scholarly journals Differential Localization and Invasion of Tumor Cells in Mouse Models of Human and Murine Leukemias

2020 ◽  
Vol 53 (3) ◽  
pp. 43-53
Author(s):  
Kiyomi Mashima ◽  
Morio Azuma ◽  
Ken Fujiwara ◽  
Takeshi Inagaki ◽  
Iekuni Oh ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Mouse Models ◽  
Differential Localization

755 CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A803-A803 ◽  
Author(s):  
Alvaro Teijeira ◽  
Saray Garasa ◽  
Itziar Migueliz ◽  
Assunta Cirella ◽  
Ignacio Melero
Keyword(s):  
Cancer Patients ◽  
Tumor Cells ◽  
Mouse Models ◽  
Chemokine Receptor ◽  
Suppressor Cells ◽  
Neutrophil Extracellular Traps ◽  
Myeloid Derived Suppressor Cells ◽  
Extracellular Traps ◽  
Tumor Associated Neutrophils

BackgroundNeutrophils are expanded and abundant in an important fraction (up to 35% of patients) in cancer-bearing hosts. When neutrophils are expanded, they usually promote exert immunomodulatory functions promoting tumor progression and the generation of metastases. Neutrophils can undergo a specialized form of cell death called NETosis that is characterized by the extrusion of their DNA to contain infections. In cancer NETs have been described to promote metastases in mouse models. IL-8, a CXCR1/2 ligand clinically targeted by blocking antibodies, has been described to induce NETosis and is upregulated in many cancer patients. Our hypothesis is that chemokines secreted by cancer cells can mediate NETosis in tumor associated neutrophils and that NETs can be one of the immunomodulatory mechanisms provided by tumor associated neutrophils.MethodsNETosis induction of peripheral neutrophils and granulocytic myeloid derived suppressor cells by different chemotactic stimuli, tumor cell supernatants and cocultures upon CXCR1/2 blockade. NET immunodetection in mouse models and xenograft tumors upon CXCR1/2 blockade. In vitro tumor cytotoxicity assays in the presence/absence of NETs, and videomicroscopy studies in vitro and by intravital imaging to test NETs inhibition of immune cytotoxicity by immune-cell/target-cell inhibition. Tumor growth studies and metastases models in the presence of NETosis inhibitors and in combination with checkpoint blockade in mouse cancer models.ResultsUnder the influence of CXCR1 and CXCR2 chemokine receptor agonists and other chemotactic factors produced by tumors, neutrophils, and granulocytic myeloid-derived suppressor cells (MDSCs) from cancer patients extrude their neutrophil extracellular traps (NETs). In our hands, CXCR1 and CXCR2 agonists proved to be the major mediators of cancer-promoted NETosis. NETs wrap and coat tumor cells and shield them from cytotoxicity, as mediated by CD8+ T cells and natural killer (NK) cells, by obstructing contact between immune cells and the surrounding target cells. Tumor cells protected from cytotoxicity by NETs underlie successful cancer metastases in mice and the immunotherapeutic synergy of protein arginine deiminase 4 (PAD4) inhibitors, which curtail NETosis with immune checkpoint inhibitors. Intravital microscopy provides evidence of neutrophil NETs interfering cytolytic cytotoxic T lymphocytes (CTLs) and NK cell contacts with tumor cells.ConclusionsCXCR1 and 2 are the main receptors mediating NETosis of tumor associated neutrophils in our in-vitro and in vivo systems expressing high levels of CXCR1 and 2 ligands. NETs limit cancer cell cytotoxicity by impeding contacts with cancer cells.

CD4+ T cells indirectly kill tumor cells via induction of cytotoxic macrophages in mouse models

2019 ◽  
Vol 68 (11) ◽  
pp. 1865-1873 ◽  
Author(s):  
Bjarne Bogen ◽  
Marte Fauskanger ◽  
Ole Audun Haabeth ◽  
Anders Tveita
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Mouse Models ◽  
Cd4 T Cells

scholarly journals SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1151 ◽  
Author(s):  
Sara Gomes ◽  
Bartolomeo Bosco ◽  
Joana B. Loureiro ◽  
Helena Ramos ◽  
Liliana Raimundo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Antitumor Activity ◽  
Tumor Cells ◽  
Mouse Models ◽  
Anticancer Agents ◽  
Human Tumor ◽  
Endoplasmic Reticulum Stress Response ◽  
Mutant P53 ◽  
Wild Type ◽  
Proliferative Effect

Half of human cancers harbor TP53 mutations that render p53 inactive as a tumor suppressor. In these cancers, reactivation of mutant p53 (mutp53) through restoration of wild-type-like function constitutes a valuable anticancer therapeutic strategy. In order to search for mutp53 reactivators, a small library of tryptophanol-derived oxazoloisoindolinones was synthesized and the potential of these compounds as mutp53 reactivators and anticancer agents was investigated in human tumor cells and xenograft mouse models. By analysis of their anti-proliferative effect on a panel of p53-null NCI-H1299 tumor cells ectopically expressing highly prevalent mutp53, the compound SLMP53-2 was selected based on its potential reactivation of multiple structural mutp53. In mutp53-Y220C-expressing hepatocellular carcinoma (HCC) cells, SLMP53-2-induced growth inhibition was mediated by cell cycle arrest, apoptosis, and endoplasmic reticulum stress response. In these cells, SLMP53-2 restored wild-type-like conformation and DNA-binding ability of mutp53-Y220C by enhancing its interaction with the heat shock protein 70 (Hsp70), leading to the reestablishment of p53 transcriptional activity. Additionally, SLMP53-2 displayed synergistic effect with sorafenib, the only approved therapy for advanced HCC. Notably, it exhibited potent antitumor activity in human HCC xenograft mouse models with a favorable toxicological profile. Collectively, SLMP53-2 is a new mutp53-targeting agent with promising antitumor activity, particularly against HCC.

