Articoli di riviste: "Mouse xenograft model"

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Zhang, Yanmei, Sau Har Lee, Cheng Wang, Yunhe Gao, Jiyang Li e Wei Xu. "Establishing metastatic patient-derived xenograft model for colorectal cancer". Japanese Journal of Clinical Oncology 50, n. 10 (24 giugno 2020): 1108–16. http://dx.doi.org/10.1093/jjco/hyaa089.

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Abstract Background Patient-derived xenograft model is a powerful and promising tool for drug discovery and cancer biology studies. The application of previous metastatic colorectal cancer models has been greatly limited by its low success rate and long time to develop metastasis. Therefore, in this study, we aim to describe an optimized protocol for faster establishment of colorectal cancer metastatic patient-derived xenograft mouse models. Methods Smaller micro tissues (˂150 μm in diameter) mixed with Matrigel were engrafted subcutaneously into NSG mice to generate the passage 1 (P1) patient-derived xenograft. The micro tumours from P1 patient-derived xenograft were then excised and orthotopically xenografted into another batch of NSG mice to generate a metastatic colorectal cancer patient-derived xenograft, P2. Haematoxylin and eosin and immunohistochemistry staining were performed to compare the characters between patient-derived xenograft tumours and primary tumours. Results About 16 out of 18 P1 xenograft models successfully grew a tumour for 50.8 ± 5.1 days (success rate 89.9%). Six out of eight P1 xenograft models originating from metastatic patients successfully grew tumours in the colon and metastasized to liver or lung in the NSG recipients for 60.9 ± 4.5 days (success rate 75%). Histological examination of both P1 and P2 xenografts closely resembled the histological architecture of the original patients’ tumours. Immunohistochemical analysis revealed similar biomarker expression levels, including CDH17, Ki-67, active β-catenin, Ki-67 and α smooth muscle actin when compared with the original patients’ tumours. The stromal components that support the growth of patient-derived xenograft tumours were of murine origin. Conclusions Metastatic patient-derived xenograft mouse model could be established with shorter time and higher success rate. Although the patient-derived xenograft tumours were supported by the stromal cells of murine origin, they retained the dominant characters of the original patient tumours.

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Komen, Job, Sanne M. van Neerven, Elsbeth G. B. M. Bossink, Nina E. de Groot, Lisanne E. Nijman, Albert van den Berg, Louis Vermeulen e Andries D. van der Meer. "The Effect of Dynamic, In Vivo-like Oxaliplatin on HCT116 Spheroids in a Cancer-on-Chip Model Is Representative of the Response in Xenografts". Micromachines 13, n. 5 (6 maggio 2022): 739. http://dx.doi.org/10.3390/mi13050739.

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The cancer xenograft model in which human cancer cells are implanted in a mouse is one of the most used preclinical models to test the efficacy of novel cancer drugs. However, the model is imperfect; animal models are ethically burdened, and the imperfect efficacy predictions contribute to high clinical attrition of novel drugs. If microfluidic cancer-on-chip models could recapitulate key elements of the xenograft model, then these models could substitute the xenograft model and subsequently surpass the xenograft model by reducing variation, increasing sensitivity and scale, and adding human factors. Here, we exposed HCT116 colorectal cancer spheroids to dynamic, in vivo-like, concentrations of oxaliplatin, including a 5 day drug-free period, on-chip. Growth inhibition on-chip was comparable to existing xenograft studies. Furthermore, immunohistochemistry showed a similar response in proliferation and apoptosis markers. While small volume changes in xenografts are hard to detect, in the chip-system, we could observe a temporary growth delay. Lastly, histopathology and a pharmacodynamic model showed that the cancer spheroid-on-chip was representative of the proliferating outer part of a HCT116 xenograft, thereby capturing the major driver of the drug response of the xenograft. Hence, the cancer-on-chip model recapitulated the response of HCT116 xenografts to oxaliplatin and provided additional drug efficacy information.

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Wang, Zhijie, Jianglong Kong, Ziteng Chen, Meiru Mao, Jiacheng Li, Hui Yuan, Ya-nan Chang, Kui Chen e Juan Li. "Human Glioma Nude Mouse Xenograft Model in situ". Diseases & Research 1, n. 1 (4 novembre 2021): 1–5. http://dx.doi.org/10.54457/dr.202101003.

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Backgrounds: Surgery and chemotherapy are difficult because of the specific location of the glioma. The establishment of a suitable in situ model of glioma is the premise of the treatment of glioma. 8 week-old female BALB/c nude mice were chose to establish the glioma model. Methods: For the orthotopic glioma mice model, 1 × 105 cells/5 μL U87-MG-Luc or U87-MG cells which were trypsinized and resuspended in sterile PBS were slowly injected into the right corpus striatum (1.8 mm lateral, 0.6 mm anterior to the bregma and 3.0 mm in depth) by a stereotactic fixation device using a mouse adaptor. Results: The othotopic U87 glioma mice model identified by imaging on IVIS Spectrum and magnetic resonance imaging after 2 weeks from surgery. H&E-stained tumor sections in brain of the mice model were also observed. Conclusions: After identification, the glioma mouse xenograft in situ model obtained could be used in the evaluation system of therapeutic drugs or methods.

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Sari, Gulce, Gertine W. van Oord, Martijn D. B. van de Garde, Jolanda J. C. Voermans, Andre Boonstra e Thomas Vanwolleghem. "Sexual Dimorphism in Hepatocyte Xenograft Models". Cell Transplantation 30 (1 gennaio 2021): 096368972110061. http://dx.doi.org/10.1177/09636897211006132.

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Humanized liver mouse models are crucial tools in liver research, specifically in the fields of liver cell biology, viral hepatitis and drug metabolism. The livers of these humanized mouse models are repopulated by 3-dimensional islands of fully functional primary human hepatocytes (PHH), which are notoriously difficult to maintain in vitro. As low efficiency and high cost hamper widespread use, optimization is of great importance. In the present study, we analyzed experimental factors associated with Hepatitis E virus (HEV) infection and PHH engraftment in 2 xenograft systems on a Nod-SCID-IL2Ry-/- background: the alb-urokinase plasminogen activator mouse model (uPA-NOG, n=399); and the alb-HSV thymidine kinase model (TK-NOG, n = 198). In a first analysis, HEV fecal shedding in liver humanized uPA-NOG and TK-NOG mice with comparable human albumin levels was found to be similar irrespective of the mouse genetic background. In a second analysis, sex, mouse age at transplantation and hepatocyte donor were the most determinant factors for xenograft success in both models. The sexual imbalance for xenograft success was related to higher baseline ALT levels and lower thresholds for ganciclovir induced liver morbidity and mortality in males. These data call for sexual standardization of human hepatocyte xenograft models, but also provide a platform for further studies on mechanisms behind sexual dimorphism in liver diseases.

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Pascoal, Susana, Benjamin Salzer, Eva Scheuringer, Andrea Wenninger-Weinzierl, Caterina Sturtzel, Wolfgang Holter, Sabine Taschner-Mandl, Manfred Lehner e Martin Distel. "A Preclinical Embryonic Zebrafish Xenograft Model to Investigate CAR T Cells in Vivo". Cancers 12, n. 3 (29 febbraio 2020): 567. http://dx.doi.org/10.3390/cancers12030567.

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Chimeric antigen receptor (CAR) T cells have proven to be a powerful cellular therapy for B cell malignancies. Massive efforts are now being undertaken to reproduce the high efficacy of CAR T cells in the treatment of other malignancies. Here, predictive preclinical model systems are important, and the current gold standard for preclinical evaluation of CAR T cells are mouse xenografts. However, mouse xenograft assays are expensive and slow. Therefore, an additional vertebrate in vivo assay would be beneficial to bridge the gap from in vitro to mouse xenografts. Here, we present a novel assay based on embryonic zebrafish xenografts to investigate CAR T cell-mediated killing of human cancer cells. Using a CD19-specific CAR and Nalm-6 leukemia cells, we show that live observation of killing of Nalm-6 cells by CAR T cells is possible in zebrafish embryos. Furthermore, we applied Fiji macros enabling automated quantification of Nalm-6 cells and CAR T cells over time. In conclusion, we provide a proof-of-principle study that embryonic zebrafish xenografts can be used to investigate CAR T cell-mediated killing of tumor cells. This assay is cost-effective, fast, and offers live imaging possibilities to directly investigate CAR T cell migration, engagement, and killing of effector cells.

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Davies, Jason M., Aaron E. Robinson, Cynthia Cowdrey, Praveen V. Mummaneni, Gregory S. Ducker, Kevan M. Shokat, Andrew Bollen, Byron Hann e Joanna J. Phillips. "Generation of a patient-derived chordoma xenograft and characterization of the phosphoproteome in a recurrent chordoma". Journal of Neurosurgery 120, n. 2 (febbraio 2014): 331–36. http://dx.doi.org/10.3171/2013.10.jns13598.

