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1
Cataldo, A. "ANTI-TUMOR ACTIVITY OF CPG-ODN IN OVARIAN XENOGRAFT TUMORS". Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/229558.
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Synthetic oligodeoxynucleotides expressing CpG motifs (CpG-ODN), Toll-like receptor 9 (TLR9) agonists, are able to induce innate/adaptive immune responses and can enhance the antitumor activity of DNA-damaging chemotherapy and radiation therapy in preclinical mouse models.
It was recently reported that peritumoral CpG-ODN treatment in preclinical models of ovarian cancer, activating TLR-9 expressing cells in tumor microenvironment, induces modulation of DNA repair genes and sensitizes cancer cells to DNA-damaging Cisplatin treatment.
In this thesis we investigated whether this treatment induces modulation of miRNAs in tumor cells and their relevance to chemotherapy response. Array analysis identified 20 differentially expressed miRNAs (16 down- and 4 up-regulated) in human IGROV-1 ovarian tumor cells from CpG-ODN-treated mice versus controls. Evaluation of the role of the 3 most differentially expressed miRNAs on sensitivity to Cisplatin of IGROV-1 cells revealed significant increased Cisplatin cytotoxicity upon ectopic expression of hsa-miR-302b (up-modulated in our array), but no increased effect upon reduced expression of hsa-miR-424 or hsa-miR-340 (down-modulated in our array). The impact of expression levels of all 20 differentially expressed miRNAs were associated with time to replase and overall survival probability in two data sets of ovarian cancer patients treated with platinum. It was found that hsa-miR-302b expression was significantly associated with time to relapse or overall survival in these patients. Use of bio-informatics tools identified 19 mRNAs potentially targeted by hsa-miR-302b, including HDAC4 gene, which has been reported to mediate Cisplatin sensitivity in ovarian cancer. Both HDAC4 mRNA and protein levels were significantly reduced in IGROV-1 cells overexpressing hsa-miR-302b. Altogether, these findings indicate that hsa-miR-302b acts as a ‘‘chemosensitizer’’ in human ovarian carcinoma cells and may represent a biomarker able to predict response to Cisplatin treatment. Moreover, the identification of miRNAs that improve sensitivity to chemotherapy provides the experimental underpinning for their possible future clinical use.
In the second part of this thesis we tested the efficacy of CpG-ODN in combination with other possible therapeutic agents in ovarian carcinoma ascites-bearing athymic mice, to mimic clinical treatment situations in advanced human ovarian disease.
Mice injected i.p. with IGROV-1 ovarian cancer cells were treated at different stages of ascites progression for 4 weeks with CpG-ODN alone or in combination with Bevacizumab, Polyinosinic:Polycytidylic acid (Poly(I):Poly(C)), Gefitinib, Cetuximab and Cisplatin.
In mice treated when ascitic fluid began to accumulate, CpG-ODN combined with Bevacizumab, Poly(I): Poly(C) or Gefitinib did not significantly increase Median Survival Times (MST), as compared with that using CpG-ODN alone, whereas MST in mice treated with CpG-ODN plus Cetuximab was significantly increased (>103 days for combination vs 62 days for CpG alone; P = 0.0008), with 4/8 mice alive at the end of the experiment. In mice showing evident and established ascites, evaluated with increase of abdominal volume and body weight (27.9 ± 0.8 g after vs 23 ± 1.1 g before tumor cell injection), treatment with Cisplatin in addition to CpG-ODN/Cetuximab led to significantly increased MST (105.5 days; P = 0.001), with all mice still alive at 85 days, over that using CpG ODN/Cetuximab (66 days), Cetuximab/Cisplatin (18.5 days), Cisplatin (23 days) or saline (16 days). At a very advanced stage of disease (body weight: 31.4 ± 0.9 g), when more than half of control mice had to be sacrificed 6 days after starting treatments, the triple-combination therapy still increased MST (45 days; P = 0.0089) vs controls.
These data indicated that CpG-ODN combination therapies that enhance the immune response in the tumor microenvironment and concomitantly target tumor cells are highly efficacious even in experimental advanced malignancies. Although differences in the distribution of TLR9 in mice and humans and the enrichment of this receptor on innate immune cells of athymic mice must be considered, our results indicate a promising strategy to treat ovarian cancer patients with bulky ascites.
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Williams, K. J., M. R. Albertella, B. Fitzpatrick, Paul M. Loadman, Steven D. Shnyder, E. C. Chinje, B. A. Telfer, C. R. Dunk, P. A. Harris i I. J. Stratford. "In vivo activation of the hypoxia-targeted cytotoxin AQ4N in human tumor xenograft". AACR Publications, 2009. http://hdl.handle.net/10454/4561.
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noAQ4N (banoxantrone) is a prodrug that, under hypoxic conditions, is enzymatically converted to a cytotoxic DNA-binding agent, AQ4. Incorporation of AQ4N into conventional chemoradiation protocols therefore targets both oxygenated and hypoxic regions of tumors, and potentially will increase the effectiveness of therapy. This current pharmacodynamic and efficacy study was designed to quantify tumor exposure to AQ4 following treatment with AQ4N, and to relate exposure to outcome of treatment. A single dose of 60 mg/kg AQ4N enhanced the response of RT112 (bladder) and Calu-6 (lung) xenografts to treatment with cisplatin and radiation therapy. AQ4N was also given to separate cohorts of tumor-bearing mice 24 hours before tumor excision for subsequent analysis of metabolite levels. AQ4 was detected by high performance liquid chromatography/mass spectrometry in all treated samples of RT112 and Calu-6 tumors at mean concentrations of 0.23 and 1.07 microg/g, respectively. These concentrations are comparable with those shown to be cytotoxic in vitro. AQ4-related nuclear fluorescence was observed in all treated tumors by confocal microscopy, which correlated with the high performance liquid chromatography/mass spectrometry data. The presence of the hypoxic marker Glut-1 was shown by immunohistochemistry in both Calu-6 tumors and RT112 tumors, and colocalization of AQ4 fluorescence and Glut-1 staining strongly suggested that AQ4N was activated in these putatively hypoxic areas. This is the first demonstration that AQ4N will increase the efficacy of chemoradiotherapy in preclinical models; the intratumoral levels of AQ4 found in this study are comparable with tumor AQ4 levels found in a recent phase I clinical study, which suggests that these levels could be potentially therapeutic.
3
Tin, Man Ying. "Study of the anticarcinogenic mechanisms of astragalus membranaceus in colon cancer cells and tumor xenograft". HKBU Institutional Repository, 2006. http://repository.hkbu.edu.hk/etd_ra/777.
