scholarly journals Experimental model and approaches to investigation of the acquired resistance to tumor transplantation in mice

2021 ◽  
Vol 15 (1) ◽  
pp. 49-60
Author(s):  
M. D. Lootsik ◽  
◽  
R. S. Stoika ◽  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Acquired Resistance ◽  
Harmful Effect ◽  
Mononuclear Leukocytes ◽  
Complete Suppression ◽  
Cytotoxic Lymphocytes ◽  
Transplanted Tumor ◽  
Cell Immunity ◽  
Induction Of Resistance

Introduction. An acquired resistance to experimental tumors was detected in animals that recovered from a primary transplanted tumor due to treatment or spontaneously, and demonstrated intolerance to a renewal tumor inoculation. This phenomenon is much less frequently observed, although it is of great scientific interest and medical significance. Here, we have addressed the expression of the resistance phenomenon in a model tumor in mice – Nemeth–Kelner lymphoma (NK/Ly). The aim of our study was to elaborate a reproducible method for induction of resistance to transplantation of lymphoma NK/Ly in mice and to investigate the mechanisms of its development. Methods and Results. Three schemes for induction of resistance were tested. The first one included treatment of tumor-bearing mice with vinblastine and, thereafter, reconvalescent animals were checked for the development of resistance expressed as a complete suppression of tumor growth after re-inoculation of tumor cells. Mice were inoculated intraperitoneally with NK/Ly ascitic cells and then subjected to 2–4 intraperitoneal injections of vinblastine at a dose of 1mg/g of body weight. The recovered mice were re-inoculated with tumor cells and the absence of tumor growth was considered as resistance development. The disadvantage of this approach is that less than 5% of mice achieve a long lasting recovery due to the treatment. The second scheme included the immunization of mice with intraperitoneal injection of the minimal number of viable tumor cells that do not cause tumor growth, but initiate the immune response. However, this approach was not effective, since there was no reliable number of cells correspon­ding to these demands. The minimal number of 15×103 injected cells per mouse caused a retarded but still progressive tumor growth. In the third scheme, the immunization of mice was conducted by the intraperitoneal injections of NK/Ly cells permeabilized with saponin. It should be noted that treatment with saponin leads to cell death with a minimal damage to cell morphology. The scheme of immunization with permeabilized NK/Ly cells appeared to be simple and effective. It provided a reproducible resistance to transplanted tumor and might be used as a model in studies of the mechanisms of this phenomenon. Cytological investigation of tumor and immunocompetent cells in ascites of control and of tumor-resistant mice was conducted. As revealed, the number of lymphocytes in ascites of tumor-resistant mice was about 4 times higher than such amount in the control (non-resistant) mice. A destruction of tumor cells by the adherent mono-nuclears was observed. Conclusions. The method of induction of resistance to transplantation of experimental tumor NK/Ly by immunization of mice with tumor cells permeabilized with saponin is described. The intraperitoneal inoculation of tumor cells to the tumor-resistant mice caused the marked increase of the mononuclear leukocytes population in the peritoneal fluid, which showed a harmful effect upon tumor cells. Thus, the induction of resistance to transplantation of NK/Ly lymphoma in mice might be provided mainly via the mechanisms of cell immunity, in particular, by the appearance of cytotoxic lymphocytes specific to distinct tumor cells.

scholarly journals A FACTOR FROM NORMAL TISSUES INHIBITING TUMOR GROWTH

1934 ◽  
Vol 60 (3) ◽  
pp. 293-303 ◽  
Author(s):  
James B. Murphy ◽  
Ernest Sturm
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Complete Suppression ◽  
Normal Tissues

Extracts of desiccated embryo skin and placenta have been found to exert a definite retarding action on the growth of two transplantable carcinomas of mice, but they were without effect on sarcomas. In tests involving some 828 inoculations of the tumor cells and the extracts, complete suppression of growth occurred in from 55 to 71 per cent of instances, as compared with 21 to 27 per cent in the controls, and where growth was not completely suppressed some retardation was found in practically every instance. To judge from findings in rabbits the inhibitor is not demonstrable in the placenta until the beginning of the second third of pregnancy, reaches its maximum by the last third, but disappears about 2 or 3 days before term. Extracts of fresh placenta are without effect, and no very definite inhibition was noted in extracts of a variety of other desiccated or fresh tissues. The conclusions here reported are based on the results of over 3800 inoculations.