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Object The management of patients with locally recurrent or metastatic chordoma is a challenge. Preclinical disease models would greatly accelerate the development of novel therapeutic options for chordoma. The authors sought to establish and characterize a primary xenograft model for chordoma that faithfully recapitulates the molecular features of human chordoma. Methods Chordoma tissue from a recurrent clival tumor was obtained at the time of surgery and implanted subcutaneously into NOD-SCID interleukin-2 receptor gamma (IL-2Rγ) null (NSG) mouse hosts. Successful xenografts were established and passaged in the NSG mice. The recurrent chordoma and the derived human chordoma xenograft were compared by histology, immunohistochemistry, and phospho-specific immunohistochemistry. Based on these results, mice harboring subcutaneous chordoma xenografts were treated with the mTOR inhibitor MLN0128, and tumors were subjected to phosphoproteome profiling using Luminex technology and immunohistochemistry. Results SF8894 is a novel chordoma xenograft established from a recurrent clival chordoma that faithfully recapitulates the histopathological, immunohistological, and phosphoproteomic features of the human tumor. The PI3K/Akt/mTOR pathway was activated, as evidenced by diffuse immunopositivity for phospho-epitopes, in the recurrent chordoma and in the established xenograft. Treatment of mice harboring chordoma xenografts with MLN0128 resulted in decreased activity of the PI3K/Akt/mTOR signaling pathway as indicated by decreased phospho-mTOR levels (p = 0.019, n = 3 tumors per group). Conclusions The authors report the establishment of SF8894, a recurrent clival chordoma xenograft that mimics many of the features of the original tumor and that should be a useful preclinical model for recurrent chordoma.

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Honey, Christopher R., Modestus O. K. Obochi, Hao Shen, Philippe Margaron, Stephen Yip e Julia G. Levy. "Reduced xenograft rejection in rat striatum after pretransplant photodynamic therapy of murine neural xenografts". Journal of Neurosurgery 92, n. 1 (gennaio 2000): 127–31. http://dx.doi.org/10.3171/jns.2000.92.1.0127.

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Object. The goal of this study was to develop a method of reducing neural xenograft rejection by pretreating the graft with photodynamic therapy (PDT).Methods. Xenograft cell suspensions were prepared from fetal mouse mesencephalon, after which they were incubated for 30 minutes with various concentrations of a photosensitizer, verteporfin for injection, and light exposure. The xenograft cell suspensions were injected into the dopamine-depleted striata of 40 hemiparkinsonian rats assigned to different treatment groups. Four weeks after transplantation, xenograft function (determined by methamphetamine-induced rotation) and survival (determined by immunohistochemical staining for murine neurons) were compared. Group 1 animals (xenografts pretreated with 25 ng/ml verteporfin) and Group 3 animals (no verteporfin pretreatment, but daily administration of cyclosporin A) had significantly better xenograft survival and function compared with control animals (no pretreatment with verteporfin). Group 2 animals (xenografts pretreated with 250 ng/ml verteporfin) had no significant improvement.Conclusions. This work demonstrates improved neural xenograft survival and function when using pretransplant PDT of the graft in a rodent model. The potential benefits of this new therapy are its convenience (one pretransplant treatment) and its compatibility with host immunosuppression.

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Hayakawa, Jun, Matthew Hsieh, Naoya Uchida, Kareem Washington, Oswald Phang, David Eric Anderson e John Tisdale. "A Practical Erythroid Assay in Humanized Xenograft Mouse Model". Blood 112, n. 11 (16 novembre 2008): 2446. http://dx.doi.org/10.1182/blood.v112.11.2446.2446.

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Abstract Xenografting immunodeficient mice has been employed as a surrogate human hematopoietic stem cell (HSC) assay, however, erythroid output has not been reliably reported, limiting the usefulness of this model for erythroid disorders. We have previously demonstrated that busulfan preconditioning is sufficient to produce stable, high level engraftment of human cells in NOD/SCID/IL2Rγ null mice. Importantly, this high level engraftment can be achieved with low mortality, substantially reducing the number of animals required for experiments requiring long-term follow-up. Supplementation with human holo-transferrin (Tf) allows the detection human erythrocytes in this chimeric mouse assay at low levels, providing a potential model for the study of disorders affecting human red blood cells (2007 ASH meeting #3594). In the current work, we extend our observations and establish practical in vivo erythroid assay system of human HSCs in the humanized mouse model by the addition of an in vitro culture. Bone marrow (BM) from humanized mice containing 24.8±8.7% human cells (n=6) was first exposed to recombinant human (rHu) SCF+IL3 for 3 days in order to specifically enrich for human cells in the mixed chimera. After 3 days, human cells comprised 68.1±8.5% of the culture. The enriched cells were then cultured with rHu EPO+SCF+TGF-β for 7 additional days and then in rHu EPO+SCF for 7 days. After culture, and 98.9±1.47% of cells were of human origin. After centrifugation, the pellets were visibly red. Cells were assayed with both human CD71+ and GPA+ by flow cytometry: 64.0±7.44% were CD71+ and 69.2±7.02% were GPA+, and human α, β, and γ globin were confirmed by hemoglobin electrophoresis and mass spectrometry. In order to determine the utility of this approach, we tested 3 possible applications of this methodology: gene marking erythroid progeny, modeling of human hemoglobinopathies, and modeling of hemoglobin switching. We first transplanted human cord blood (CB) CD34+ cells after lentiviral transduction with a vector encoding GFP following busulfan conditioning. Three months post-transplant, bone marrow was harvested and placed in the in vitro culture. After in vivo culture, 98.9% of cells were of human origin and 60.7% were CD71+ and 72.3% were GPA+. The majority of CD71+ or GPA+ cells were GFP+ (82.3% and 87.7%, respectively). We subsequently transplanted human PB CD34+ cells derived from individuals with sickle cell trait (SCT) as we have previously demonstrated that these cells, unlike those from individuals with sickle cell disease, can be safely mobilized and processed. Further, the percentage of HbS expressed can be reliably measured. Three months post transplant, HbS was easily detectable by hemoglobin electrophoresis. Finally, we sought to address whether this model accurately reflects human erythropoiesis by examining hemoglobin switching after transplanting either CB expressing HbF or PB HSCs expressing HbA and monitoring the output of HbF and HbA over time. Early post-transplant, bone marrow derived from CB recipients expressed predominantly HbF after culture whereas that derived from PB HSC recipients expressed predominantly HbA. HbF declined during follow up and was replaced by HbA over 6 months of follow up from CB recipients, whereas HbA expression remained stable from PB HSC recipients. The time course of hemoglobin switching is similar to human ontogeny. In summary, our practical approach to model human erythropoiesis in the xenograft mouse should prove useful in the both the study of human erythroid disorders as well as therapeutic interventions.

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Frees, S., I. Moskalev, P. Raven, N. D’Costa, Z. Tan, W. Struss, C. Chavez-Munoz e A. So. "Orthotopic sunitinib resistant renal cell carcinoma xenograft mouse model". European Urology Supplements 16, n. 3 (marzo 2017): e1477. http://dx.doi.org/10.1016/s1569-9056(17)30898-9.

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Thaler, Sonja, Angelika M. Burger, Thomas Schulz, Boris Brill, Alexandra Bittner, Patrick A. Oberholzer, Reinhard Dummer e Barbara S. Schnierle. "Establishment of a mouse xenograft model for mycosis fungoides". Experimental Dermatology 13, n. 7 (luglio 2004): 406–12. http://dx.doi.org/10.1111/j.0906-6705.2004.00201.x.

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Bruckner, Ramona, Noga Marsiano, Einat Nissim-Eliraz, Eilam Nir, Silvia Lang, Marianne Spalinger, Gerhard Rogler, Simcha Yagel, Michael M. Scharl e Nahum Y. Shpigel. "New Human Gut Xenograft Mouse Model for Intestinal Fistulas". Gastroenterology 152, n. 5 (aprile 2017): S784. http://dx.doi.org/10.1016/s0016-5085(17)32718-x.

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Zhao, Yunqi, Ran Chen, Yun Wang e Yixin Yang. "α-Pinene Inhibits Human Prostate Cancer Growth in a Mouse Xenograft Model". Chemotherapy 63, n. 1 (26 ottobre 2017): 1–7. http://dx.doi.org/10.1159/000479863.

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Background: α-Pinene is one of the most widely found terpenoids in nature. Substantial evidence shows that α-pinene has cancer prevention properties. In this study, the PC-3 cell line was used to establish subcutaneous xenograft tumors in nude mice. Methods: Cytotoxicity was measured with the MTT assay, and apoptosis and cell cycle analyses were conducted using flow cytometry in vitro. The PC-3 cell line was used to establish subcutaneous xenograft tumors in nude mice. Results: We found that treatment with α-pinene significantly inhibited human prostate cancer cell growth and induced apoptosis and cell cycle arrest in the cell line-based model. Furthermore, tumor progression was inhibited more in mice treated with α-pinene than in control mice. We detected less Ki67 and proliferation cell nuclear antigen in paraffin sections from xenograft tumor specimens taken from α-pinene-treated mice than in those from the control group. Meanwhile, α-pinene treatment induced apoptosis in xenograft tumors as determined by the TUNEL assay. Conclusions: These data strongly suggest that α-pinene inhibits prostate cancer growth in a xenograft model and may be an effective therapeutic agent for prostate cancer treatment.