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Pfeffer, Nils Christian Verfasser], i Udo [Akademischer Betreuer] [Schumacher. "Expression of HIF-1alpha and GLUT-1 in human xenograft tumors in immundeficient mice / Nils Christian Pfeffer. Betreuer: Udo Schumacher". Hamburg : Staats- und Universitätsbibliothek Hamburg, 2013. http://d-nb.info/1038789192/34.
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Maftei, Constantin Alin Verfasser], Christine [Akademischer Betreuer] Bayer, Peter [Akademischer Betreuer] [Vaupel i Gabriele [Akademischer Betreuer] Multhoff. "Determination of the dynamics of tumor hypoxia during radiation therapy using biological imaging on mouse xenograft tumors / Constantin Alin Maftei. Gutachter: Peter Vaupel ; Gabriele Multhoff. Betreuer: Christine Bayer". München : Universitätsbibliothek der TU München, 2013. http://d-nb.info/1034134779/34.
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Carpenter, Kent James. "Inhibition of PIM and AXL Kinases As Potential Treatments for a Variety of Hematological Malignancies and Solid Tumors". BYU ScholarsArchive, 2014. https://scholarsarchive.byu.edu/etd/3842.
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This thesis is divided into three chapters. In each case, the goal is to achieve inhibition of a growth kinase (PIM or AXL) and subsequent arrest of cell growth and induction of apoptosis (in vitro cell culture models) or decrease in tumor volume (in vivo xenograft studies). Chapter one and chapter two discuss inhibition of proviral integration site for Moloneymurine leukemia virus (PIM) kinases. The three PIM kinases, PIM-1, PIM-2, and PIM-3, are a subfamily of serine/threonine kinases that are known to be involved in signaling pathways as downstream effectors of signal transducer and activator of transcription-5 (STAT5) signaling and inhibitors of apoptosis. PIM kinases are implicated in a large percentage of hematological malignancies and solid tumors. Because they have been shown to correlate with disease progression and poor prognosis in many of these conditions, PIM kinase inhibitors are being developed and investigated for therapeutic use. The aim of this study in chapter one was to evaluate the role of PIM 1, 2 and 3 in urothelial carcinomas, using second generation Pan-PIM kinase inhibitor TP-3654. Retrospective immunohistochemical analysis of bladder cancer specimens found that PIM 1, 2, and 3 was expressed in a significant number of cases. PIM-1 was expressed in 4 bladder cancer cell lines and TP-3654 treatment was able to inhibit BAD phosphorylation to induce apoptosis. The second aim of this study was to investigate the effects of TP-3654 on the interaction of c-MYC with PIM kinase family members. The data indicate that PIM-1 only interacts with c-MYC in the acute myeloid leukemia (AML) and multiple myeloma (MM) cell lines studied, and that PIM-1 siRNA knockdown or treatment with TP-3654 is able to decrease this interaction. The third chapter discusses inhibition of the receptor tyrosine kinase Axl. Pancreatic cancer is a highly lethal disease characterized by malignant cells that rapidly disseminate from the primary tumor to form local and distant metastases. Axl is overexpressed in over 50% of pancreatic cancers and expression of Axl in these cancers is highly associated with a poor prognostic outcome for patients. Small molecule inhibitors of AXL are currently under investigation, as AXL is associated with cell migration mediated by epithelial-mesenchymal transition (EMT). The aim of this study was to investigate the effects of a small molecule inhibitor of AXL, TP-0903, on pancreatic cancer cell lines. Consistent with the known function of Axl, TP-0903 inhibited Gas6-induced migration and invasion of pancreatic cancer cells invitro and potently induced apoptosis. Additionally, we found that inhibition of AXL decreased expression of EMT marker genes and induced mesenchymal pancreatic cancer cell lines to take on an epithelial phenotype. TP-0903 also significantly inhibited the growth of pancreatic cancer cell lines grown in xenograft tumor mouse model and taken together, the results suggest Axl is a potential therapeutic target in pancreatic cancer and TP-0903 as a potential therapeutic agent.
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SARONNI, DAVIDE. "TYROSINE KINASE INHIBITORS IN NEUROENDOCRINE TUMORS: FROM IN VITRO TO ZEBRAFISH MODEL". Doctoral thesis, Università degli Studi di Milano, 2022. http://hdl.handle.net/2434/917967.
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(1) Background: Neuroendocrine neoplasms (NENs) are a group of tumors that arise from neuroendocrine cells throughout the body, with the lungs and gastrointestinal tract being the most common sites of origin. In patients with NENs and distant metastases, surgery is generally not curative. Although well-differentiated and low-grade NENs, classified as neuroendocrine tumors (NETs), are usually less aggressive than poorly-differentiated NENs, they can develop distant metastases in about 15% of cases. These patients require chronic medical management. However, the clinical efficacy of these treatments is limited by the low objective response rate, due to the occurrence of tumor resistance and the high biological heterogeneity of these neoplasms.
(2) Research problem: We addressed this study on two rare NETs: lung neuroendocrine tumors (LNETs) and medullary thyroid carcinoma (MTC). LNETs represent about 2% of lung tumors, while MTCs are rare thyroid tumors caused by mutations in the RET proto-oncogene. Both NETs are well-differentiated neoplasms and are known to be highly vascularized. Therefore, they represent a potential target for tyrosine kinase inhibitors (TKIs) selective for receptors involved in angiogenesis. The aim of this project was to evaluate the antitumor activity of several new TKIs both in vitro, using LNETs (NCI-H727, UMC-11 and NCI-H835) and MTC (TT and MZ-CRC-1) cell lines, and in vivo, adopting a novel zebrafish xenograft model to study angiogenesis. In LNETs we tested: sulfatinib, a small molecule that inhibits the Vascular Endothelial Growth Factor Receptor (VEGFR) 1, 2, and 3, and the Fibroblast Growth Factor Receptor type 1 (FGFR1); cabozantinib, a multi-target inhibitor selective for VEGFR2, c-Met, Kit, Axl and Flt3; and axitinib, a multi-target TKI of VEGFR1, 2, 3 and Platelet-Derived Growth Factor Receptor-beta (PDGFRβ). In MTC we tested: sulfatinib; SPP86, a RET-specific inhibitor; and SU5402, an inhibitor of the FGFR1 and VEGFR2.
(3) Methodology: In LNETs and MTC cells the effects of selected TKIs have been evaluated in vitro through: MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assays, for assessing cell viability; flow-cytometer analysis, for the evaluation of cell cycle and apoptosis; and wound-healing assay, to study cell migration. In vivo we took advantage of the transgenic zebrafish line of Tg(fli1a:EGFP)y1. Through the xenotransplantation of NET cells in the subperidermal space near the subintestinal vein, we assessed the effects of TKIs on tumor-induced angiogenesis and cancer dissemination.