Immune evasion by CD200: New approaches to targeted therapies for chronic lymphocytic leukemia (CLL)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2519-2519
Author(s):  
A. Kretz-Rommel ◽  
N. Dakappagari ◽  
F. Qin ◽  
J. McWhirter ◽  
D. Oltean ◽  
...  
Keyword(s):  
Immune System ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Immune Evasion ◽  
Human Lymphocytes ◽  
Lymphocytic Leukemia ◽  
Tumor Growth Inhibition ◽  
Cell Injection ◽  
Cell Immunity

2519 Background: Although the human immune system is capable of raising an immune response against many cancer types, that response is insufficient to eradicate the cancer in most patients, possibly due to immune evasion through negative regulation of the immune system by the tumor. We identified the immune-suppressive molecule CD200 to be upregulated 1.5–5.4-fold on CLL cells in all 80 patients examined. Interaction of CD200 with its receptor alters cytokine profiles from Th1 to Th2 in mixed lymphocyte reactions, and results in the induction of regulatory T cells, which are thought to hamper tumor-specific effector T cell immunity. We addressed whether CD200 expression on tumor cells plays a role in immune evasion, thereby preventing elimination of tumor cells by the immune system in a xenograft hu/SCID mouse model, and whether treatment with an antagonistic anti-CD200 antibody affects tumor growth. Methods: The human non-Hodgkins lymphoma cell lines RAJI and Namalwa were transduced with human CD200 and injected subcutaneously together with human peripheral blood lymphocytes (PBL) into NOD/SCID mice. Tumor growth over time was compared among mice that either received CD200-expressing tumor cells or received tumor cells lacking CD200 expression. In subsequent experiments, mice were treated with chimeric or humanized anti-CD200 antibodies (doses ranged from 1 to 20 mg/kg) by intravenous injection. Treatment was either started immediately or 7 days after tumor cell injection. Results: As expected, PBLs reduced CD200-negative RAJI or Namalwa tumor growth by up to 75%. In contrast, growth of RAJI or Namalwa tumors expressing CD200 at levels comparable to that of CLL was not reduced by PBLs. Administration of anti-CD200 antibodies at 5 mg/kg resulted in nearly complete tumor growth inhibition (1/10 mice developed a small tumor) over the course of the study even when treatment was started 7 days after tumor cell injection. Conclusions: CD200 expression on tumor cells inhibits the ability of human lymphocytes to eradicate tumor cells. Treatment of CD200-expressing tumors with antagonistic anti-CD200 antibodies inhibits tumor growth, indicating the potential for anti-CD200 therapy as a promising approach for CLL. No significant financial relationships to disclose.

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. 

ANTITUMOR EFFECT OF COLLOIDAL SILVER BISILICATE IN EXPERIMENTAL IN VITRO AND IN VIVO STUDIES

2019 ◽  
Vol 65 (5) ◽  
pp. 760-765
Author(s):  
Margarita Tyndyk ◽  
Irina Popovich ◽  
A. Malek ◽  
R. Samsonov ◽  
N. Germanov ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Human Tumor ◽  
Significant Inhibition ◽  
In Vivo Studies ◽  
Ehrlich Carcinoma ◽  
In Vivo Experiments

The paper presents the results of the research on the antitumor activity of a new drug - atomic clusters of silver (ACS), the colloidal solution of nanostructured silver bisilicate Ag6Si2O7 with particles size of 1-2 nm in deionized water. In vitro studies to evaluate the effect of various ACS concentrations in human tumor cells cultures (breast cancer, colon carcinoma and prostate cancer) were conducted. The highest antitumor activity of ACS was observed in dilutions from 2.7 mg/l to 5.1 mg/l, resulting in the death of tumor cells in all studied cell cultures. In vivo experiments on transplanted Ehrlich carcinoma model in mice consuming 0.75 mg/kg ACS with drinking water revealed significant inhibition of tumor growth since the 14th day of experiment (maximally by 52% on the 28th day, p < 0.05) in comparison with control. Subcutaneous injections of 2.5 mg/kg ACS inhibited Ehrlich's tumor growth on the 7th and 10th days of the experiment (p < 0.05) as compared to control.

scholarly journals Hsp70 Interacts with the TREM-1 Receptor Expressed on Monocytes and Thereby Stimulates Generation of Cytotoxic Lymphocytes Active against MHC-Negative Tumor Cells

2021 ◽  
Vol 22 (13) ◽  
pp. 6889
Author(s):  
Tatiana N. Sharapova ◽  
Elena A. Romanova ◽  
Olga K. Ivanova ◽  
Denis V. Yashin ◽  
Lidia P. Sashchenko
Keyword(s):  
Innate Immunity ◽  
Tumor Cells ◽  
Heat Shock Protein 70 ◽  
Antitumor Immunity ◽  
Lymphocyte Subpopulations ◽  
Regulatory Mechanisms ◽  
Cytotoxic Lymphocytes ◽  
Special Significance ◽  
Cytotoxic Lymphocyte ◽  
Negative Tumor