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Richartz, Nina, Eva Duthil, Anthony Ford, Elin Hallan Naderi, Sampada Bhagwat, Karin M. Gilljam, Marta Maria Burman, Ellen Ruud, Heidi Kiil Blomhoff e Seham Skah. "Targeting cyclooxygenase by indomethacin decelerates progression of acute lymphoblastic leukemia in a xenograft model". Blood Advances 3, n. 21 (28 ottobre 2019): 3181–90. http://dx.doi.org/10.1182/bloodadvances.2019000473.

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Benda, Birgitta, Hans-Gustaf Ljunggren, Robert Peach, Jan-Olov Sandberg e Olle Korsgren. "Co-Stimulatory Molecules in Islet Xenotransplantation: CTLA4Ig Treatment in CD40 Ligand-Deficient Mice". Cell Transplantation 11, n. 7 (ottobre 2002): 715–20. http://dx.doi.org/10.3727/000000002783985440.

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Previous work has demonstrated that short-term systemic administration of cytotoxic T lymphocyte antigen-4 (CTLA-4) Ig blocks human pancreatic islet xenograft rejection in mice and induces long-term, donor-specific tolerance, whereas studies on pig pancreatic islet rejection in mice have failed to demonstrate a role for CTLA4Ig in preventing rejection. Treatment with anti-CD40 ligand (L) monoclonal antibodies alone is somewhat effective in prolonging the survival of islet xenografts, but ineffective when applied to skin xenografts. However, simultaneous blockade of the CD28 and CD40 co-stimulatory pathways prolongs the survival of pig skin on recipient mice. To evaluate the role of CD28 and CD40 co-stimulatory pathways in pig islet-like cell cluster (ICC) xenograft rejection in mice, CD40L-deficient mice transplanted with fetal porcine ICCs were given posttransplant treatment with human (h) CTLA4Ig or a human IgG1 chimeric mAb (hL6). Xenografts were evaluated 6 or 12 days after transplantation. Fetal porcine ICC xenografts were protected from rejection in hCTLA4Ig-treated CD40L-deficient mice, whereas xenograft rejection persisted in untreated CD40L-deficient mice. Simultaneous blockade of the CD28 and CD40 co-stimulatory pathways is mandatory to inhibit ICC xenograft rejection in the pig-to-mouse model, because the CD28 and CD40 co-stimulatory pathways seem capable of efficiently substituting for one another.

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Del Buono, R., K. A. Fleming, A. L. Morey, P. A. Hall e N. A. Wright. "A nude mouse xenograft model of fetal intestine development and differentiation". Development 114, n. 1 (1 gennaio 1992): 67–73. http://dx.doi.org/10.1242/dev.114.1.67.

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This report describes a novel in vivo model of intestinal differentiation. Fourteen day, undifferentiated fetal rat small intestine, stripped of the major part of its mesenchyme, suspended in a type I collagen gel and then xenografted into a nude mouse, undergoes small intestinal morphogenesis and cytodifferentiation. All four major epithelial lineages, namely Paneth, goblet, columnar and endocrine are present. Double-label nonisotopic in situ hybridization, employing biotinylated and digoxigenin-labelled whole rat DNA and whole mouse DNA probes, was performed to distinguish donor cells from host cell types. The outer longitudinal smooth muscle layer, and the major part of the lamina propria, including pericryptal fibroblasts, are of host mouse origin; the inner circular smooth muscle layer is of donor rat origin. Cells of the muscularis propria and lamina propria acquired smooth muscle alpha-actin, presumably under the influence of the donor endoderm. Furthermore, this xenograft develops a host vascular network, and cells with the morphological appearance of lymphocytes are present within the intestinal epithelium. The production of chemotactic factors by the endoderm is postulated because grafting of collagen gel alone results in a minimal invasion by stromal cells which do not express smooth muscle alpha-actin.

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Liaw, Tracy T. Y. E., Patricia P. A. Burke, X. Chen, Theresa T. M. LaVallee, Richard Lock e Maria Kavallaris. "ENMD-1198 in Combination with Vincristine Shows Synergistic Activity in Leukemia Cells and Prolonged Mouse Survival in Human Leukemia Xenografts." Blood 110, n. 11 (16 novembre 2007): 859. http://dx.doi.org/10.1182/blood.v110.11.859.859.

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Abstract ENMD-1198 (2-methoxyestra-1, 3, 5, (10), 16-tetraene-3-carboxamide), an analogue of 2 methoxyestradiol (2ME2 or Panzem®), is a microtubule destabilizing agent that binds to the colchicine-binding site of β-tubulin. ENMD-1198 has shown anti-angiogenic and anti-proliferative activities in several tumour models and is currently being evaluated in a Phase 1 clinical trial. To date however, the efficacy and mechanisms of action of ENMD-1198 in leukemia are not well-studied or fully understood. Hence, in order to assess the efficacy of ENMD-1198 in leukemia, a clinically relevant model of primary human ALL cells xenografted into immuno-deficient (NOD/SCID) mice was used (1). Three human ALL xenografts (ALL3, ALL7 and ALL19) that exhibit intrinsic differences in response to vincristine (VCR) (1) were treated with 100 mg/kg ENMD-1198 by gavage (daily for 28 days), commencing treatment when engraftment rates reached 1% human CD45+ in mouse peripheral blood. Treatment with ENMD-1198 significantly increased the mouse survival rates compared to vehicle control in all three xenografts (Leukemia Growth Delay (LGD) for ALL3 = 17.3 days, p < 0.005; ALL7 = 21.5 days, p < 0.005; ALL19 = 16.7 days, p < 0.005). Interestingly, ALL7, the least sensitive xenograft to vincristine, showed the best response to ENMD-1198 with a growth delay factor of 21 days. To determine whether the combination of ENMD-1198 and VCR has therapeutic advantages in leukemia, anti-proliferative studies of the drug combination in CCRF-CEM leukemia cells were carried out. A synergistic effect was observed when ENMD-1198 and VCR were combined. The effect of this drug combination was further examined in the ALL human xenograft mouse model. Mice inoculated with ALL7 xenograft were treated with 50 mg/kg ENMD-1198 (daily for 28 days) and 0.5 mg/kg VCR (weekly for 4 weeks) by intraperitoneal injection. The drug combination significantly prolonged mouse survival rates compared to single ENMD-1198 and VCR treatments (LGD 35.19days; p < 0.005). Functional analysis of the drug combination treatment in CCRF-CEM cells in vitro showed that the cells arrested at G2/M followed by sub-G1 (apoptosis) phase, with decreased HIF-1α and JAK-2 proteins. Apoptosis in vitro was associated with increased DR5, active caspase 3 and cleaved PARP proteins in CCRF-CEM cells treated with the combination. In summary, ENMD-1198 alone, and in combination with VCR, has shown promising results in the treatment of preclinical models of leukemia.

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Shen, Yen Ting, Rashi Asthana, Casper Peeters, Christine Allen, Carlo DeAngelis e Micheline Piquette-Miller. "Potential Limitations of Bioluminescent Xenograft Mouse Models: A Systematic Review". Journal of Pharmacy & Pharmaceutical Sciences 23 (13 maggio 2020): 177–99. http://dx.doi.org/10.18433/jpps30870.

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Purpose: Bioluminescent imaging (BLI) is a versatile technique that offers non-invasive and real-time monitoring of tumor development in preclinical cancer research. However, the technique may be limited by several factors that can lead to misinterpretation of the data. This review aimed to investigate the validity of current BLI tumor models and provide recommendations for future model development. Methods: Two major databases, MedLine and EMBASE, were searched from inception to July 2018 inclusively. Studies utilizing mouse xenograft models with demonstration of linear correlations between bioluminescent signal and tumor burden were included. Coefficients of correlation and determination were extracted along with data relating to animal model parameters. Results: 116 studies were included for analysis. It was found that the majority of models demonstrate good correlation regardless of the model type. Selection of a single cell clone with highest luciferase expression resulted in a significantly better correlation. Lastly, appropriate tumor measurement techniques should be utilized when validating the BLI model. Conclusions: In general, BLI remains a valid tool for pre-clinical assessment of tumor burden. While no single factor may be identified as a general limitation, data should be interpreted with caution.

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Morin, Aurélie, Carmen Ruggiero, Estelle Robidel, Mabrouka Doghman-Bouguerra, Atze T. Das, Rémy Castellano, Emmanuelle Josselin, Judith Favier e Enzo Lalli. "Establishment of a mouse xenograft model of metastatic adrenocortical carcinoma". Oncotarget 8, n. 31 (7 aprile 2017): 51050–57. http://dx.doi.org/10.18632/oncotarget.16909.

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Savidge, T. C., A. N. Shmakov, A. L. Morey, D. Ferquson e A. D. Phillips. "25 HUMAN INTESTINAL PROLIFERATION IN A SCID MOUSE XENOGRAFT MODEL". Journal of Pediatric Gastroenterology and Nutrition 19, n. 3 (ottobre 1994): 335. http://dx.doi.org/10.1097/00005176-199410000-00037.