(4) Key Results: In LNET cell lines we observed a dose-dependent decrease in cell viability after incubation with all TKIs. This effect seems to be related to the perturbation of the cell cycle and induction in apoptosis. In NCI-H727 wound healing assay showed a significant reduction in cell migration only after incubation with cabozantinib. In the zebrafish model, we found a significant reduction of the tumor-induced angiogenesis in implanted LNET cell lines after treatment with all TKIs. Cabozantinib and axitinib were more potent than sulfatinib in inhibition of angiogenesis, while cabozantinib was the most efficient in reducing cell migration from the transplantation site to the tail. In MTC cell lines, sulfatinib, SU5402 and SPP86 showed a decrease in cell viability, confirmed by the significant reduction in S phase cell population. Moreover, sulfatinib and SPP86 showed for both cell lines a significant induction of apoptosis. Sulfatinib and SPP86 inhibited the migration of TT and MZCRC-1 cells, evaluated through the wound healing assay, while SU5402 was able to inhibit migration only in TT cells. In vivo we observed a significant reduction of TT cells-induced angiogenesis in zebrafish embryos after treatment with sulfatinib and SPP86.
(5) Conclusions: Despite sulfatinib resulted the most potent compound in terms of inhibition of LNET cell proliferation, cabozantinib showed in vivo the most effective impact in reducing tumor-induced angiogenesis. Cabozantinib was the only TKI able to inhibit in vivo the dissemination of implanted LNET cells. According to these data, cabozantinib could represent a potential candidate in the therapy of patients with highly vascularized LNET. In MTC cell lines, SPP86 and sulfatinib displayed a similar antitumor activity both in vitro and in vivo, suggesting a good efficacy of specific RET inhibitors (SPP86) with potentially less adverse effects than multitarget TKIs (sulfatinib). In addition, this study showed that the zebrafish model for NETs represents an innovative tool for drug screening with several advantages compared with rodent models: rapidity of procedure, animal immune suppression is not required, lower number of tumor cells for implant and the optical transparency provides a real-time monitoring of cell-stromal interactions and cancer progression in living animals.
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Walter, Thomas. "Métastases hépatiques de tumeurs endocrines digestives : développement de modèles animaux pour l’étude des mécanismes biologiques et l’évaluation préclinique des thérapeutiques". Thesis, Lyon 1, 2010. http://www.theses.fr/2010LYO10241.
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Les métastases hépatiques de tumeurs endocrines digestives sont hypervasculaires et hétérogènes. Les mécanismes de développement de ces métastases hépatiques, en particulier le rôle de l’angiogenèse tumorale associée à ces tumeurs, sont complexes. Ceci explique la difficulté de prédire le profil évolutif de ces tumeurs et de trouver des facteurs prédictifs de réponses aux traitements médicaux utilisés. L’objectif de notre travail a été de mieux comprendre : le rôle de l’angiogenèse dans le développement des métastases hépatiques de tumeurs endocrines digestives ; les mécanismes d’actions et en particulier leur activité anti-angiogénique, de deux types de molécules (analogue de la somatostatine et inhibiteur de mTOR). Nos résultats nous ont permis à travers une double approche expérimentale, in vitro et in vivo de : (a) montrer la complexité de la régulation de la synthèse et de la sécrétion du VEGF par les cellules endocrines néoplasiques ; (b) confirmer expérimentalement la dissociation entre expression du VEGF et capacités angiogéniques d’une part, propriétés invasives et métastatiques d’autre part, dans les tumeurs endocrines digestives ; (c) montrer expérimentalement que l’inhibition de l’angiogenèse peut contribuer à l’effet anti-tumoral de substances d’intérêt thérapeutique dans les tumeurs endocrines digestivesLiver metastases of digestive endocrine tumors are hypervascular and heterogeneous. The mechanisms of development of these metastases, especially the role of angiogenesis, are complex. This explains the difficulty to predict the natural history of these tumors and to find predictive factors of response to medical treatments. Our aim was to evaluate: the role of angiogenesis in the development of liver metastasis from digestive endocrine tumors; mechanisms of action, especially antiangiogenic activity, of two drugs (somatostatin analogues and mTOR inhibitor). We were able to demonstrate through an in vitro and in vivo experimental approach that: (a) the regulation of VEGF synthesis and secretion is complex, with different roles according to the cell studied; (b) there is a dissociation between VEGF expression and angiogenic capacities, on one hand, and invasive and metastatic properties, on the other hand; (c) the inhibition of angiogenesis may contribute to the anti-tumoral effect of several drugs of therapeutic interest in digestive endocrine tumors
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Faizi, M. A. H. P. "The effect of hyperthermia and irradiation on a human ovary tumour xenograft". Thesis, Bucks New University, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.380292.
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Huang, Ting [Verfasser], i Aladár [Gutachter] Szalay. "Vaccinia Virus-mediated Therapy of Solid Tumor Xenografts: Intra-tumoral Delivery of Therapeutic Antibodies / Ting Huang. Gutachter: Aladar Szalay". Würzburg : Universität Würzburg, 2015. http://d-nb.info/1108780555/34.
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Sandoval, José Luis Bico Rosa Gamero. "Modulation of breast cancer tumour-initiating cells in cell lines and patient-derived tumour xenografts". Thesis, University of Cambridge, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708658.
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Quang, Ly. "Photosensitizing effects of M-Tetrahydroxypheylchlorin on human tumor xenografts : correlation with sensitizer uptake, tumor doubling time and tumor histology /". [S.l.] : [s.n.], 1999. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Tabassum, Doris Priscilla. "Exploring Intra-tumor Cooperation in Metastasis and Drug Resistance using Heterogeneous Xenograft Models of Breast Cancer". Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493472.
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Breast cancer is a highly heterogeneous disease, having not only several intrinsic sub-types but also significant sub-clonal heterogeneity within tumors. Intra-tumor heterogeneity can have profound impact on tumor evolution, disease progression and response to therapy. Furthermore, these phenomena can also be influenced by interactions of cancer cells with those of the microenvironment, thereby adding an extra layer of complexity to the study of tumor biology.
To investigate the impact of sub-clonal heterogeneity on tumor phenotypes, we developed a heterogeneous mouse xenograft model of breast cancer. Our model revealed that tumor growth can be driven by a minor clone, expressing IL11, in a non-cell autonomous fashion mediated through the microenvironment. We also found that non-cell autonomous driving and clonal interference stabilizes sub-clonal heterogeneity, thereby enabling inter-clonal interactions leading to new phenotypic traits.
