A Severe Combined Immunodeficient–hu <i>In vivo</i> Mouse Model of Human Primary Mantle Cell Lymphoma

Wang, Michael; Zhang, Liang; Han, Xiaohong; Yang, Jing; Qian, Jianfei; Hong, Sang Hyun; Lin, Pei; Shi, Yuankai; Romaguera, Jorge; Kwak, Larry W.; Yi, Qing

doi:10.1158/1078-0432.ccr-07-4409

Cited by 25 publications

(22 citation statements)

References 29 publications

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“…Freshly isolated human MCL cells can survive and thrive after direct injection into the microenvironment of human fetal bone. 21 Therefore, MCL, as well as MM, are ideal tumor models for investigating the interaction between the tumor and its microenvironment.On the basis of the similarity between MCL and MM, we hypothesized that IL-6 also may be a key growth and survival cytokine for MCL cells. In this study, we investigated the role of IL-6 and its signaling in the survival, growth, and drug resistance of MCL.…”

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Role of the microenvironment in mantle cell lymphoma: IL-6 is an important survival factor for the tumor cells

Zhang

Yang

Qian

et al. 2012

Blood

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Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma frequently involved in the lymph nodes, bone marrow, spleen, and gastrointestinal tract. We examined the role of IL-6 in MCL. Human MCL cells expressed the membrane gp130 and soluble gp80, and some of them also secreted IL-6. Neutralizing autocrine IL-6 and/or blocking IL-6 receptors in IL-6(+)/gp80(+) MCL cells inhibited cell growth, enhanced the rate of spontaneous apoptosis, and increased sensitivity to chemotherapy drugs. For IL-6(-) or gp80(low) MCL cells, paracrine or exogenous IL-6 or gp80 protected the cells from stress-induced death. Knockdown of gp80 in gp80(high) MCL cells rendered the cells more sensitive to chemotherapy drugs, even in the presence of exogenous IL-6. In contrast, overexpression of gp80 in gp80(low)/IL-6(+) MCL cells protected the cells from chemotherapy drug-induced apoptosis in vitro and compromised the therapeutic effect of chemotherapy in vivo. IL-6 activated the Jak2/STAT3 and PI3K/Akt pathways in MCL, and the inhibition of these pathways completely or partially abrogated IL-6-mediated protection of MCL cells. Hence, our study identifies IL-6 as a key cytokine for MCL growth and survival and suggests that targeting the IL-6 pathway may be a novel way to improve the efficacy of chemotherapy in MCL patients.

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confidence: 99%

Role of the microenvironment in mantle cell lymphoma: IL-6 is an important survival factor for the tumor cells

Zhang

Yang

Qian

et al. 2012

Blood

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“…Tumor burdens were evaluated weekly by measuring the tumor size. The primary MCL-bearing SCID-hu mouse model in which primary MCL cells are engrafted in subcutaneously implanted human fetal bone chips was generated as previously described (26). Briefly, approximately 4 to 6 weeks after human fetal bone chip implantation, 5 Â 10 6 purified primary MCL cells were injected directly into the subcutaneously implanted human fetal bone within the SCID-hu hosts, after the mice were anesthetized with ketamine (75 mg/kg) and xylazine (12.5 mg/kg; Lloyd).…”

Section: Mcl-bearing Scid/primary Mcl-bearing Scid-hu Mouse Modelsmentioning

confidence: 99%

In Vitro and In Vivo Therapeutic Efficacy of Carfilzomib in Mantle Cell Lymphoma: Targeting the Immunoproteasome

Zhang

Pham

Newberry

et al. 2013

Molecular Cancer Therapeutics

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Mantle cell lymphoma (MCL) remains incurable due to its inevitable pattern of relapse after treatment with current existing therapies. However, the promise of a cure for MCL lies in the burgeoning area of novel agents. In this study, we elucidated the therapeutic effect and mechanism of carfilzomib, a novel long-acting second-generation proteasome inhibitor, in MCL cells. We found that carfilzomib induced growth inhibition and apoptosis in both established MCL cell lines and freshly isolated primary MCL cells in a dose-dependent manner. In contrast, carfilzomib was less toxic to normal peripheral blood mononuclear cells from healthy individuals. The carfilzomib-induced apoptosis of MCL cells was mediated by the activation of JNK, Bcl-2, and mitochondria-related pathways. In addition, carfilzomib inhibited the growth and survival signaling pathways NF-kB and STAT3. Interestingly, we discovered that expression of immunoproteasome (i-proteasome) subunits is required for the anti-MCL activity of carfilzomib in MCL cells. In MCL-bearing SCID mice/primary MCL-bearing SCID-hu mice, intravenous administration of 5 mg/kg carfilzomib on days 1 and 2 for 5 weeks slowed/abrogated tumor growth and significantly prolonged survival. Our preclinical data show that carfilzomib is a promising, potentially less toxic treatment for MCL. Furthermore, an intact i-proteasome, especially LMP2, appears to be necessary for its anti-MCL activity, suggesting that i-proteasome could serve as a biomarker for identifying patients who will benefit from carfilzomib. Mol Cancer Ther; 12(11); 2494-504. Ó2013 AACR.