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Valbuena, Gustavo, Hailey Halliday, Viktoriya Borisevich, Yenny Goez e Barry Rockx. "A Human Lung Xenograft Mouse Model of Nipah Virus Infection". PLoS Pathogens 10, n. 4 (3 aprile 2014): e1004063. http://dx.doi.org/10.1371/journal.ppat.1004063.

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Bruckner, R. S., N. Marsiano, E. Nissim-Eliraz, E. Nir, S. Lang, M. Spalinger, G. Rogler, S. Yagel, M. Scharl e N. Y. Shpigel. "DOP059 New human gut xenograft mouse model for intestinal fistulas". Journal of Crohn's and Colitis 11, suppl_1 (26 gennaio 2017): S61. http://dx.doi.org/10.1093/ecco-jcc/jjx002.096.

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Ragel, Brian T., Randy L. Jensen, David L. Gillespie, Stephen M. Prescott e William T. Couldwell. "Celecoxib inhibits meningioma tumor growth in a mouse xenograft model". Cancer 109, n. 3 (2007): 588–97. http://dx.doi.org/10.1002/cncr.22441.

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Winter, Gordon, Andrea B. F. Koch, Jessica Löffler, Mika Lindén, Christoph Solbach, Alireza Abaei, Hao Li, Gerhard Glatting, Ambros J. Beer e Volker Rasche. "Multi-Modal PET and MR Imaging in the Hen’s Egg Test-Chorioallantoic Membrane (HET-CAM) Model for Initial In Vivo Testing of Target-Specific Radioligands". Cancers 12, n. 5 (15 maggio 2020): 1248. http://dx.doi.org/10.3390/cancers12051248.

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The validation of novel target-specific radioligands requires animal experiments mostly using mice with xenografts. A pre-selection based on a simpler in vivo model would allow to reduce the number of animal experiments, in accordance with the 3Rs principles (reduction, replacement, refinement). In this respect, the chick embryo or hen’s egg test–chorioallantoic membrane (HET-CAM) model is of special interest, as it is not considered an animal until day 17. Thus, we evaluated the feasibility of quantitative analysis of target-specific radiotracer accumulation in xenografts using the HET-CAM model and combined positron emission tomography (PET) and magnetic resonance imaging (MRI). For proof-of-principle we used established prostate-specific membrane antigen (PSMA)-positive and PSMA-negative prostate cancer xenografts and the clinically widely used PSMA-specific PET-tracer [68Ga]Ga-PSMA-11. Tracer accumulation was quantified by PET and tumor volumes measured with MRI (n = 42). Moreover, gamma-counter analysis of radiotracer accumulation was done ex-vivo. A three- to five-fold higher ligand accumulation in the PSMA-positive tumors compared to the PSMA-negative tumors was demonstrated. This proof-of-principle study shows the general feasibility of the HET-CAM xenograft model for target-specific imaging with PET and MRI. The ultimate value for characterization of novel target-specific radioligands now has to be validated in comparison to mouse xenograft experiments.

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Tejeda, M., D. Gaál, I. Szűcs e A. Telekes. "Avemar inhibits the growth of mouse and human xenograft mammary carcinomas comparable to endocrine treatments". Journal of Clinical Oncology 25, n. 18_suppl (20 giugno 2007): 21132. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.21132.

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21132 Background: An in vitro study demonstrated that Avemar increased the effect of Tamoxifen on MCF7 (ER+) mammary carcinoma cells. Methods: MXT (ER+) mouse mammary tumor tissue was transplanted s.c. into BDF1 mice. The tumor bearing animals were treated p.o. with Avemar. Then the most effective Avemar dose (3.0 g/kg), Tamoxifen (0.5 mg/kg s.c.), Examestane (10 mg/kg i.p.) and Anastrasol (5 mg/kg i.p.) monotherapies and their combinations with Avemar was compared. All treatments were given once daily, for 10 days, starting 7 days after the tumor transplantation. The same experimental schedule was repeated using T47/D (ER+) human breast carcinoma cell lines transplanted into C.B-17/Icr-scid/scid mouse. Finally, the growth of T47/D and MDA-MB-231 (ER-) xenografts treated by Avemar was compared. Tumor volume was measured up to 25 days after transplantation in MXT and 55 days in xenograft. Results: In MXT model all monotherapies and combinations led to retardation of tumor growth. Combination of Avemar with any of the endocrine treatment enhanced the efficacy compared to endocrine monotherapy. Out of the four monotherapies the best result was achieved by Avemar (50% inhibition). The combination of Avemar with Examestane increased the tumor growth inhibition to 60.4% compared to control. The other treatments did not exceed the effect of Avemar monotherapy. In xenograft model Avemar produced 50% tumor growth inhibition compared to control and was more effective than the other treatments Examestane (26%), Anastrasol (25%) or Tamoxifen (42%). Combined treatment with Avemar always improved efficacy within the range of 3–10%. Avemar showed similar efficacy when T47/D (49%) and MDA-MB-231 (52%) xenografts were compared. Conclusions: The tumor growth inhibitory effect of Avemar on ER positive MXT mouse breast carcinoma as well as in T47/D xenograft models are comparable (equal or better) to standard endocrine treatments. Avemar certainly did not reduce the effect of endocrine treatments. The antitumor activity of Avemar did not depend on the estrogen receptor status. No significant financial relationships to disclose.

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Yalcin, M., E. Dyskin, L. Lansing, D. J. Bharali, S. S. Mousa, A. Bridoux, A. H. Hercbergs et al. "Tetraiodothyroacetic Acid (Tetrac) and Nanoparticulate Tetrac Arrest Growth of Medullary Carcinoma of the Thyroid". Journal of Clinical Endocrinology & Metabolism 95, n. 4 (1 aprile 2010): 1972–80. http://dx.doi.org/10.1210/jc.2009-1926.

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Abstract Context: Tetraiodothyroacetic acid (tetrac) blocks angiogenic and tumor cell proliferation actions of thyroid hormone initiated at the cell surface hormone receptor on integrin αvβ3. Tetrac also inhibits angiogenesis initiated by vascular endothelial growth factor and basic fibroblast growth factor. Objective: We tested antiangiogenic and antiproliferative efficacy of tetrac and tetrac nanoparticles (tetrac NP) against human medullary thyroid carcinoma (h-MTC) implants in the chick chorioallantoic membrane (CAM) and h-MTC xenografts in the nude mouse. Design: h-MTC cells were implanted in the CAM model (n = 8 per group); effects of tetrac and tetrac NP at 1 μg/CAM were determined on tumor angiogenesis and tumor growth after 8 d. h-MTC cells were also implanted sc in nude mice (n = 6 animals per group), and actions on established tumor growth of unmodified tetrac and tetrac NP ip were determined. Results: In the CAM, tetrac and tetrac NP inhibited tumor growth and tumor-associated angiogenesis. In the nude mouse xenograft model, established 450–500 mm3 h-MTC tumors were reduced in size over 21 d by both tetrac formulations to less than the initial cell mass (100 mm3). Tumor tissue hemoglobin content of xenografts decreased by 66% over the course of administration of each drug. RNA microarray and quantitative real-time PCR of tumor cell mRNAs revealed that both tetrac formulations significantly induced antiangiogenic thrombospondin 1 and apoptosis activator gene expression. Conclusions: Acting via a cell surface receptor, tetrac and tetrac NP inhibit growth of h-MTC cells and associated angiogenesis in CAM and mouse xenograft models.

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Krasny, Lukas, Philip Bland, Jessica Burns, Nadia Carvalho Lima, Peter T. Harrison, Laura Pacini, Mark L. Elms et al. "A mouse SWATH-mass spectrometry reference spectral library enables deconvolution of species-specific proteomic alterations in human tumour xenografts". Disease Models & Mechanisms 13, n. 7 (3 giugno 2020): dmm044586. http://dx.doi.org/10.1242/dmm.044586.

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ABSTRACTSWATH-mass spectrometry (MS) enables accurate and reproducible proteomic profiling in multiple model organisms including the mouse. Here, we present a comprehensive mouse reference spectral library (MouseRefSWATH) that permits quantification of up to 10,597 proteins (62.2% of the mouse proteome) by SWATH-MS. We exploit MouseRefSWATH to develop an analytical pipeline for species-specific deconvolution of proteomic alterations in human tumour xenografts (XenoSWATH). This method overcomes the challenge of high sequence similarity between mouse and human proteins, facilitating the study of host microenvironment-tumour interactions from ‘bulk tumour’ measurements. We apply the XenoSWATH pipeline to characterize an intraductal xenograft model of breast ductal carcinoma in situ and uncover complex regulation consistent with stromal reprogramming, where the modulation of cell migration pathways is not restricted to tumour cells but also operates in the mouse stroma upon progression to invasive disease. MouseRefSWATH and XenoSWATH open new opportunities for in-depth and reproducible proteomic assessment to address wide-ranging biological questions involving this important model organism.