Utilizing the same model, we identified cooperative interactions between IL11- and FIGF- expressing sub-clones that enhance the metastatic behavior of the tumor as a whole. We found that metastatic cooperation between these two populations result in larger and heterogeneous lung metastasis. Using expression profiles from primary tumors and corresponding metastatic lesions, we identified several key immune-regulatory and extracellular matrix (ECM) remodeling pathways that promote metastasis in our model system.
Lastly, we examined heterotypic interactions between tumor cells and cancer associated fibroblasts (CAFs) to understand the mechanism of resistance to lapatinib. Using a 3D co-culture model, we identified significant sub-type-specific changes in gene expression, metabolic, and therapeutic sensitivity profiles of breast cancer cells induced by CAFs. We identified JAK2/STAT3 pathway and CAF-secreted hyaluronan as major factors contributing to CAF-mediated protection. We also found that close spatial proximity to CAFs impacts therapeutic responses by affecting proliferation rates of cancer cells.
In summary, we have used in vitro and in vivo models systems to identify key interactions within populations of tumors cells, as well as between tumor microenvironmental components and cancer cells, to identify mechanisms that influence tumorigenesis, metastasis and drug response. We believe that these findings will increase our understanding of breast cancer heterogeneity and enable us to design better therapeutic regimens to eradicate the disease.Medical Sciences
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Burke, Frances. "Modelling the anti-tumour effect of interferon-gamma in human ovarian cancer". Thesis, Open University, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309815.
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Bains, Lauren Jean. "Using magnetic resonance imaging and immunohistochemistry to monitor the response of HCT-116 xenograft tumours to tirapazamine". Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/31832.
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Tirapazamine is a prodrug which is activated under hypoxic conditions and
has shown promise in treating hypoxic tumours. Using MRI and histochemistry,
the response of HCT116 xenograft tumours to tirapazamine was investigated
and quantified. Dynamic contrast-enhanced and diffusion weighted
MRI scans were acquired both before and after treatment with tirapazamine
in under two hours of imaging time per session. MRI data was used to produce
maps of the apparent diffusion coefficient (ADC), area-under-the-curve
(IAUC), and pharmacokinetic parameters (Ktrans, ve, vv). Carbocyanine
and BrdU/haematoxylin staining were used to produce histological images
of perfusion and necrosis.
Implanted fiducial markers were used to align MRI data before and after
treatment, and to align MRI slices with histological sections. Qualitative
and quantitative comparisons between MRI and histological images showed
good agreement between the two. Data from both modalities showed that
tirapazamine causes significant changes in diffusion and decreases in perfusion
within 24 hours after treatment; widespread vascular shutdown and
central necrosis were observed in treated tumours. The agreement of dynamic
contrast-enhanced MRI and diffusion weighted MRI with accepted
immunohistochemical methods suggests that the MRI techniques presented
here are effective methods of monitoring the response of hypoxic, heterogeneous
tumours to treatment with tirapazamine.
This is the first MR investigation to measure the effects of tirapazamine
in an in vivo tumour model. The non-invasive imaging protocol developed
here has the potential for direct translation to the clinic in a potential
trial. Interestingly, the response of tumours to tirapazamine is evidenced
by marked vascular shutdown detected using dynamic contrast enhanced
MR imaging, supporting the hypothesis that tirapazamine's mechanism of
action may include vascular effects.Science, Faculty of
Physics and Astronomy, Department of
Graduate
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Le, Thu-Ha. "Protein dynamics in responder and non-responder solid tumor xenografts during oncolytic viral therapy". kostenfrei, 2008. http://www.opus-bayern.de/uni-wuerzburg/volltexte/2009/3201/.
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Maekawa, Hisatsugu. "A Chemosensitivity Study of Colorectal Cancer Using Xenografts of Patient-Derived Tumor Initiating Cells". Kyoto University, 2018. http://hdl.handle.net/2433/235985.
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Carmichael, James. "A model for the modulation of cancer chemotherapy using human tumour xenografts". Thesis, University of Edinburgh, 1986. http://hdl.handle.net/1842/20372.
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Volk, Lisa Danielle. "The Combination of Nab-Paclitaxel and Bevacizumab Therapy Synergistically Improves Tumor Response in Xenograft Breast Cancer Models". Available to subscribers only, 2008. http://proquest.umi.com/pqdweb?did=1674100511&sid=1&Fmt=2&clientId=1509&RQT=309&VName=PQD.
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Thesis (M.S.)--Southern Illinois University Carbondale, 2008."Department of Medical Microbiology, Immunology, and Cell Biology." Includes bibliographical references (p. 86-119). Also available online.
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Zabaglo, Lila. "The relationship between hypoxia, proliferation and apoptosis in murine CaNT tumours and human HT29 xenografts". Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394375.
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Yoshida, Toru. "Antiandrogen bicalutamide promotes tumor growth in a novel androgen-dependent prostate cancer xenograft model derived from a bicalutamide-treated patient". Kyoto University, 2006. http://hdl.handle.net/2433/135622.
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McCandless, John Richard 1954. "Alpha-6 beta-1 and alpha-6 beta-4 integrin expression and the vascularization of human prostate tumor xenografts". Thesis, The University of Arizona, 1997. http://hdl.handle.net/10150/278603.
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Growth and metastasis of tumors appear to be dependent on the ability of tumor cells to recruit blood vessels. Integrins are a class of cell adhesion molecules that may have a role in angiogenesis. In this study the effect of the expression of two integrins, α6β1 and α6β4, on microvessel density in human prostate tumor xenografts in SCID mice was evaluated. Five methods (one-person count, two-person count, digital analysis of immunostained tissues, and digital analysis of vascular corrosion casts) were used to measure microvessel density. Results indicate that alpha6 integrin expression correlates negatively with tumor vessel density. and with tumor cell proliferation but not the extent of the tumor burden. β4 integrin expression does not appear to affect tumor vessel density, tumor cell proliferation, nor tumor burden. Comparison of methods of quantitation suggest that computer-assisted vessel counting may offer advantages over optical counting or computer-assisted area measurement.
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Marighetti, P. "RESIDUAL DORMANT CANCER STEM CELL FOCI ARE RESPONSIBLE FOR TUMOR RELAPSE AFTER ANGIOGENIC METRONOMIC THERAPY IN HEPATOCELLULAR CARCINOMA XENOGRAFTS". Doctoral thesis, Università degli Studi di Milano, 2012. http://hdl.handle.net/2434/169919.
