A combination of 5-fluorouracil and membrane-bound antibody inhibits B-cell lymphoma growth in a mouse model system

Lactobacillus fermentum CQPC08 (LF-CQPC08) is a newly discovered strain of bacteria isolated and identified from traditional pickled vegetables in Sichuan, China. We used 4-nitroquinoline 1-oxide to establish an experimental tongue cancer mouse model to evaluate the preventive effect of LF-CQPC08 on tongue cancer in vivo. Lactobacillus delbruechii subsp. bulgaricus, is a common commercial strain and is used as a positive control to compare the effect with LF-CQPC08. The preventive strength and mechanism of LF-CQPC08 on tongue cancer were determined by measuring the biochemical indicators in mouse serum and tissues. Our results showed LF-CQPC08 inhibits the decline of splenic index, thymus index, percentage of phagocytic macrophages, and phagocytic index effectively. LF-CQPC08 also increased levels of mouse serum granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage-CSF (GM-CSF), immunoglobulin (Ig)G, IgM levels of serum interleukin (IL)-4, IL-12, tumor necrosis factor-alpha, and interferon-gamma levels, thereby inhibiting the decline in immunity caused by tongue cancer. It also increased the activity levels of superoxide dismutase and glutathione peroxidase and decreased the levels of malondialdehyde in the tissues of the tongue cancer mouse model, thereby suppressing the oxidative stress damage in the tissue caused by tongue cancer. Through quantitative PCR, LF-CQPC08 upregulated the mRNA expression of nuclear factor-erythroid 2 related factor 2 (Nrf2), heme oxygenase-1 (HO-1), glutathione-S-transferases-π (GST-π), and Bcl-2-associated X protein (Bax), and downregulated the mRNA expression of p53, p63, p73, phosphatase and tensin homolog (PTEN), B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL) in the tongue tissues of the tongue cancer mouse. These results indicated that LF-CQPC08 reduced the influence of tongue cancer on the immune system and oxidative balance and improved the immunity and enhanced antioxidant capacity of the mouse model, thereby preventing tongue cancer. LF-CQPC08 could be used as a microbial resource with a preventive effect on tongue cancer.

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Chloroquine Inhibits Autophagy, Enhances p53-Dependent Apoptosis, and Delays Tumor Recurrence in a Mouse Model of B Cell Lymphoma.

Blood ◽

10.1182/blood.v106.11.2421.2421 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2421-2421 ◽

Cited By ~ 2

Author(s):

Ravi K. Amaravadi ◽

Duonan Yu ◽

Andrei Thomas-Tikhonenko ◽

Craig B. Thompson

Keyword(s):

Mouse Model ◽

Fusion Protein ◽

B Cell ◽

Nuclear Localization ◽

Target Genes ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Burkitt’S Lymphoma ◽

Burkitt's Lymphoma ◽

Recurrent Tumors

Abstract Burkitt’s lymphoma is an example of an aggressive B cell neoplasm characterized by overexpression of the c-myc oncogene and frequent inactivation of the tumor suppressor gene p53. A non-transgenic mouse model of Burkitt’s lymphoma was generated by retroviral transduction of the human c-myc gene into bone marrow cells derived from the p53-estrogen receptor (p53ER) knock-in mouse. The resulting myc/p53ER cells produce an aggressive B cell lymphoma when injected subcutaneously into the flanks of syngeneic mice. When tumor-bearing mice are treated with tamoxifen intraperitoneally, the p53ER fusion protein is targeted to the nucleus where p53-dependent apoptosis can take place. On successive in vivo passages, cells develop the ability to survive p53 activation and escape p53ER-dependent apoptosis despite tamoxifen treatment and nuclear localization of the p53ER fusion protein. We hypothesized that cells resistant to p53-dependent apoptosis utilize autophagy as an essential survival mechanism. Thus, these tumors could be sensitive to chloroquine, a lysosomotropic inhibitor of autophagy that has been used extensively in humans as an antimalarial and for the treatment of rheumatoid arthritis. Daily intraperitoneal chloroquine or hydroxychloroquine treatment of mice bearing myc/p53ER tumors in the absence of tamoxifen resulted in a delay in tumor growth. When tamoxifen was added to induce nuclear localization of p53ER, mice that received tamoxifen plus chloroquine had a complete tumor response while mice that received tamoxifen plus saline had transient tumor shrinkage followed quickly by regrowth. Tamoxifen plus chloroquine treatment enhanced the expression of p53-dependent target genes and increased caspase activation compared to tamoxifen plus saline treatment. A higher percentage of cells in tumors treated with tamoxifen plus chloroquine underwent apoptosis compared to tumors treated with tamoxifen plus saline. Moreover, tumors that recurred in the mice treated with daily tamoxifen plus chloroquine did so after a significantly longer latency period then mice treated with tamoxifen plus saline. Recurrent tumors showed loss of expression of p53 target genes. Electron microscopy of recurrent tumors confirmed the accumulation of vacuoles in chloroquine treated tumors compared to controls, suggesting inhibition of lysosome function leads to the accumulation of ineffective autophagic vacuoles. These results indicate that inhibiting autophagy with lysosomotropic chloroquine derivatives could be a useful therapeutic addition to treatment regimens for aggressive B cell lymphomas.