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Gamble, John T., Daniel J. Elson, Juliet A. Greenwood, Robyn L. Tanguay e Siva K. Kolluri. "The Zebrafish Xenograft Models for Investigating Cancer and Cancer Therapeutics". Biology 10, n. 4 (24 marzo 2021): 252. http://dx.doi.org/10.3390/biology10040252.

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In order to develop new cancer therapeutics, rapid, reliable, and relevant biological models are required to screen and validate drug candidates for both efficacy and safety. In recent years, the zebrafish (Danio rerio) has emerged as an excellent model organism suited for these goals. Larval fish or immunocompromised adult fish are used to engraft human cancer cells and serve as a platform for screening potential drug candidates. With zebrafish sharing ~80% of disease-related orthologous genes with humans, they provide a low cost, high-throughput alternative to mouse xenografts that is relevant to human biology. In this review, we provide background on the methods and utility of zebrafish xenograft models in cancer research.

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Chen, Hongkui, Min Zheng, Wenhui Zhang, Yuan Long, Yu Xu e Man Yuan. "Research Status of Mouse Models for Non-Small-Cell Lung Cancer (NSCLC) and Antitumor Therapy of Traditional Chinese Medicine (TCM) in Mouse Models". Evidence-Based Complementary and Alternative Medicine 2022 (21 settembre 2022): 1–13. http://dx.doi.org/10.1155/2022/6404853.

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Non-small-cell lung cancer (NSCLC) is known as one of the most lethal cancers, causing more than 1 million deaths annually worldwide. Therefore, the development of novel therapeutic drugs for NSCLC has become an urgent need. Herein, various mouse models provide great convenience not only for researchers but also for the development of antitumor drug. Meanwhile, TCM, as a valuable and largely untapped resource pool for modern medicine, provides research resources for the treatment of various diseases. Until now, cell-derived xenograft (CDX) model, patient-derived xenograft (PDX) model, syngeneic model, orthotopic model, humanized mouse model (HIS), and genetically engineered mouse models (GEMMs) have been reported in TCM evaluation. This review shows the role and current status of kinds of mouse models in antitumor research and summarizes the application progress of TCM including extracts, formulas, and isolated single molecules for NSCLC therapy in various mouse models; more importantly, it provides a theoretical exploration of what kind of mouse models is ideal for TCM efficacy evaluation in future. However, there are still huge challenges and limitations in the development of mouse models specifically for the TCM research, and none of the available models are perfectly matching the characteristics of TCM, which suppress the tumor growth through various mechanisms, especially by regulating immune function. Nevertheless, with fully functional immune system existing in syngeneic model and humanized mouse model (HIS), it is still suggested that these two models are more suitable for development of TCM especially for TCM extracts or formulas. Moreover, continued efforts are needed to generate more reliable mouse models to test TCM formulas in future research.

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Terziyska, Nadia, Katarina Farkasova, Ernst Wagner, Manfred Ogris e Irmela Jeremias. "In Vivo Imaging In the Individualized Mouse Model of Acute Lymphoblastic Leukemia Enables Highly Sensitive and Continuous Follow up of Patient-Derived Xenografts". Blood 116, n. 21 (19 novembre 2010): 3259. http://dx.doi.org/10.1182/blood.v116.21.3259.3259.

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Abstract Abstract 3259 In the individualized xenograft mouse model, acute leukemia cells from patients are transplanted into severely immuno-deficient mice to serve as a preclinical animal model. The use of this mouse model for pre-clinical therapy trials is hampered by the low sensitivity of existing readouts disabling the reliable follow up of single animals. Both secretion of leukemic cells into the blood flow as well as clinical signs, if at all, occur at late states of the disease; readouts in further organs by, e.g., immunohistochemistry or flow cytometry analysis, require organ extraction and can thus be performed only once per mouse. To overcome this obstacle, we established in vivo imaging in the xenograft mouse model of acute lymphoblastic leukemia (ALL). We engrafted pediatric acute leukemia cells from patients at diagnostic bone marrow aspiration of either diagnosis or relapse. In agreement with published data, mice developed leukemia within weeks to months. Engraftment was followed by easy passaging of cells into further generations of mice. We established lentiviral transduction of xenograft cells which enabled expression of transgenes in these cells. Using lentiviral transduction, we stained patient-derived xenograft ALL-cells using luciferase as a reporter. Transgenic xenograft leukemia cells were visualized once per week by bioluminescence in vivo imaging using a charge-coupled device camera. Our first data show that in vivo imaging enabled the reliable and continuous follow up of single animals over time. The sensitivity of in vivo imaging in measuring leukemic engraftment was significantly higher compared to current readouts like examination of blood cells. In vivo imaging data support that the leukemic pattern of metastases of patient-derived xenograft ALL-cells in mice highly resembles the distribution of the disease in men. Upon intravenous injection, cells first home to the liver, where they stay alive only for a few weeks. Long-term engraftment is seen in the bone marrow of many different bones and constantly increases over time. Engraftment in spleen indicates rather late stages of disease. This kinetic of engraftment remained constant between several transgenic xenograft samples and between different mice engrafted with the same sample. Taken together, we have established molecular modulation of xenograft cells which enables expression of luciferase and in vivo bioluminescence imaging as a new sensitive and continuous in vivo readout in mice. In vivo imaging will allow realizing precise preclinical trials in the individualized mouse model in the future. Disclosures: No relevant conflicts of interest to declare.

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Rhyasen, Garrett, Mark Wunderlich, James C. Mulloy e Daniel T. Starczynowski. "Development and Characterization of a Novel Human Xenograft Model Using an MDS Patient-Derived Cell Line". Blood 120, n. 21 (16 novembre 2012): 3814. http://dx.doi.org/10.1182/blood.v120.21.3814.3814.

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Abstract Abstract 3814 Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders, defined by ineffective hematopoiesis, blood cytopenias, myeloid dysplasia, and an increased risk of acute myeloid leukemia (AML). Immunodeficient mice engineered to support human tumor xenografts represent a pivotal development in the study of human cancers. The xenograft model has been an attractive approach to interrogate human AML; in contrast, MDS patient samples exhibit negligible or poor engraftment, with no evidence of disease in immunocompromised recipient mice. To circumvent this limitation we developed a novel xenograft mouse model using an MDS cell line, MDSL. The MDSL cell line was derived from the non-leukemic phase of an MDS patient with refractory anemia-ringer sideroblasts, and has maintained growth-factor dependence and sensitivity to Lenalidomide. Two immunocomprismised mouse stains were used for xenotransplantation of MDSL cell: NOD/LtSz-scid IL2RG (NSG) and NOD/LtSz-scid IL2RG-SGM3 (NSGS). NSGS mice are identical to NSG except that they have been engineered to express three human cytokines, SCF, GM-CSF and IL-3, to improve engraftment of human hematopoietic cells. Following transplantation of MDSL cells by either intrafemoral or intravenous injection, NSG and NSGS animals exhibited human cell grafts in the bone marrow, peripheral blood, and spleen. Subsequently, mice developed a fatal disease exhibiting features of human MDS, including anemia and thrombocytopenia, which coincides with clonal expansion and increased human cell graft in all hematopoietic organs. The median survival for NSGS and NSG mice was 21 and 55 days post-injection, respectively. The shortened latency in NSGS mice suggests that the expression of human cytokines accelerates the growth and enhances survival of the MDSL cells in vivo. MDSL cells isolated from the bone marrow of primary recipient mice were capable of initiating an MDS-like disease in secondary recipients. Given that few preclinical options for MDS are available, we also evaluated whether this model is suitable for therapeutic studies. Since MDSL cells are sensitive to Lenalidomide and IRAK1 Inhibitor (Rhyasen et al, ASH 2011), we evaluated the effects of these drugs in the xenograft model. After xenotransplantation of MDSL cells, NSGS mice were administered either Lenalidomide or IRAK1 Inhibitor. Our preliminary findings indicate that mice xenografted with MDSL cells are amenable to drug delivery and show a response to treatment. In summary this work describes a novel xenograft model of human MDS, the first to develop clinical features resembling human disease. In addition, we predict that this model will also be useful for preclinical studies to examine novel and existing MDS therapies. Disclosures: No relevant conflicts of interest to declare.

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Goyama, Susumu, Mark Wunderlich e James C. Mulloy. "Xenograft models for normal and malignant stem cells". Blood 125, n. 17 (23 aprile 2015): 2630–40. http://dx.doi.org/10.1182/blood-2014-11-570218.

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Abstract The model systems available for studying human hematopoiesis, malignant hematopoiesis, and hematopoietic stem cell (HSC) function in vivo have improved dramatically over the last decade, primarily due to improvements in xenograft mouse strains. Several recent reviews have focused on the historic development of immunodeficient mice over the last 2 decades, as well as their use in understanding human HSC and leukemia stem cell (LSC) biology and function in the context of a humanized mouse. However, in the intervening time since these reviews, a number of new mouse models, technical approaches, and scientific advances have been made. In this review, we update the reader on the newest and best models and approaches available for studying human malignant and normal HSCs in immunodeficient mice, including newly developed mice for use in chemotherapy testing and improved techniques for humanizing mice without laborious purification of HSC. We also review some relevant scientific findings from xenograft studies and highlight the continued limitations that confront researchers working with human HSC and LSC in vivo.