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Hepatocellular carcinoma (HCC) is the fifth most common solid tumor and the third leading cause of cancer-related death. Current available chemotherapeutic options are not curative due in part to their resistance to conventional therapies.
We have generated orthotopic HCC mouse models in immunodeficient NOD/SCID/IL2rγ null mice by injection of AFP- and/or luciferase-expressing HCC cell lines and primary cells from patients, where tumor growth and spread can be accurately monitored in a non-invasive way. Low dose metronomic administration of cyclophosphamide (LDM-CTX) causes in this model complete regression of the tumor mass with a significant increase in survival (p<0.0001), and reduction in aberrant angiogenesis, IL-6 and TNFα (but not VEGF) levels, hyperproliferation, and alteration of normal liver parenchyma, compared to untreated animals. However, the presence of residual circulating hAFP levels suggested that some tumor cells were still present in livers of treated mice. Immunohistochemistry revealed that those cells had a hAFP+/CD13+/PCNA- phenotype, suggesting that they were dormant cancer stem cells (CSC). Indeed, off-therapy mice developed rapidly tumor growth, which was still sensitive to LDM-CTX therapy. The capacity of developing hepatoshperes in vitro was drastically reduced upon LDM-CTX treatment, which resulted in selection of CD13+ cells, showing that these cells are particularly resistant to therapy. Co-treatment of the CD13-targeting drug bestatin with LDM-CTX resulted in a dramatic reduction in tumor burden.
Therefore, our results demonstrate the therapeutic efficacy of administering LDM-CTX and targeting the residual CD13+ CSC-like population in these novel orthotopic HCC models, and strongly suggests that this therapy could be implemented in clinical trials.
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Liwschitz, Maxim [Verfasser]. "Wirkungen einer kombinierten Hemmung von Angiopoetin 2 und VEGF auf die Tumor-Angiogenese in einem Xenograft-Maus-Modell des kolonrektalen Karzinoms / Maxim Liwschitz". Köln : Deutsche Zentralbibliothek für Medizin, 2016. http://d-nb.info/1084240637/34.
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Tanaka, Kuniaki. "Direct Delivery of piggyBac CD19 CAR T Cells Has Potent Anti-tumor Activity against ALL Cells in CNS in a Xenograft Mouse Model". Kyoto University, 2021. http://hdl.handle.net/2433/261609.
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de, Sousa Emma Louise. "The use of novel xenografting methods to reveal differential gene expression between breast cancer at primary and metastatic sites". Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:20c957a8-68c7-43f1-b0f6-722ae71dfb5a.
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In developed countries, breast cancer is the commonest malignancy among women. Understanding the mechanisms involved in breast cancer progression and the influence of the microenvironment on cancer cell proliferation, results in better treatments. This study aimed to optimise breast cancer xenograft rates using a novel chamber developed for tissue engineering purposes. The established tumours were subjected to enzyme digestion, creating a single cell suspension, which was then injected into immunocompromised mice at primary, metastatic and intra-cardiac sites. The resulting tumours in the mammary fat pad (MFP) and bone were compared using species-specific reverse-transcription polymerase chain reaction (RT-PCR) and cDNA microarray, to examine the influence of the microenvironment on gene expression. The achieved xenograft graft rates of 25% were similar to those previously reported. The matrix metalloproteinase family of enzymes (MMPs) degrade extracellular matrix, influencing invasion and migration of malignant cells. RT-PCR results showed that the majority of the MMPs expressed in the cancers were stromal rather than tumour in origin. MT1-MMP, MMP-2 and MMP-11 had significantly higher expression levels in the MFP than in the bone, but MMP-9 was expressed more in the bone than MFP. There was also an up-regulation of stromal production of MT1-MMP and MMP-13 in the MFP in the presence of tumour. This may have significance when considering which MMPs are the most appropriate targets for inhibition during cancer treatment. The most significant of the differentially expressed genes on microarray analysis were trefoil factor 1 (TFF1) and insulin growth-factor binding protein 3 (IGFBP-3), both expressed significantly more in tumours from the MFP than the bone. The thesis presented demonstrates some of the complexities of tumour-stromal interactions and supports Paget’s seed-soil theory, confirming in several ways the variation in gene expression in breast cancer between primary and metastatic sites.
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Huang, Yingbo. "Intrapulmonary Inoculation of Multicellular Tumor Spheroids to Construct an Orthotopic Lung Cancer Xenograft Model that Mimics Four Clinical Stages of Non-small Cell Lung Cancer". Scholarly Commons, 2019. https://scholarlycommons.pacific.edu/uop_etds/3596.
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Lung cancer leads in mortality among all types of cancer in the US and Non-small cell lung cancer (NSCLC) is the major type of lung cancer. Immuno-compromised mice bearing xenografts of human lung cancer cells represent the most common animal models for studying lung cancer biology and for evaluating potential anticancer agents. However, orthotopic lung cancer models based on intrapulmonary injection of suspended cancer cells feature premature leakage of the cancer cells to both sides of the lung within five days, which generates a quick artifact of metastasis and thus belies the development and progression of lung cancer as seen in the clinic.
Based on intrapulmonary inoculation of multicellular spheroids (MCS), we have developed the first orthotopic xenograft model of lung cancer that simulates all four clinical stages of NSCLC progression in mice over one month: Stage 1 localized tumor at the inoculation site; Stage 2 multiple tumor nodules or larger tumor nodule on the same side of the lung; Stage 3 cancer growth on heart surface; and Stage 4 metastatic cancer on both sides of the lung. The cancer development was monitored conveniently by in vivo fluorescent imaging and validated by open-chest anatomy, ex vivo fluorescent imaging, and histological studies. The model enjoys high rates of postoperative survival (100%) and parenchymal tumor establishment (88.9%). The roughness of the inoculated MCS is associated negatively with the time needed to develop metastatic cancer (p=0.0299).
In addition, we have constructed a co-culture MCS that consisted of A549-iRFP lung cancer cells and WI38 normal human fibroblast cells. The pro-proliferation effect and the high expression of α-smooth muscle actin (α-SMA) by the co-cultured WI38 cells indicated their transformation from normal fibroblasts to cancer-associated fibroblasts (CAFs). The morphology of the co-culture MCS features a round shape, a tight internal structure, and quicker development of roughness. The large roughness value of co-culture MCS suggests that small co-culture MCS could be inoculated into mice lung with a small needle to reduce the surgical trauma.
Taken together, a new orthotopic model of NSCLC has been developed, which would facilitate future development of medications against lung cancer.