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A Germinal Center- Derived B Cell Lymphoma Model

Blood ◽

10.1182/blood.v116.21.2008.2008 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2008-2008

Author(s):

Ryan T Phan ◽

Khang Nguyen ◽

Sonia Romero ◽

Alice Nicolson ◽

Phillipp Nham ◽

...

Keyword(s):

B Cells ◽

Mouse Model ◽

B Cell ◽

Germinal Center ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Chromosomal Translocations ◽

Dna Breaks ◽

Dna Rearrangements ◽

Human B Cell

Abstract Abstract 2008 Most human B-cell lymphomas represent mature phenotypes of germinal center (GC) or post-GC origin and are frequently associated with chromosomal translocations, often involving the rearrangement of immunoglobulin (Ig) loci to various cellular oncogenes, leading to oncogenic activation. The mechanisms underlying these processes, however, are not well understood. Several studies suggest that these genetic lesions arise from errors of physiologic DNA rearrangements in GC B cells, namely class switch recombination (CSR) and somatic hypermutation (SHM). Here we report the generation of a mouse model in which DNA breaks are physiologically instituted in mature B cells, yet inefficiently repaired via specific deletion of DNA repair gene XRCC4 in GC B cells, thus effectively creating an in vivo environment for errors in DNA rearrangements. These activated B cells exhibit significant increased chromosomal IgH locus breaks and reduced CSR. In p53-deficient background, these mice develop B-cell lymphoma from 5.5 to 16 months. These clonally developed tumors characteristically harbor chromosomal translocations and phenotypically resemble mature phenotypes. Many of these tumors bear mutated V genes, suggesting that those cells have transited through GC. Thus, this mouse model mimics human B-cell lymphoma and might be useful for the development of therapeutic interventions in B-cell lymphoma. Disclosures: No relevant conflicts of interest to declare.

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A transgenic mouse model for TEL-JAK2-induced B-cell lymphoma/leukemia

Leukemia ◽

10.1038/sj.leu.2404026 ◽

2005 ◽

Vol 20 (1) ◽

pp. 182-185 ◽

Cited By ~ 15

Author(s):

N R dos Santos ◽

J Ghysdael

Keyword(s):

Mouse Model ◽

B Cell ◽

Transgenic Mouse ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Transgenic Mouse Model

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Synergy of Myc, cell cycle regulators and the Akt pathway in the development of aggressive B-cell lymphoma in a mouse model

Leukemia ◽

10.1038/leu.2014.224 ◽

2014 ◽

Vol 28 (11) ◽

pp. 2270-2272 ◽

Cited By ~ 6

Author(s):

K Arita ◽

S Tsuzuki ◽

K Ohshima ◽

T Sugiyama ◽

M Seto

Keyword(s):

Cell Cycle ◽

Mouse Model ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Akt Pathway ◽

Cell Cycle Regulators ◽

Aggressive B Cell Lymphoma

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Reproducing Transformation of Indolent B-cell Lymphoma by T-cell Immunosuppression of L.CD40 Mice

10.1101/477273 ◽

2018 ◽

Author(s):

Christelle Vincent-Fabert ◽

Alexis Saintamand ◽

Amandine David ◽

Mehdi Alizadeh ◽

François Boyer ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Mouse Model ◽

B Cell ◽

Immune Suppression ◽

Clinical Course ◽

Cell Lymphoma ◽

Immune Surveillance ◽

B Cell Lymphoma

AbstractTransformation of an indolent B-cell lymphoma is associated with a more aggressive clinical course and poor survival. The role of immune surveillance in the transformation of a B-cell indolent lymphoma towards a more aggressive form is poorly documented. To experimentally address this question, we used the L.CD40 mouse model, which is characterized by B-cell specific continuous CD40 signaling, responsible for spleen indolent clonal or oligoclonal B-cell lymphoma after one year in 60% cases. Immunosuppression was obtained either by T/NK cell depletion or by treatment with the T-cell immunosuppressive drug cyclosporin A. Immunosuppressed L.CD40 mice had larger splenomegaly with increased numbers of B-cells in both spleen and peripheral blood. High-throughput sequencing of immunoglobulin variable segments revealed that clonal expansion was increased in immunosuppressed L.CD40 mice. Tumor B cells of immunosuppressed mice were larger with an immunoblastic aspect, both on blood smears and spleen tissue sections, with increased proliferation rate and increased numbers of activated B-cells. Collectively, these features suggest that immune suppression induced a shift from indolent lymphomas into aggressive ones. Thus, as a preclinical model, immunosuppressed L.CD40 mice reproduce aggressive transformation of an indolent B-cell tumor and highlight the role of the immune surveillance in its clinical course, opening new perspective for immune restoration therapies.Summary statementHighlighting the role of immune surveillance, transformation of indolent B-cell lymphoma into an aggressive malignancy is experimentally reproduced after T-cell immune suppression in the L.CD40 preclinical mouse model.

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