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LIN, KEVIN Y., ALEXANDER F. BAGLEY, ALEXIA Y. ZHANG, DANIEL L. KARL, SAM S. YOON e SANGEETA N. BHATIA. "GOLD NANOROD PHOTOTHERMAL THERAPY IN A GENETICALLY ENGINEERED MOUSE MODEL OF SOFT TISSUE SARCOMA". Nano LIFE 01, n. 03n04 (settembre 2010): 277–87. http://dx.doi.org/10.1142/s1793984410000262.

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Plasmonic nanomaterials are poised to impact the clinical management of cancer through their ability to convert externally applied energy into localized heat at sites of diseased tissue. However, characterization of plasmonic nanomaterials as cancer therapeutics has been limited to xenograft models, creating a need to extend these findings to more clinically relevant models of cancer. Here, we evaluate the method of photothermal ablation therapy in a genetically engineered mouse model (GEMM) of sarcoma, which more accurately recapitulates the human disease in terms of structure and biology than subcutaneous xenograft models. Using polyethylene glycol (PEG)-coated gold nanorods (PEG-NRs), we quantitatively evaluate the ability of nanoparticles to penetrate and accumulate in sarcomas through passive targeting mechanisms. We demonstrate that PEG-NR–mediated photothermal heating results in significant delays in tumor growth with no progression in some instances. Lastly, by evaluating our photothermal ablation protocol in a GEMM, we observe off-target heating effects that are not detectable in xenograft models and which may be of future clinical interest.

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Schmitt, Nanni, Eva Altrock, Johann-Christoph Jann, Johanna Flach, Carla Sens-Albert, Justine Danner, Stefanie Uhlig et al. "Placebo Controlled Functional Analysis of Eltrombopag in a Preclinical Xenograft Model of Myelodysplastic Syndromes (MDS)". Blood 132, Supplement 1 (29 novembre 2018): 942. http://dx.doi.org/10.1182/blood-2018-99-116341.

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Abstract Introduction: Thrombocytopenia is a common complication among MDS patients. Thus, many patients are dependent on platelet (PLT) transfusions, which give short-term therapeutic relief but are also associated with considerable clinical risks. In this context, thrombopoietin receptor agonists (TRAs) are under investigation as alternative treatment option, albeit with the concern that these substances may promote adverse events in MDS. However, beside potential positive effects on thrombopoiesis in MDS patients the TRA Eltrombopag (EPAG) has also been shown to exert positive disease modifying effects in vitro (Roth et al., Blood 2012). Using a MDS xenograft model, we here investigate the efficacy of EPAG and its influence on clonal composition on primary patient derived MDS xenografts and present data from an ongoing study. Methods: Currently, samples from n=18 MDS patients (MDS del(5q)=2, MDS-MLD=6, MDS-RS-MLD=1 MDS-EB-1=2, MDS-EB-2=7) have been xenografted into NSG mice by intrafemoral co-injection of CD34+ hematopoietic stem cells and mesenchymal stromal cells using a modified protocol according to Medyouf et al., Cell Stem Cell 2014. Long term engraftment is assessed 12 weeks post-transplant by intrafemoral bone marrow (BM) biopsy and mice with positive human engraftment are subsequently treated with either EPAG (50mg/kg) or vehicle control for 18 weeks. During that time, the mice are bled every two weeks and BM aspiration is performed every six weeks. Human hematopoietic cells are FACS sorted. In peripheral blood, human PLTs are specifically and absolutely counted with a FACS assay based on hCD41+ cells and beads. To track clonal composition of MDS samples upon xenografting and EPAG treatment in comparison to placebo control, the original patient sample and the final MDS xenograft sample are being whole exome sequenced (WES). Interspersed time points are analyzed with a patient individual amplicon based deep sequencing approach (Mossner et al., Blood 2016) to calculate dynamics of variant allele frequencies (VAF) in dependency of treatment. Results: To date, n=12 patient samples have been analyzed for human engraftment after 12 weeks post-transplant. Of these, n=7 (58%) have shown positive human engraftment and are being treated with EPAG versus placebo. To this end, one case has been completely followed up, including final molecular analysis. This MDS high risk case (MDS-EB-2) with a clinical PLT count of 29x109 PLT/L was transplanted into n=3 NSG mice. While two mice treated with EPAG survived the complete duration of the experiment, the placebo mouse died prematurely due to severe weight loss after 6 weeks of treatment. Further, EPAG treatment led to an initial rise of human PLT levels, while the placebo treated mouse presented a continuous decline of human PLTs, showing the efficacy of EPAG on human xenografts in the model. This observation has been confirmed in another case currently still under treatment. Molecular tracking by WES confirmed MDS patient specific molecular lesions in the MDS xenograft such as monosomy 7 and the disease related mutations CBL, DNMT3A and EZH2 with VAFs of 83%/43%/23% respectively. The monosomy 7 was detectable in all mice. CBL and DNMT3A exhibited similar VAFs in mouse EPAG1 (VAF=100%/54%), EPAG2 (VAF=100%/34%) and placebo (VAF=100%/50%). The EZH2 mutation was only detected in mouse EPAG2 (VAF=11%). Interestingly, the placebo mouse acquired a de novo mutation of U2AF1 (VAF=10%), which was not detectable in the initial patient sample or the EPAG treated mice. This spliceosomal mutation is associated with a higher risk of transformation to AML and shorter survival (Graubert et al., Nat Genet 2012; Makishima et al., Blood 2012). Conclusions: Our data show first proof of principle results that new treatment options can be tested successfully in a preclinical murine xenograft model of primary MDS patient samples in a placebo controlled experimental setting. This approach allows the performance of patient individual substance testing that can segregate substance specific effects from natural disease progression in the same patient. Clinical parameters such as human PLT production and molecular clonal composition can be measured with a high confidence in vivo. Our current data show preliminary support for the hypothesis that EPAG may be efficacious in increasing PLT production in MDS patients without adversely influencing the underlying clonal composition. Disclosures Nowak: Novartis: Research Funding.

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Logié, Armelle, Philippe Boudou, Liliane Boccon-Gibod, Eric Baudin, Gilles Vassal, Martin Schlumberger, Yves Le Bouc e Christine Gicquel. "Establishment and Characterization of a Human Adrenocortical Carcinoma Xenograft Model*". Endocrinology 141, n. 9 (1 settembre 2000): 3165–71. http://dx.doi.org/10.1210/endo.141.9.7668.

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Abstract Adrenocortical carcinomas are rare malignant tumors. They have a poor prognosis, as they are often diagnosed late and are usually resistant to chemotherapy. The lack of a suitable animal model for these tumors has been a major obstacle to the evaluation of new therapeutic agents. The aim of this study was to establish and characterize xenografts of the human adrenocortical carcinoma NCI H295R cell line as a model of adrenocortical carcinoma for future therapeutic trials. This cell line was sc injected (6 × 106 cells) into nude mice (n = 20). Solid tumors were locally measurable after 45 days at 90% of the inoculation sites. The xenografts were similar histologically to the original adrenocortical carcinoma from which the cell line was derived. The xenografts precisely reproduced the dysregulation of the insulin-like growth factor (IGF) system[ overexpression of the IGF-II and IGF-binding protein-2 (IGFBP-2) genes] typical of adrenocortical carcinoma. Similarly to adrenocortical carcinomas, human IGFBP-2 (but not IGF-II) was secreted in mouse plasma. We analyzed steroid production (cortisol, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone,Δ 4-androstenedione, 11-deoxycortisol, corticosterone, and testosterone). Xenografts produced all three class of steroids, with the preferential production of androgens of the Δ4 pathway. The H295R xenograft model is a good model of human adrenocortical carcinoma, as it mimics dysregulation of the IGF system usually found in these tumors. It also produces IGFBP-2 and steroids that can be used as tumor markers. This model may therefore be useful for evaluating therapeutic agents.

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Bruckner, R. S., N. Marsiano, E. Nissim-Eliraz, E. Nir, M. Leutenegger, C. Gottier, S. Lang et al. "P034 Validation of a novel xenograft mouse model for intestinal fistulas". Journal of Crohn's and Colitis 12, supplement_1 (16 gennaio 2018): S109—S110. http://dx.doi.org/10.1093/ecco-jcc/jjx180.161.

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Bruckner, Ramona, Noga Marsiano, Einat Nissim-Eliraz, Eilam Nir, Martin Leutenegger, Claudia Gottier, Silvia Lang et al. "1085 - Validation of a Novel Xenograft Mouse Model for Intestinal Fistulas". Gastroenterology 154, n. 6 (maggio 2018): S—212. http://dx.doi.org/10.1016/s0016-5085(18)31100-4.

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Padussis, J. C., C. K. Augustine, P. A. Zipfel, H. Toshimitsu e D. S. Tyler. "61: Bevacizumab Augmentation of Temozolomide in a Mouse Melanoma Xenograft Model". Journal of Surgical Research 151, n. 2 (febbraio 2009): 198–99. http://dx.doi.org/10.1016/j.jss.2008.11.825.