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Lamas, Bruno. "Caractérisation de l'activité fonctionnelle et métabolique des cellules NK en situation de stress nutritionnels : approche expérimentale in vitro et in vivo". Thesis, Clermont-Ferrand 1, 2012. http://www.theses.fr/2012CLF1PP02/document.
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Les cellules Natural Killer (NK), actrices majeures de la vigilance anti-tumorale, sont modulées par des facteurs nutritionnels et métaboliques. L'inhibition de leur activité favorise le développement tumoral. Un régime alimentaire hypercalorique induisant l'obésité est un facteur de risque de développer un cancer du sein. Au niveau du micro-environnement tumoral mammaire, la biodisponibilité en certaines molécules contrôle non seulement les cellules néoplasiques mais, également les cellules immunes infiltrées. Ainsi, la leptine, sécrétée à forte concentration par les adipocytes mammaires, pourrait favoriser la croissance tumorale et altérer les cellules NK. L'arginine fortement consommée par les cellules tumorales et les cellules suppresseurs dérivées des myéloïdes pourrait faire défaut aux cellules NK. L'objectif de cette thèse est de caractériser les activités fonctionnelles et métaboliques des cellules NK en situation de stress nutritionnel. Dans un premier temps, nous avons exploré, in vivo, l'impact d'un régime hypercalorique sur l'activité des cellules NK et sur le développement tumoral mammaire. Ensuite, nous avons cherché à identifier les potentielles altérations fonctionnelles des cellules NK en mimant, in vitro, les conditions retrouvées au niveau du micro-environnement tumoral telles que la présence de concentration élevée en leptine et la déplétion en arginine. Des souris Balb-c "nude" femelles ont été soumises à un régime hypercalorique (HC) versus une diète normo-calorique (NC) pendant 6 mois. Au bout de 5 mois, des cellules tumorales mammaires (MCF-7 ; groupes NCT et HCT) ou le véhicule (groupes NC et HC) ont été implantés au niveau de la quatrième paire de glandes mammaires. Sous régime HC, le développement tumoral s'accompagne d'une perte de masse grasse, de masse maigre et de poids corporel avec un volume et un poids de tumeur augmentés. Cette diète induit au niveau tumoral une sur-expression des ARNm d'enzymes impliquées dans la glycolyse et une sous-expression des acteurs du cycle de Krebs. Sous régime HC, l'expression de la caspase 3 clivée et des récepteurs des oestrogènes β et de la progestérone est réduite alors que celle du Ki67 est accrue. Les cellules NK des souris HC ont une cytotoxicité diminuée. Bien que la présence de tumeur stimule l'activité lytique des cellules NK, la cytotoxicité de ces cellules reste inférieure dans le groupe HCT comparativement à celle du groupe NCT. La leptine stimule, in vitro, de façon dose-dépendante l'activité métabolique des cellules NK. A fortes concentrations, elle active leur cytotoxicité vis-à-vis des cellules cibles MDA-MB-231. Cet effet passe par une stimulation de l'expression de TRAIL et de l'IFN-γ par les cellules NK. En revanche, vis-à-vis des cellules cibles MCF7, les cellules NK présentent une activité lytique réduite en présence de fortes concentrations de leptine, probablement en lien avec une réduction de l'expression de la perforine. En réponse à une déplétion en arginine dans le milieu de culture, la prolifération et la cytotoxicité des cellules NK sont abaissées. L'altération de la reconnaissance des cellules cibles par les récepteurs NKp46 et NKp30, la moindre transmission du signal activateur par la chaine ζ et la faible production d'IFN-γ peuvent expliquer l'inhibition de la cytotoxicité des cellules NK. Ainsi, un apport énergétique élevé favorise le développement tumoral mammaire notamment eninhibant la cytotoxicité des cellules NK. De plus, la leptine à fortes concentrations stimule ou réduit, in vitro, la cytotoxicité des cellules NK selon la nature des cellules cancéreuses mammaires cibles. Une déplétion en arginine, in vitro, quant à elle, inhibe la prolifération et la cytotoxicité des cellules NK. Ces travaux contribuent à mieux comprendre l'impact du micro-environnement sur la réponse antitumorale des cellules NKNatural killer (NK) cells are critical mediators of anti-tumor immunity. A high-calorie diet inducing obesity is associated with breast cancer development. NK cells are modulated by dietary and metabolic factors and a decrease in their lytic activity promotes mammary tumor development. In the breast microenvironment, high concentration of leptin can be secreted by mammary adipocytes and thereby could stimulate tumor growth and control immune cells. Arginine, strongly consumed by tumor and myeloid-derived suppressor cells, could be lacking to NK cells. The aim of this work is to characterize the functional and metabolic activities of NK cells in response to nutritional stress. Initially, we explored in vivo the impact of a high-calorie diet on NK cells activity and mammary tumor development. Then, we identified potential functional alterations in NK cells by mimicking the conditions found in the tumor microenvironment such as the presence of high leptin concentration and arginine depletion. Female Balb-c nude mice were fed a high-caloric diet (HC) versus a standard caloric diet (SC) for 6 months. After five months, mammary tumor cells (MCF-7, SCT, HCT) or MatrigelTM (SC, HC) were implanted into the fourth mammary fat pads. The tumor development in HC diet-fed mice was associated with a decrease in body weight, body fat and lean mass and an increase in volume and weight of tumors. This diet induced tumor over-expression, at the transcriptional level, of enzymes involved in glycolysis and a down-expression of citrate cycle actors. Protein tumor levels of cleaved caspase 3, estrogen β and progesterone receptors were reduced while Ki67 was increased in the HC diet-fed mice. NK cell cytotoxicity of HC diet-fed mice was reduced. Although the presence of tumor stimulated NK cell lytic activity, this later was lower in the HCT group compared to the one of SCT mice. In vitro, leptin stimulated, in dose-dependent manner, the metabolic activity of NK cells. High leptin concentrations enhanced NK cell cytotoxicity against the MDA-MB-231 target cells. This phenomenon involved the increase of expression of TRAIL and IFN-γ in NK cells. However, against the MCF-7 target cells, NK cell lytic activity was reduced in the presence of high concentrations of leptin, probably in link to the decreased perforin expression. NK cell proliferation and cytotoxicity were impaired in response to arginine depletion. This inhibition of NK cell cytotoxicity could be linked to a low target cells recognition by NKp46 and NKp30, a reduced activating signal transmission by ζ chain and a low production of IFN-γ. Thus, high energy intake promotes mammary tumor development in particular by inhibiting NK cell cytotoxicity. In vitro, high leptin concentrations stimulate or reduce NK cell cytotoxicity according to the breast cancer cell targets. Furthermore, arginine depletion inhibits NK cell proliferation and cytotoxicity in vitro. These findings provide insight into the microenvironment impacts on NK cell antitumor response in tumor development
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Nguyen, Hoang Duong [Verfasser], i Aladár [Akademischer Betreuer] Szalay. "Vaccinia virus mediated expression of human erythropoietin in colonized human tumor xenografts results in faster tumor regression and increased red blood cell biogenesis in mice / Hoang Duong Nguyen. Betreuer: Aladar Szalay". Würzburg : Universität Würzburg, 2012. http://d-nb.info/1102818941/34.
