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 Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models of Primary and Recurrent Meningioma

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1478
Author(s):  
Huiyuan Zhang ◽  
Lin Qi ◽  
Yuchen Du ◽  
L. Frank Huang ◽  
Frank K. Braun ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Mouse Models ◽  
Primary Tumor ◽  
Malignant Tumors ◽  
Expression Profiles ◽  
World Health ◽  
Who Grade ◽  
Orthotopic Xenograft

Background. Meningiomas constitute one-third of all primary brain tumors. Although typically benign, about 20% of these tumors recur despite surgery and radiation, and may ultimately prove fatal. There are currently no effective chemotherapies for meningioma. We, therefore, set out to develop patient-derived orthotopic xenograft (PDOX) mouse models of human meningioma using tumor. Method. Of nine patients, four had World Health Organization (WHO) grade I tumors, five had WHO grade II tumors, and in this second group two patients also had recurrent (WHO grade III) meningioma. We also classified the tumors according to our recently developed molecular classification system (Types A, B, and C, with C being the most aggressive). We transplanted all 11 surgical samples into the skull base of immunodeficient (SCID) mice. Only the primary and recurrent tumor cells from one patient—both molecular Type C, despite being WHO grades II and III, respectively—led to the formation of meningioma in the resulting mouse models. We characterized the xenografts by histopathology and RNA-seq and compared them with the original tumors. We performed an in vitro drug screen using 60 anti-cancer drugs followed by in vivo validation. Results. The PDOX models established from the primary and recurrent tumors from patient K29 (K29P-PDOX and K29R-PDOX, respectively) replicated the histopathology and key gene expression profiles of the original samples. Although these xenografts could not be subtransplanted, the cryopreserved primary tumor cells were able to reliably generate PDOX tumors. Drug screening in K29P and K29R tumor cell lines revealed eight compounds that were active on both tumors, including three histone deacetylase (HDAC) inhibitors. We tested the HDAC inhibitor Panobinostat in K29R-PDOX mice, and it significantly prolonged mouse survival (p < 0.05) by inducing histone H3 acetylation and apoptosis. Conclusion. Meningiomas are not very amenable to PDOX modeling, for reasons that remain unclear. Yet at least some of the most malignant tumors can be modeled, and cryopreserved primary tumor cells can create large panels of tumors that can be used for preclinical drug testing.

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.

scholarly journals Metastatic Esophageal Carcinoma Cells Exhibit Reduced Adhesion Strength and Enhanced Thermogenesis

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1213
Author(s):  
Zihe Huo ◽  
Mariana Sá Santos ◽  
Astrid Drenckhan ◽  
Stefan Holland-Cunz ◽  
Jakob R. Izbicki ◽  
...  
Keyword(s):  
Esophageal Carcinoma ◽  
Tumor Cells ◽  
Cell Lines ◽  
Adhesion Strength ◽  
Primary Tumor ◽  
Carcinoma Cell ◽  
Metastatic Potential ◽  
Primary Tumors ◽  
Metastatic Cell ◽  
Carcinoma Cell Lines

Despite continuous improvements in multimodal therapeutic strategies, esophageal carcinoma maintains a high mortality rate. Metastases are a major life-limiting component; however, very little is known about why some tumors have high metastatic potential and others not. In this study, we investigated thermogenic activity and adhesion strength of primary tumor cells and corresponding metastatic cell lines derived from two patients with metastatic adenocarcinoma of the esophagus. We hypothesized that the increased metastatic potential of the metastatic cell lines correlates with higher thermogenic activity and decreased adhesion strength. Our data show that patient-derived metastatic esophageal tumor cells have a higher thermogenic profile as well as a decreased adhesion strength compared to their corresponding primary tumor cells. Using two paired esophageal carcinoma cell lines of primary tumor and lymph nodes makes the data unique. Both higher specific thermogenesis profile and decreased adhesion strength are associated with a higher metastatic potential. They are in congruence with the clinical patient presentation. Understanding these functional, biophysical properties of patient derived esophageal carcinoma cell lines will enable us to gain further insight into the mechanisms of metastatic potential of primary tumors and metastases. Microcalorimetric evaluation will furthermore allow for rapid assessment of new treatment options for primary tumor and metastases aimed at decreasing the metastatic potential.

What are the risk factors for residual tumor cells after endoscopic complete resection in gastric epithelial neoplasia?

2014 ◽  
Vol 29 (2) ◽  
pp. 487-492 ◽  
Author(s):  
Gak Won Yun ◽  
Jie-Hyun Kim ◽  
Yong Chan Lee ◽  
Sang Kil Lee ◽  
Sung Kwan Shin ◽  
...  
Keyword(s):  
Risk Factors ◽  
Tumor Cells ◽  
Residual Tumor ◽  
Complete Resection ◽  
Gastric Epithelial Neoplasia

scholarly journals Primary tumor cells obtained from MNU-induced mammary carcinomas show immune heterogeneity which can be modulated by low-efficiency transfection of CD40L gene

2009 ◽  
Vol 8 (2) ◽  
pp. 136-142 ◽  
Author(s):  
Gunes Esendagli ◽  
Hande Canpinar ◽  
Guldal Yilmaz ◽  
Aysen Gunel-Ozcan ◽  
M. Oguz Guc ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Primary Tumor ◽  
Mammary Carcinomas ◽  
Low Efficiency

A New Recombinant Fibronectin/Cadherin Protein-Hydrophobically Modified Glycol Chitosan/Paclitaxel Layer-By-Layer Self-Assembly Strategy for the Postoperative Therapy of Osteosarcoma and Correlated Bone Injury

2021 ◽  
Vol 17 (9) ◽  
pp. 1765-1777
Author(s):  
Zaiyang Liu ◽  
Yiqun Wu ◽  
Hongjuan Dai ◽  
Shasha Li ◽  
Ying Zhu ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Tumor Cells ◽  
Self Assembly ◽  
Blood Circulation ◽  
Residual Tumor ◽  
Layer By Layer ◽  
Glycol Chitosan ◽  
Hydrophobically Modified ◽  
Bone Injury

Osteosarcoma is one of the most aggressive cancers which greatly threatens the health of adolescents and surgery is difficult to resect the whole piece of tumor tissue. The residual tumor cells might proliferate at the tumor site and invade into the blood circulation, leading to tumor recurrence and metastasis. Besides, the invasion of tumor cells could also lead to bone injury. We designed a recombinant fibronectin-cadherin fusion protein/hydrophobically modified glycol chitosan-PTX nanoparticles (rFN-CDH/HGC-PTX) layer-by-layer self-assembly polymer based on biphasic calcium phosphate ceramic (BCP) (BCP-PEI-(rFN/CDH-PTX/HGC)n-rFN/CDH). The SEM, FTIR, XPS and contact angle experiments proved the successful synthesis of the polymer. The chemotherapy drug PTX and bone-repairing-related rFN/CDH fusion protein could be stably released within one week and the in vitro experiments exhibited the efficacy of the polymer to kill residual tumor cells and promote the proliferation of osteoblast, confirming that our polymer was a superior material for postoperative osteosarcoma therapy.

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