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Kurata, T., S. Fushida, M. Okazaki, T. Tsukada, J. Kinoshita, K. Oyama e T. Ohta. "2206 Establishing a peritoneal dissemination xenograft mouse model of gastric cancer". European Journal of Cancer 51 (settembre 2015): S401. http://dx.doi.org/10.1016/s0959-8049(16)31122-4.

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Janic, B., S. L. Brown, F. Liu, G. Mao, I. J. Chetty, B. Movsas e N. Wen. "Gold Nanoparticles as Radiosensitizers in MDA MB 231 Xenograft Mouse Model". International Journal of Radiation Oncology*Biology*Physics 105, n. 1 (settembre 2019): E677—E678. http://dx.doi.org/10.1016/j.ijrobp.2019.06.995.

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Uppal, Ritika, Zdravka Medarova, Christian T. Farrar, Guangping Dai, Anna Moore e Peter Caravan. "Molecular Imaging of Fibrin in a Breast Cancer Xenograft Mouse Model". Investigative Radiology 47, n. 10 (ottobre 2012): 553–58. http://dx.doi.org/10.1097/rli.0b013e31825dddfb.

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Boehncke, W. H. "The psoriasis xenograft SCID mouse model: a tool in translational research". British Journal of Dermatology 166, n. 3 (22 febbraio 2012): 473. http://dx.doi.org/10.1111/j.1365-2133.2011.10741.x.

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Seifert, J. K., J. Zhao, J. Ahkter, E. Bolton, T. Junginger e D. L. Morris. "Cryoablation of Human Colorectal Cancerin Vivoin a Nude Mouse Xenograft Model". Cryobiology 37, n. 1 (agosto 1998): 30–37. http://dx.doi.org/10.1006/cryo.1998.2099.

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Faderl, Stefan, Carlos Bueso-Ramos, Zhiming Liu, Ashutosh Pal, William Bornmann, Diana V. Ciurea, David Harris, Inbal Hazan-Halevy, Hagop M. Kantarjian e Zeev Estrov. "Kit inhibitor APcK110 extends survival in an AML xenograft mouse model". Investigational New Drugs 29, n. 5 (3 giugno 2010): 1094–97. http://dx.doi.org/10.1007/s10637-010-9459-6.

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Shan, Xiaochuan, Cedric Dos Santos, Chenghui Zhou, Georges Habineza Ndikuyeze, Anthony Secreto, Joshua Glover, Winifred Trotman, Martin Carroll e Gwenn Danet-Desnoyers. "Improved Patient-Derived Xenograft Model for Acute Myeloid Leukemia". Blood 124, n. 21 (6 dicembre 2014): 3491. http://dx.doi.org/10.1182/blood.v124.21.3491.3491.

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Abstract (sommario):

Abstract We previously demonstrated that the NSG (NOD-Scid-IL2Rgcnull) xenotransplantation is an improved model for human AML samples, allowing us to better understand and characterize AML biology, especially in the context of drug therapy studies (Sanchez et al., Leukemia 2009). However, we observed that approximately half of AML patients’ samples either did not engraft in NSG mice (based on <0.1% human blasts in mouse bone marrow) or showed low (0.1 to 1% blasts) and highly variable engraftment. Recently, NSG mice expressing human SCF, GM-CSF and IL-3 transgenes (NSG-S) have been reported to enhance the engraftment of normal hematopoietic stem cells and primary AML cells, although only a few AML patients were evaluated (Wunderlich M et al, Leukemia 2010). This report describes a comprehensive paired analysis of engraftment of AML samples in NSG and NSG-S mice. T-cell depleted AML cells (5 -10 x 106 per mouse) were injected intravenously in sub-lethally irradiated mice (n=5/AML sample). Leukemia engraftment was assessed up to 16 weeks after injection in peripheral blood (PB), spleen (SPL) and bone marrow (BM) based on the percentage and absolute number of human leukemic blasts (huCD45+CD33+/-CD3-) in each tissue. Samples from 71 AML patients, representing all FAB and prognosis groups, were injected in NSG mice and only 35 samples (49%) engrafted based on human blasts >0.5% in mouse BM. From these 35 NSG-engrafting samples, 14 were also injected in NSG-S mice and all of them engrafted. Leukemic burden was significantly (p ≤ 0.05) increased in NSG-S versus NSG mice: 39±21% vs 22±23% BM blasts, 21±15% vs 7±10% SPL blasts, 2,732±6,488 vs 141±221 blasts/ml PB. Interestingly, the dramatic increase in peripheral blast count observed in NSG-S mice provides new opportunities to use PB to monitor drug response for the many patient samples that show no or very low peripheral engraftment in NSG mice. However, for 7 of these 14 NSG-engrafting AML samples, the use of NSG-S mice as recipients was associated with rapid engraftment, excessive leukemic burden, anemia, weight loss and lethargy requiring early sacrifice and leading to shorter overall survival (54±26 days in NSG-S vs >90 days in NSG). Out of the 36 patients’ samples that failed to engraft in NSG mice, 19 were tested for engraftment in NSG-S mice. Remarkably, 14 out 19 (74%) samples engrafted (17±16% BM blasts, 8±12% SPL, and 1,418±4,609/ml PB blasts at Day 77 post-transplant) and the kinetics of engraftment were slower compared to AML samples that can engraft in both mouse strains. These results suggest that the presence of human SCF, GM-CSF and IL-3 in NSG-S is sufficient to rescue leukemia-initiating cells for most AML samples that fail to engraft in NSG mice. Only 5 out of 33 samples (15%) failed to engraft in NSG and NSG-S mice, indicating that the NSG-S BM microenvironment remains suboptimal for a small minority of AML samples. We are investigating if NSG-S engraftment is correlated to CD116, CD117, CD123 expression, cytogenetics, mutations, and prognosis. Overall, our results show that NSG-S mice represent a significant improvement over previous patient-derived xenograft models since they can (1) accelerate and enhance leukemic engraftment compared to NSG mice, and (2) support engraftment for 85% of our AML patients, making this model particularly useful for pre-clinical studies. Disclosures Dos Santos: Janssen R&D: Research Funding. Danet-Desnoyers:Janssen R&D: Research Funding.

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Galvin, K. M., J. Huck, O. Burenkova, K. Burke, D. Bowman, V. Shinde, B. Stringer, M. Zhang, M. Manfredi e K. Meetze. "Preclinical pharmacodynamic studies of Aurora A inhibition by MLN8054". Journal of Clinical Oncology 24, n. 18_suppl (20 giugno 2006): 13059. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.13059.

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13059 Background: The mitotic kinase Aurora A is implicated in the development of multiple tumor types. MLN8054 is an oral, potent and selective small-molecule inhibitor of Aurora A with broad efficacy in preclinical models of cancer. Inhibition of Aurora A by MLN8054 induces accumulation of mitotic cells, followed by apoptosis. This study explores relationships between Aurora A inhibition, mitotic index, and tumor growth inhibition for xenograft models with different sensitivity to MLN8054. The marker response in mouse skin was also studied. Methods: Mice bearing subcutaneous xenografts were dosed orally qd or bid with MLN8054 for 21 days. Pharmacodynamic markers were studied after 1–2 doses. Formalin-fixed xenograft tissues were stained with the mitotic markers pHisH3 and MPM2, or with an antibody to the T288 autophosphorylation site on Aurora A. Tumor growth inhibition (TGI) was calculated using the formula 100 - [ΔT/ΔC * 100], where ΔT is the volume change for treated tumors, and ΔC is the volume change for control tumors. Results: HCT116 human colon xenografts were sensitive to MLN8054 on a qd or bid schedule (84% and 96% TGI respectively for 30mg/kg dose). The T288 autophosphorylation site was used to directly demonstrate inhibition of Aurora A, which resulted in dose-dependent duration of the elevation in mitotic index. Efficacy was similar for qd vs bid dosing of 30mg/kg MLN8054, and accordingly we found that a single dose was sufficient to elevate the mitotic index for about 20–24h in this model. SW480 human colon xenografts have MLN8054 sensitivity similar to that of HCT116, but more modest effects on mitotic index were observed. The mitotic index profile of SW480 is similar to that of MDA-MB-231 xenografts, the most insensitive model studied. Elevated mitotic index was also observed in mouse skin. Conclusions: We found that mitotic index measurements coupled with the T288 autophosphorylation site as a direct marker of Aurora A activity are useful for monitoring inhibition of Aurora A by MLN8054 in tumor and/or skin biopsies. In a sensitive model, greater duration of mitotic index elevation results in greater efficacy. Our continuing work aims to better understand the differences in marker and efficacy responses between xenograft lines, incorporating the pT288 antibody as a direct marker of Aurora A inhibition. [Table: see text]

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Zhang, Wen-Ying, Zhen-Dong Jin, Feng Liu, Hai-Hua Yuan e Bin Jiang. "Antitumor Activity of Intratumoral Ethanol Injection in an Orthotopic Pancreatic Cancer Cell Mouse Xenograft Model". Gastroenterology Research and Practice 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/7149565.