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Hübner, Doreen, Christiane Rieger, Ralf Bergmann, Martin Ullrich, Sebastian Meister, Marieta Toma, Ralf Wiedemuth i in. "An orthotopic xenograft model for high-risk non-muscle invasive bladder cancer in mice: influence of mouse strain, tumor cell count, dwell time and bladder pretreatment". Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2018. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-231536.
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Background
Novel theranostic options for high-risk non-muscle invasive bladder cancer are urgently needed. This requires a thorough evaluation of experimental approaches in animal models best possibly reflecting human disease before entering clinical studies. Although several bladder cancer xenograft models were used in the literature, the establishment of an orthotopic bladder cancer model in mice remains challenging.
Methods
Luciferase-transduced UM-UC-3LUCK1 bladder cancer cells were instilled transurethrally via 24G permanent venous catheters into athymic NMRI and BALB/c nude mice as well as into SCID-beige mice. Besides the mouse strain, the pretreatment of the bladder wall (trypsin or poly-L-lysine), tumor cell count (0.5 × 106–5.0 × 106) and tumor cell dwell time in the murine bladder (30 min – 2 h) were varied. Tumors were morphologically and functionally visualized using bioluminescence imaging (BLI), magnetic resonance imaging (MRI), and positron emission tomography (PET).
Results
Immunodeficiency of the mouse strains was the most important factor influencing cancer cell engraftment, whereas modifying cell count and instillation time allowed fine-tuning of the BLI signal start and duration – both representing the possible treatment period for the evaluation of new therapeutics. Best orthotopic tumor growth was achieved by transurethral instillation of 1.0 × 106 UM-UC-3LUCK1 bladder cancer cells into SCID-beige mice for 2 h after bladder pretreatment with poly-L-lysine. A pilot PET experiment using 68Ga-cetuximab as transurethrally administered radiotracer revealed functional expression of epidermal growth factor receptor as representative molecular characteristic of engrafted cancer cells in the bladder.
Conclusions
With the optimized protocol in SCID-beige mice an applicable and reliable model of high-risk non-muscle invasive bladder cancer for the development of novel theranostic approaches was established.
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Hübner, Doreen, Christiane Rieger, Ralf Bergmann, Martin Ullrich, Sebastian Meister, Marieta Toma, Ralf Wiedemuth i in. "An orthotopic xenograft model for high-risk non-muscle invasive bladder cancer in mice: influence of mouse strain, tumor cell count, dwell time and bladder pretreatment". BioMed Central, 2017. https://tud.qucosa.de/id/qucosa%3A30688.
Pełny tekst źródłaStreszczenie:
Background
Novel theranostic options for high-risk non-muscle invasive bladder cancer are urgently needed. This requires a thorough evaluation of experimental approaches in animal models best possibly reflecting human disease before entering clinical studies. Although several bladder cancer xenograft models were used in the literature, the establishment of an orthotopic bladder cancer model in mice remains challenging.
Methods
Luciferase-transduced UM-UC-3LUCK1 bladder cancer cells were instilled transurethrally via 24G permanent venous catheters into athymic NMRI and BALB/c nude mice as well as into SCID-beige mice. Besides the mouse strain, the pretreatment of the bladder wall (trypsin or poly-L-lysine), tumor cell count (0.5 × 106–5.0 × 106) and tumor cell dwell time in the murine bladder (30 min – 2 h) were varied. Tumors were morphologically and functionally visualized using bioluminescence imaging (BLI), magnetic resonance imaging (MRI), and positron emission tomography (PET).
Results
Immunodeficiency of the mouse strains was the most important factor influencing cancer cell engraftment, whereas modifying cell count and instillation time allowed fine-tuning of the BLI signal start and duration – both representing the possible treatment period for the evaluation of new therapeutics. Best orthotopic tumor growth was achieved by transurethral instillation of 1.0 × 106 UM-UC-3LUCK1 bladder cancer cells into SCID-beige mice for 2 h after bladder pretreatment with poly-L-lysine. A pilot PET experiment using 68Ga-cetuximab as transurethrally administered radiotracer revealed functional expression of epidermal growth factor receptor as representative molecular characteristic of engrafted cancer cells in the bladder.
Conclusions
With the optimized protocol in SCID-beige mice an applicable and reliable model of high-risk non-muscle invasive bladder cancer for the development of novel theranostic approaches was established.
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Leung, Hui Min. "Multimodal Imaging of Tumor Microenvironment in Murine Window Chamber Models Using Optical, Magnetic Resonance, and Nuclear Imaging Techniques". Diss., The University of Arizona, 2015. http://hdl.handle.net/10150/594543.
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Pre-clinical study of cancer often involves imaging different aspects of a tumor, ranging from visualizing sub-cellular detail to imaging of the tumor anatomy. Multimodal imaging seeks to combine imaging techniques with complementary strengths and use them to provide a more complete picture of the disease. In this dissertation work, the development of various optical, nuclear and magnetic resonance imaging (MRI) techniques applicable to the study of cancer xenografts in murine window chamber models was carried out. Two types of window chamber models were used in this work: the dorsal skinfold WC (DSFWC) model and the mammary WC (MWC) model. The MWC was specifically used to study breast cancer xenografts. In this work, optical pH imaging with a pH-sensitive fluorescent agent was used to evaluate methods to achieve tumor-specific pH modulation. Temporary tumor acidification was performed by administration of an agent that consists of glucose and meta-iodobenzylguanidine. On the other hand, re-normalization of pHₑ in acidic tumor tissue was achieved by administration of buffer solutions, such as sodium bicarbonate. A broadband reflectance spectral imaging system was developed to perform in vivo imaging of oxygen saturation in the MWC murine model. The imaging system was used to study tissue oxygenation changes in animals that receive chemotherapy. Preliminary results were obtained to evaluate the utility of the MWC murine model in imaging the spatiotemporal changes in oxygen saturation (SaO₂) as an early biomarker of response to neo-adjuvant chemotherapy. To study metabolic activity, nuclear imaging of radiolabeled fluorodeoxyglucose (18F-FDG) was carried out using a beta-imager, as well as a pre-clinical PET system. The 2D nuclear imaging capability of the beta-imager was cross-validated with the 3D PET imaging system. Anatomical and functional MRI was performed on the MWC murine model. Anatomical MRI was used to study tumor growth rates, which aid in the identification of animals that responded to chemotherapy. In addition, diffusion-weighted (DW) MRI, dynamic-contrast-enhancement (DCE) MRI, and perfusion MRI were performed to study various functional aspects of the tumor xenografts. Lastly, work was done to incorporate patient derived xenograft (PDX) tumors into the MWC murine model. As opposed to xenografts grown from cultured cancer cells, PDX tumors better recapitulate characteristics of human tumors. This new cancer model is aimed at improving the translational power of pre-clinical studies employing window chamber models.