Methods to Study Primary Tumor Cells and Residual Tumor Cells in Mouse Models of Oncogene Dependence

2015 ◽  
pp. 381-394
Author(s):  
Caroline Botta ◽  
Cedric Darini ◽  
Guillaume Darrasse-Jèze ◽  
Katrina Podsypanina
Keyword(s):  
Tumor Cells ◽  
Mouse Models ◽  
Primary Tumor ◽  
Residual Tumor

scholarly journals Circulating Tumor Cells as a Biomarker of Response to Treatment in Patient-Derived Xenograft Mouse Models of Pancreatic Adenocarcinoma

PLoS ONE ◽  
2014 ◽  
Vol 9 (2) ◽  
pp. e89474 ◽  
Author(s):  
Robert J. Torphy ◽  
Christopher J. Tignanelli ◽  
Joyce W. Kamande ◽  
Richard A. Moffitt ◽  
Silvia G. Herrera Loeza ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Pancreatic Adenocarcinoma ◽  
Circulating Tumor Cells ◽  
Mouse Models ◽  
Response To Treatment ◽  
Patient Derived Xenograft

Biodegradable polymeric micelle-encapsulated doxorubicin suppresses tumor metastasis by killing circulating tumor cells

Nanoscale ◽  
2015 ◽  
Vol 7 (12) ◽  
pp. 5270-5280 ◽  
Author(s):  
Senyi Deng ◽  
Qinjie Wu ◽  
Yuwei Zhao ◽  
Xin Zheng ◽  
Ni Wu ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Mouse Models ◽  
Tumor Metastasis ◽  
Polymeric Micelle ◽  
Potential Applications

Doxorubicin (Dox) micelles showed improved anti-metastasis activity by killing circulating tumor cells (CTCs) in zebrafish and mouse models, which may have potential applications in cancer therapy.

The New CXCR4 Inhibitor MDX-1338 Exerts Anti-Tumor Activity in Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1844-1844 ◽  
Author(s):  
Aldo M Roccaro ◽  
Antonio Sacco ◽  
Michelle Kuhne ◽  
AbdelKareem Azab ◽  
Patricia Maiso ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tumor Cells ◽  
Mouse Models ◽  
Research Funding ◽  
Therapeutic Agents ◽  
Dependent Manner ◽  
Apoptotic Pathways ◽  
Dose Dependent

Abstract Abstract 1844 Background. We have previously shown the SDF1/CXCR4 axis plays a major role in homing and trafficking of multiple myeloma (MM) to the bone marrow (BM), and disruption of the interaction of tumor cells with the BM leads to enhanced sensitivity to therapeutic agents. We hypothesize that the novel anti-CXCR4 antibody, BMS936564/MDX-1338, may prevent the homing and adhesion of MM cells to the BM and will sensitize them to therapeutic agents. Methods. Primary MM cells (CD138+); MM cell lines (MM.1S, RPMI.8226); and primary MM bone marrow stromal cells (BMSCs) were used. Migration towards SDF-1 and BMSCs has been evaluated. Cytotoxicity and DNA synthesis were measured by MTT and thymidine uptake, respectively. Cell signaling and apoptotic pathways were studied by Western Blot. Synergism was calculated using the Chou-Talalay method. In vivo MM tumor growth was evaluated with xenograft mouse models. Results. MDX-1338 inhibited migration of MM cells toward SDF-1a and primary MM BMSCs, in a dose-dependent manner. Adhesion of primary MM cells to BMSCs was also inhibited by BMS936564/MDX-1338 in a dose-dependent manner, while also inducing cytotoxicity on primary BM-derived CD138+ cells. BMS936564/MDX-1338 targeted MM cells in the context of BM milieu by overcoming BMSC-induced proliferation of tumor cells. In addition, BMS936564/MDX-1338 synergistically enhanced bortezomib-induced cytotoxicity in MM cells. BMS936564/MDX-1338-dependent activation of apoptotic pathways in MM cells was documented, as shown by cleavage of caspase-9 and PARP. SDF-1a-induced ERK-, Akt-, and Src-phosphorilation was inhibited by BMS936564/MDX-1338 in a dose-dependent manner. Importantly, BMS936564/MDX-1338 inhibited MM cell proliferation in vivo in xenograft mouse models. Conclusion. These studies therefore show that targeting CXCR-4 in MM by using BMS936564/MDX-1338 represents a valid therapeutic strategy in this disease. Disclosures: Roccaro: Roche:. Kuhne:BMS: Employment. Pan:Bristol-Myers Squibb: Employment. Cardarelli:Bristol-Myers Squibb: Employment. Ghobrial:Noxxon: Research Funding; Bristol-Myers Squibb: Research Funding; Millennium: Research Funding; Noxxon:; Millennium:; Celegene:; Novartis:.

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