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Purpose. Pancreatic cancer is a lethal disease and usually is diagnosed at advanced stages of disease. This study assessed the effects of intratumoral ethanol injection using an endoscopic ultrasound (EUS) probe on the control of pancreatic cancer in a mouse orthotopic xenograft model. Materials and Methods. The subcutaneous and orthotopic human pancreatic cancer cell mouse xenograft models were established. Different concentrations of ethanol (0–95%) were injected into subcutaneous xenograft tumors. In the orthotopic tumor model, ethanol was injected into the tumor lesions under the guidance of a high-frequency EUS probe. Tumor volume, relative tumor volume (RTV), and histopathology were evaluated. The serum amylase level was analyzed at baseline and 24 h after treatment in the orthotopic tumor model. Results. Injection of 40–95% ethanol induced tumor necrosis in the subcutaneous tumor model, while there was no statistical difference between the RTVs of the two groups (P=0.81). In the orthotopic tumor model, the RTV of the 80% ethanol treatment group was less than that of the saline injection group (P<0.01); and histologically, there was a large area of necrosis observed in the 80% ethanol group. The serum amylase level was slightly elevated at 24 h after injection and returned to the baseline level at 7 days. Conclusion. Injection of 80% ethanol into xenograft tumor lesions of orthotopic pancreatic cancer resulted in tumor necrosis, and the procedure was safe and effective. Future studies will further confirm its antitumor activity as well as assess its safety and feasibility.

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Janakiraman, Harinarayanan, Scott A. Becker, Alexandra Bradshaw, Mark P. Rubinstein e Ernest Ramsay Camp. "Critical evaluation of an autologous peripheral blood mononuclear cell-based humanized cancer model". PLOS ONE 17, n. 9 (12 settembre 2022): e0273076. http://dx.doi.org/10.1371/journal.pone.0273076.

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The use of humanized mouse models for oncology is rapidly expanding. Autologous patient-derived systems are particularly attractive as they can model the human cancer’s heterogeneity and immune microenvironment. In this study, we developed an autologous humanized mouse cancer model by engrafting NSG mice with patient-derived xenografts and infused matched peripheral blood mononuclear cells (PBMCs). We first defined the time course of xenogeneic graft-versus-host-disease (xGVHD) and determined that only minimal xGVHD was observed for up to 8 weeks. Next, colorectal and pancreatic cancer patient-derived xenograft bearing NSG mice were infused with 5x106 human PBMCS for development of the humanized cancer models (iPDX). Early after infusion of human PBMCs, iPDX mice demonstrated engraftment of human CD4+ and CD8+ T cells in the blood of both colorectal and pancreatic cancer patient-derived models that persisted for up to 8 weeks. At the end of the experiment, iPDX xenografts maintained the features of the primary human tumor including tumor grade and cell type. The iPDX tumors demonstrated infiltration of human CD3+ cells with high PD-1 expression although we observed significant intra and inter- model variability. In summary, the iPDX models reproduced key features of the corresponding human tumor. The observed variability and high PD-1 expression are important considerations that need to be addressed in order to develop a reproducible model system.

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Tan, Xi, Qiulan Luo, Shiqing Zhou, Wei Huang, Xiaocong Feng, Wenyong Chen, Chaojie Yang e Yunying Li. "Erchen Plus Huiyanzhuyu Decoction Inhibits the Growth of Laryngeal Carcinoma in a Mouse Model of Phlegm-Coagulation-Blood-Stasis Syndrome via the STAT3/Cyclin D1 Pathway". Evidence-Based Complementary and Alternative Medicine 2020 (23 aprile 2020): 1–14. http://dx.doi.org/10.1155/2020/2803496.

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Erchen plus Huiyanzhuyu decoction (EHD), a Chinese herbal medicine (CHM) formula that consists of Erchen decoction and Huiyanzhuyu decoction, has achieved satisfactory results in the clinic. The main function of EHD is to remove phlegm and blood stasis, and EHD is suitable for phlegm-coagulation-blood-stasis (PCBS) syndrome in laryngeal cancer (LC). In this study, a xenograft mouse model of LC with PCBS syndrome was constructed by feeding a high-fat diet, swimming in ice water, and subcutaneously injecting epinephrine hydrochloride for 2 weeks. Based on the successful Chinese medicine syndrome model, Hep2-luciferase-GFP cells were injected subcutaneously under the armpit of the right upper limb in mice to form tumours. A mouse model of LC with PCBS syndrome was established via heterotopic transplantation. Then, the mice received intragastric administration of different concentrations of EHD daily, and cisplatin (DDP) was intraperitoneally injected every week for 21 days. Tumour fluorescence in mice was measured with a living animal imager on days 7, 14, 21, and 28 during treatment. The results of this experiment confirmed that a mouse model of Chinese medicine syndrome was successfully constructed. Moreover, EHD slowed the growth of xenograft tumours in nude mice; decreased the expression levels of STAT3, p-STAT3, and cyclin D1; and upregulated the expression level of P27. In brief, EHD inhibited laryngeal tumour growth in a xenograft mouse model of PCBS syndrome and regulated the STAT3/cyclin D1 signalling pathway. This study was the first to construct a Chinese medicine xenograft mouse model of LC with PCBS syndrome; in addition, this study clarified that EHD regulated the STAT3/cyclin D1 signalling pathway to inhibit the growth of LC and that EHD may be a promising novel therapeutic compound for the treatment of patients with LC.

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Pawellek, A., G. Hewlett, J. Kreuter, H. Rübsamen-Waigmann e O. Weber. "Xenograft Model for Identifying Chemotherapeutic Agents against Papillomaviruses". Antimicrobial Agents and Chemotherapy 45, n. 4 (1 aprile 2001): 1014–21. http://dx.doi.org/10.1128/aac.45.4.1014-1021.2001.

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ABSTRACT The report describes the establishment and characterization of a mouse xenograft transplantation model for the study of papillomavirus infection of bovine skin. Calf scrotal skin was inoculated with bovine papillomavirus type 2 before grafting it to the dorsum of severe combined immunodeficient mice. The grafted skin contained epidermis, dermis, and a thin layer of fat. After 5 months the induced warts not only showed histological features of papillomavirus infections but also tested positive for viral DNA and papillomavirus capsid antigen. The formation of infectious virions was demonstrated by inoculation of new transplants with crude extract from the induced warts as well as in a cell culture focus assay. Topical application of bromovinyl-2′-deoxyuridine led to a reduction in viral DNA content in the developing wart. This small-animal xenograft model should be useful for characterizing antiviral compounds and providing an understanding of the regulation of papillomavirus infections.

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Tanaka, Chiharu, Kaoru Furihata, Seiji Naganuma, Mitsunari Ogasawara, Reiko Yoshioka, Hideki Taniguchi, Mutsuo Furihata e Keisuke Taniuchi. "Establishment of a mouse model of pancreatic cancer using human pancreatic cancer cell line S2-013-derived organoid". Human Cell 35, n. 2 (12 febbraio 2022): 735–44. http://dx.doi.org/10.1007/s13577-022-00684-7.

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AbstractA well-established preclinical model of pancreatic cancer needs to be established to facilitate research on new therapeutic targets. Recently established animal models of pancreatic cancer, including patient-derived tumor models and organoid models, are used for pre-clinical drug testing and biomarker discovery. These models have useful characteristics over conventional xenograft mouse models based on cell lines in preclinical studies, but still cannot accurately predict the clinical outcomes of new treatments and have not yet been broadly implemented in research. We employed pancreatic cancer organoid culture methods using the pancreatic cancer cell line S2-013, and performed pathological and immunohistochemical analyses to characterize tumor xenografts obtained from a mouse model implanted with S2-013 cell line-derived organoids. Serum levels of the pancreatic cancer tumor marker CA19-9 were measured by ELISA. We generated human pancreatic cancer organoids using a co-culture of S2-013 cells, human endothelial cells derived from human umbilical vein endothelial cells, and human mesenchymal stem cells, and established a mouse model with subcutaneously transplanted human pancreatic cancer organoids (S2-013-organoid model). Although blood clotting crater-like formation developed in the middle of subcutaneous xenografts in the S2-013-conventional model, created by subcutaneously injecting S2-013 cells into the right flank of nude mice, the size of xenografts in the S2-013-organoid model gradually increased without crater-like formation. Importantly, tumor xenografts obtained from the S2-013-organoid model exhibited a clinical human pancreatic cancer tissue-like cellular morphology, tissue architecture, and polarity, and actively formed cancer stroma containing mature blood vessels with the high expression of the vascular tight junction marker CD31. In subcutaneous xenografts of S2-013-conventional mice, no blood vessel density or widely expanding areas of necrotic regions were present. Consequently, serum levels of CA19-9 in the S2-013-organoid model correlated with tumor volumes. In addition, epithelial–mesenchymal transition, the conversion of epithelial cells to the mesenchymal phenotype, was observed in tumor xenografts of the S2-013-organoid model. The S2-013-organoid model provides tumor xenografts consisting of clinical human pancreatic cancer-like tissue formation with the effective development of vascularized stroma, and may be valuable for facilitating studies on pre-clinical drug testing and biomarker discovery.

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