Murine mammary carcinoma 4T1 induces a leukemoid reaction with splenomegaly: Association with tumor-derived growth factors

duPré, Sally A.; Hunter, Kenneth W.

doi:10.1016/j.yexmp.2006.06.007

Cited by 238 publications

(266 citation statements)

References 43 publications

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“…Because all neutrophils from mice with CML-like MPN are more prone to generating NETs, we asked whether neutrophils from mice bearing solid tumors would also be more sensitive to NET formation. As described previously by DuPré et al (22), injection of the 4T1 mammary carcinoma cell line into BALB/c mice induced a large increase in peripheral blood neutrophils ( Fig. 2A) that correlated with tumor growth (Fig.…”

Section: Solid Tumors Generate a Leukemoid Reaction And Predisposesupporting

confidence: 73%

“…G-CSF increases neutrophil numbers in the circulation and activates them. The 4T1 tumor cells produce G-CSF, and its presence in the serum of tumor-bearing mice is associated with a leukemoid-like reaction (22). Elevated G-CSF levels were observed in the plasma of the CMLlike mice and both the mammary and lung carcinoma models compared with control mice (Fig.…”

Section: Spontaneous Net Formation In Cancer Is Associated With the Pmentioning

confidence: 91%

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Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis

Demers

Krause

Schatzberg

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

744

752

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Cancer-associated thrombosis often lacks a clear etiology. However, it is linked to a poor prognosis and represents the second-leading cause of death in cancer patients. Recent studies have shown that chromatin released into blood, through the generation of neutrophil extracellular traps (NETs), is procoagulant and prothrombotic. Using a murine model of chronic myelogenous leukemia, we show that malignant and nonmalignant neutrophils are more prone to NET formation. This increased sensitivity toward NET generation is also observed in mammary and lung carcinoma models, suggesting that cancers, through a systemic effect on the host, can induce an increase in peripheral blood neutrophils, which are predisposed to NET formation. In addition, in the late stages of the breast carcinoma model, NETosis occurs concomitant with the appearance of venous thrombi in the lung. Moreover, simulation of a minor systemic infection in tumor-bearing, but not control, mice results in the release of large quantities of chromatin and a prothrombotic state. The increase in neutrophil count and their priming is mediated by granulocyte colony-stimulating factor (G-CSF), which accumulates in the blood of tumor-bearing mice. The prothrombotic state in cancer can be reproduced by treating mice with G-CSF combined with low-dose LPS and leads to thrombocytopenia and microthrombosis. Taken together, our results identify extracellular chromatin released through NET formation as a cause for cancer-associated thrombosis and unveil a target in the effort to decrease the incidence of thrombosis in cancer patients.

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Section: Solid Tumors Generate a Leukemoid Reaction And Predisposesupporting

confidence: 73%

Section: Spontaneous Net Formation In Cancer Is Associated With the Pmentioning

confidence: 91%

Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis

Demers

Krause

Schatzberg

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

744

752

View full text Add to dashboard Cite

show abstract

“…This is mainly caused by a strong increase in both percentage and total number of granulocytes among the total splenocytes population. In literature this is known as a leukemoid reaction, which is earlier described in tumour-bearing mice and in different types of human cancers (Nimieri et al, 2003;DuPre and Hunter, 2007). When the complete mixture of FO, SOM and high protein/leucine was added to the diet of tumour-bearing animals, the leukemoid reaction was not reduced.…”

Section: Discussionmentioning

confidence: 84%

Beneficial immune modulatory effects of a specific nutritional combination in a murine model for cancer cachexia

et al. 2008

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The majority of patients with advanced cancer are recognised by impaired immune competence influenced by several factors, including the type and stage of the tumour and the presence of cachexia. Recently, a specific nutritional combination containing fish oil, specific oligosaccharide mixture, high protein content and leucine has been developed aimed to support the immune system of cancer patients in order to reduce the frequency and severity of (infectious) complications. In a recently modified animal model cachexia is induced by inoculation of C26 tumour cells in mice. In a pre-cachectic state, no effect was observed on contact hypersensitivity, a validated in vivo method to measure Th1-mediated immune function, after adding the individual nutritional ingredients to the diet of tumour-bearing mice. However, the complete mixture resulted in significantly improved Th1 immunity. Moreover, in a cachectic state, the complete mixture reduced plasma levels of pro-inflammatory cytokines and beneficially affected ex vivo immune function. Accordingly, the combination of the nutritional ingredients is required to obtain a synergistic effect, leading to a reduced inflammatory state and improved immune competence. From this, it can be concluded that the specific nutritional combination has potential as immune-supporting nutritional intervention to reduce the risk of (infectious) complications in cancer patients.

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“…We utilized the 4T1 murine mammary carcinoma model, a widely used non-transgenic breast cancer model, which metastasizes to lungs, liver, brain and bone similar to human breast cancer. [24][25][26][27] We inoculated Balb/c mice orthotopically with 4T1 tumor cells and compared mice treated with anti-PD-1 (clone J43; hamster IgG) to other available checkpoint blockade antibodies such as anti-CTLA-4 (clone UC-10; hamster IgG) or anti-PD-L1 (clone 10F.9G2; Rat IgG). Polyclonal hamster IgG and monoclonal rat IgG were used as isotype controls for the hamster anti murine PD-1 and CTLA-4 antibodies and the rat anti murine PD-L1 antibody.…”

Section: Resultsmentioning

confidence: 99%

Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer

et al. 2015

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Monoclonal antibodies (mAbs) targeting coinhibitory molecules such as PD-1, PD-L1 and CTLA-4 are increasingly used as targets of therapeutic intervention against cancer. While these targets have led to a critical paradigm shift in treatments for cancer, these approaches are also plagued with limitations owing to cancer immune evasion mechanisms and adverse toxicities associated with continuous treatment. It has been difficult to reproduce and develop interventions to these limitations preclinically due to poor reagent efficacy and reagent xenogenecity not seen in human trials. In this study, we investigated adverse effects of repeated administration of PD-1 and PD-L1 mAbs in the murine 4T1 mammary carcinoma model. We observed rapid and fatal hypersensitivity reactions in tumor bearing mice within 30-60 min after 4-5 administrations of PD-L1 or PD-1 mAb but not CTLA-4 antibody treatment. These events occurred only in mice bearing the highly inflammatory 4T1 tumor and did not occur in mice bearing noninflammatory tumors. We observed that mortality was associated with systemic accumulation of IgG1 antibodies, antibodies specific to the PD-1 mAb, and accumulation of Gr-1 high neutrophils in lungs which have been implicated in the IgG mediated pathway of anaphylaxis. Anti-PD-1 associated toxicities were alleviated when PD-1 blockade was combined with the therapeutic HSP90 inhibitor, ganetespib, which impaired immune responses toward the xenogeneic PD-1 mAb. This study highlights a previously uncharacterized fatal hypersensitivity exacerbated by the PD-1/PD-L1 axis in the broadly used 4T1 tumor model as well as an interesting relationship between this particular class of checkpoint blockade and tumor-dependent immunomodulation.

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Murine mammary carcinoma 4T1 induces a leukemoid reaction with splenomegaly: Association with tumor-derived growth factors

Cited by 238 publications

References 43 publications

Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis

Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis

Beneficial immune modulatory effects of a specific nutritional combination in a murine model for cancer cachexia

Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer

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