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“…Mouse models of MCL reported in the literature include two large groups: (1) genetically engineered mice predisposed to develop a MCL-like disease and (2) immunodeficient mice capable of bearing human MCL xenografts. [8][9][10][11] Recently, characterization of a mouse xenograft model using primary MCL cells was reported; however, it was unfortunately technically demanding and difficult to implement. 11 Currently, the most widely used MCL xenograft model utilizes the subcutaneous injection of established MCL cell lines into immunodeficient mice.…”

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confidence: 99%

“…[8][9][10][11] Recently, characterization of a mouse xenograft model using primary MCL cells was reported; however, it was unfortunately technically demanding and difficult to implement. 11 Currently, the most widely used MCL xenograft model utilizes the subcutaneous injection of established MCL cell lines into immunodeficient mice. [12][13][14][15] To further improve on the current available MCL mouse models, we established and characterized several reproducible metastatic mouse models of human MCL by the inoculation of human primary MCL cells or MCL cell lines (Jeko-1, Mino, Rec-1, Granta-519, and Hbl-2) via tail vein injection (i.v.)…”

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Mouse models of mantle cell lymphoma, complex changes in gene expression and phenotype of engrafted MCL cells: implications for preclinical research

Klánová

Soukup

Jakša

et al. 2014

Laboratory Investigation

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Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma (NHL) associated with poor prognosis. Animal models of MCL are scarce. We established and characterized various in vivo models of metastatic human MCL by tail vein injection of either primary cells isolated from patients with MCL or established MCL cell lines (Jeko-1, Mino, Rec-1, Hbl-2, and Granta-519) into immunodeficient NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ mice. MCL infiltration was assessed with immunohistochemistry (tissues) and flow cytometry (peripheral blood). Engraftment of primary MCL cells was observed in 7 out of 12 patient samples. The pattern of engraftment of primary MCL cells varied from isolated involvement of the spleen to multiorgan infiltration. On the other hand, tumor engraftment was achieved in all five MCL cell lines used and lymphoma involvement of murine bone marrow, spleen, liver, and brain was observed. Overall survival of xenografted mice ranged from 22±1 to 54±3 days depending on the cell line used. Subsequently, we compared the gene expression profile (GEP) and phenotype of the engrafted MCL cells compared with the original in vitro growing cell lines (controls). We demonstrated that engrafted MCL cells displayed complex changes of GEP, protein expression, and sensitivity to cytotoxic agents when compared with controls. We further demonstrated that our MCL mouse models could be used to test the therapeutic activity of systemic chemotherapy, monoclonal antibodies, or angiogenesis inhibitors. The characterization of MCL murine models is likely to aid in improving our knowledge in the disease biology and to assist scientists in the preclinical and clinical development of novel agents in relapsed/refractory MCL patients. Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma (NHL) characterized by the chromosomal translocation t(11;14)(q13;q32) leading to overexpression of cyclin D1. 1 Apart from this canonical aberration, MCL may harbor a large number of recurrent cytogenetic changes that further deregulate cell cycle machinery (for example, deletion of 9p21 (CDKN2A) and amplification of 12q13 (CDK4)) or interfere with cellular response to DNA damage (for example, alterations of 11q22-q23 (ATM), 17p13 (TP53) and overexpression of MDM2). 2-5 MCL is associated with poor prognosis. 6,7 In order to improve the outcome of MCL patients, the rational development and preclinical/clinical testing of new agents are necessary. Reliable and reproducible in vivo models of MCL are thus urgently needed. In vivo models have several advantages over in vitro approaches. For example, they enable the study of MCL biology in its microenvironment, including engraftment, growth rate, spread patterns, or tumor associated neovascularization.

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A Severe Combined Immunodeficient–hu In vivo Mouse Model of Human Primary Mantle Cell Lymphoma

Cited by 25 publications

References 29 publications

Role of the microenvironment in mantle cell lymphoma: IL-6 is an important survival factor for the tumor cells

Role of the microenvironment in mantle cell lymphoma: IL-6 is an important survival factor for the tumor cells

In Vitro and In Vivo Therapeutic Efficacy of Carfilzomib in Mantle Cell Lymphoma: Targeting the Immunoproteasome

Mouse models of mantle cell lymphoma, complex changes in gene expression and phenotype of engrafted MCL cells: implications for preclinical research

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