The search for and analysis of new ligands for innate immunity receptors are of special significance for understanding the regulatory mechanisms of immune response. Here we show that the major heat shock protein 70 (Hsp70) can bind to and activate TREM-1, the innate immunity receptor expressed on monocytes. The Hsp70–TREM-1 interaction activates expression of TNFα and IFNγ mRNAs in monocytes and stimulates IL-2 secretion by РВМСs. Moreover, incubation of РВМСs with Hsp70 leads to an appearance of cytotoxic lymphocyte subpopulations active against the MHC-negative tumor cells. In addition, both the CD4+ Т-lymphocytes and CD14+ monocytes are necessary for the Hsp70 signal transduction and a consequent activation of the cytotoxic lymphocytes. We believe that data presented in this study will broaden the views on the involvement of Hsp70 in the antitumor immunity.

scholarly journals Exosomes from Plasma of Neuroblastoma Patients Contain Doublestranded DNA Reflecting the Mutational Status of Parental Tumor Cells

2021 ◽  
Vol 22 (7) ◽  
pp. 3667
Author(s):  
Chiara Degli Esposti ◽  
Barbara Iadarola ◽  
Simone Maestri ◽  
Cristina Beltrami ◽  
Denise Lavezzari ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Acquired Resistance ◽  
Membrane Vesicles ◽  
Preschool Age ◽  
Molecular Diagnostic ◽  
Non Invasive ◽  
Mutational Status ◽  
Whole Exome ◽  
Parental Tumor ◽  
Intercellular Communications

Neuroblastoma (NB) is an aggressive infancy tumor, leading cause of death among preschool age diseases. Here we focused on characterization of exosomal DNA (exo-DNA) isolated from plasma cell-derived exosomes of neuroblastoma patients, and its potential use for detection of somatic mutations present in the parental tumor cells. Exosomes are small extracellular membrane vesicles secreted by most cells, playing an important role in intercellular communications. Using an enzymatic method, we provided evidence for the presence of double-stranded DNA in the NB exosomes. Moreover, by whole exome sequencing, we demonstrated that NB exo-DNA represents the entire exome and that it carries tumor-specific genetic mutations, including those occurring on known oncogenes and tumor suppressor genes in neuroblastoma (ALK, CHD5, SHANK2, PHOX2B, TERT, FGFR1, and BRAF). NB exo-DNA can be useful to identify variants responsible for acquired resistance, such as mutations of ALK, TP53, and RAS/MAPK genes that appear in relapsed patients. The possibility to isolate and to enrich NB derived exosomes from plasma using surface markers, and the quick and easy extraction of exo-DNA, gives this methodology a translational potential in the clinic. Exo-DNA can be an attractive non-invasive biomarker for NB molecular diagnostic, especially when tissue biopsy cannot be easily available.

scholarly journals Epithelial-Mesenchymal Transition and MicroRNAs in Colorectal Cancer Chemoresistance to FOLFOX

Pharmaceutics ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 75
Author(s):  
Paula I. Escalante ◽  
Luis A. Quiñones ◽  
Héctor R. Contreras
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Methylenetetrahydrofolate Reductase ◽  
Epithelial Mesenchymal Transition ◽  
Late Onset ◽  
Dihydropyrimidine Dehydrogenase ◽  
Acquired Resistance ◽  
Potential Effect ◽  
Mesenchymal Transition ◽  
Folfox Chemotherapy

The FOLFOX scheme, based on the association of 5-fluorouracil and oxaliplatin, is the most frequently indicated chemotherapy scheme for patients diagnosed with metastatic colorectal cancer. Nevertheless, development of chemoresistance is one of the major challenges associated with this disease. It has been reported that epithelial-mesenchymal transition (EMT) is implicated in microRNA-driven modulation of tumor cells response to 5-fluorouracil and oxaliplatin. Moreover, from pharmacogenomic research, it is known that overexpression of genes encoding dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), the DNA repair enzymes ERCC1, ERCC2, and XRCC1, and the phase 2 enzyme GSTP1 impair the response to FOLFOX. It has been observed that EMT is associated with overexpression of DPYD, TYMS, ERCC1, and GSTP1. In this review, we investigated the role of miRNAs as EMT promotors in tumor cells, and its potential effect on the upregulation of DPYD, TYMS, MTHFR, ERCC1, ERCC2, XRCC1, and GSTP1 expression, which would lead to resistance of CRC tumor cells to 5-fluorouracil and oxaliplatin. This constitutes a potential mechanism of epigenetic regulation involved in late-onset of acquired resistance in mCRC patients under FOLFOX chemotherapy. Expression of these biomarker microRNAs could serve as tools for personalized medicine, and as potential therapeutic targets in the future.

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