproducible, and it reliably recapitulates the human disease.

Effect Of Activated And Non-Activated Protein C On Mouse Tumor Metastases

1981 ◽  
Author(s):  
T B Gasic ◽  
J L Catalfamo ◽  
G J Gasic
Keyword(s):  
Tumor Cells ◽  
Protein C ◽  
Activated Protein C ◽  
Membrane Vesicles ◽  
Mouse Tumor ◽  
Plasma Membrane Vesicles ◽  
Tumor Spread ◽  
Tumor Metastases

Platelet aggregation (PA) and fibrin deposition appears to be involved in the establishment of blood-borne tumor cells as metastases. Since it has been reported that activated Protein C have fibrinolytic activity or can inhibit coagulation, we investigated whether activated Protein C may inhibit tumor spread. Preliminary studies in the mouse system indicated that (a) activated Protein C prolonged the kaolin cephalin clotting time of plasma treated in vitro (>10min.)or of plasma obtained from in vivo treated mice (55 vs 30 sec.), (b) activated Protein C can inhibit PA by plasma membrane vesicles shed by metastasizing tumor cells; this effect was much greater with rat gel filtered platelets than with heparinized mouse PRP. The inhibition effect was also present in vivo, since 56 ug of activated Protein C, injected ip 15 min. before iv injection of tumor vesicles (200 ug protein), reduced significantly thrombocytopenia and signs of respiratory sickness produced by the vesicles.After these studies, activated Protein C, as well as nonact ivated Protein C, was given ip 15 min. and 3 hr after iv inoculation of 5×104 MCA mouse sarcoma tumor cells. Three weeks later mice were killed and lung tumors sized and counted. The data shown in the Table (average and range) indicate that activated Protein C decreases metastasis, while Protein C increases both the size and the number of tumors.While the presumptive effect of activated Protein C on metastasis might be related to its anticoagulant and antiplatelet activities, we know nothing how Protein C enhances metastases in our experiments.

Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

2019 ◽  
Vol 2 (4) ◽  
pp. 83-98 ◽  
Author(s):  
André De Lima Mota ◽  
Bruna Vitorasso Jardim-Perassi ◽  
Tialfi Bergamin De Castro ◽  
Jucimara Colombo ◽  
Nathália Martins Sonehara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Carbonic Anhydrases ◽  
In Vivo Models ◽  
Ca Ix ◽  
Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression. 

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