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Devaud, Christel. "Etude in vivo du potentiel anti-tumoral des lymphocytes Tγδ Vδ2 négatifs humains dans un modèle murin". Thesis, Bordeaux 2, 2009. http://www.theses.fr/2009BOR21684/document.
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Les lymphocytes T ?d seraient des effecteurs essentiels dans la réponse immunitaire aux stress induits notamment par les infections et la tumorigénèse. Plusieurs arguments dont leur localisation intra-épithéliale mais aussi leurs capacités effectrices multiples et rapides les caractérisent comme des acteurs primordiaux dans l’immunité anti-tumorale. Mon projet de thèse consistait à examiner le potentiel anti-tumoral des lymphocytes T ?d humains, Vd2 négatifs (neg), dans un contexte in vivo, grâce à l’utilisation d’un modèle murin. Des études antérieures menées au laboratoire démontraient une expansion de lymphocytes T Vd2neg dans la circulation sanguine de transplantés rénaux développant une infection à cytomégalovirus (CMV). Des clones T Vd2neg, isolés de ces patients, présentaient une forte réactivité in vitro contre des cellules infectées par le CMV mais aussi contre des cellules tumorales notamment d’origine colique (comme la lignée HT29). Un ligand commun induit par l’infection à CMV et la transformation tumorale, reconnu par les clones T Vd2neg serait à l’origine de cette double réactivité. La première partie de mon projet s’est concentrée sur l’étude du potentiel anti-tumoral de ces clones T Vd2neg in vivo, qui comprenait leur capacité à atteindre des cellules tumorales d’origines coliques (HT29) et à les lyser. Dans un modèle de xénogreffe dans des souris immunodéficientes, nous avons démontré que les clones TVd2neg, injectés dans le péritoine (i.p) pouvaient retarder la croissance de tumeurs solides HT29 sous-cutanées. D’après nos résultats, cette inhibition du développement tumoral proviendrait d’une action précoce et spécifique des cellules T Vd2neg et impliquerait le récepteur à chimiokine CCR3. Nos données suggèrent donc que des lymphocytes T Vd2neg, réactifs contre le CMV, pourraient migrer in vivo jusqu’au site d’injection des cellules tumorales et inhiber la croissance de la tumeur probablement grâce à leur acticité cytolytique. La deuxième partie de mon projet de thèse proposait d’approfondir l’étude du rôle des lymphocytes T Vd2neg contre les tumeurs coliques. Ainsi nous avons testé, in vivo, l’implication de lymphocytes T Vd1+ humains, une population représentative des épithéliums intestinaux, dans le cancer métastatique colorectal (CMC). Nous avons développé un modèle d’implantation orthotopique de cellules tumorales HT29 dans des souris immunodéficientes, qui mime le développement du CMC chez l’homme. Des tumeurs primaires intra-caecales et des métastases pulmonaires et hépatiques se développent chez les souris. De plus, nous avons pu suivre leur croissance grâce à l’introduction de la luciférase dans les HT29 et à une technique d’imagerie in vivo en bioluminescence. Nos résultats montrent qu’un traitement continu des souris par des injections de lignée T Vd1+ en i.p inhibe le développement des tumeurs primaires et retarde l’apparition des métastases à distance. Ces données soutiennent l’implication des lymphocytes T Vd2neg dans le contrôle des CMC. De façon intéressante, elles mettent en avant une implication anti-métastatique des cellules T Vd2neg. L’ensemble de nos travaux souligne le rôle des cellules T Vd2neg dans la réponse immunitaire contre les cancers colorectaux et étaye leur potentiel d’action lors de la progression des tumeurs vers des métastases, ouvrant ainsi des perspectives pour l’utilisation de ces cellules dans les thérapies des CMCGamma delta (?d) T lymphocytes contribute to host immune competence uniquely especially during stress immune responses to infections and tumors. Because ?d T cells colonize epithelial surfaces, where they can exert rapid and pleiotropic effector functions, they are critical protagonists in anti-cancer response. During my Phd project we explored the anti-tumor potential of Vd2 negatives (neg) ?d T lymphocytes, in vivo using a mouse xenograft tumor model. A few years ago, studies in our laboratory showed an increase of peripheral blood Vd2neg ?d T lymphocytes in allograft recipients infected by cytomegalovirus (CMV). Interestingly, Vd2neg ?d T clones isolated from these patients showed a cytotoxic activity against CMV infected fibroblast in vitro. Moreover, they were able to kill colon cancer cells (HT29) in vitro, in contrast to normal epithelial cells. Cancer cell- as well as CMV infected cell- killing involved T cell receptor (TCR) engagement, independently of major histocompatibility complex (CMH) recognition, probably with a common ligand. The first part of my Phd project was undertaken to evaluate the in vivo tumor reactivity of anti-CMV Vd2neg clones, including their ability to inhibit tumor growth as well as their migratory potential toward colon cancer cells. In immunodeficient mice, we showed that systemic intraperitoneal (i.p) injections with human Vd2neg clones inhibited the growth of HT29 hypodermal tumors xenografts. Furthermore, our results demonstrated that Vd2neg T cells had an early and specific anti-tumor effect, and that such activity could be hampered in vivo using an anti-CCR3 antibody. Our study suggest that Vd2neg T cells with an anti-viral potential are able to reach a tumor site in vivo, and inhibit tumoral growth exercising a cytolytic activity. The second part of my Phd project proposed to get further insights on the role of Vd2neg T cells in the immune surveillance against colon cancer. To this aim, we tested, the involvement of human Vd1+ T lymphocytes, a substantial fraction of T cells in intestinal epithelia, in limiting tumor spread in vivo, using a mouse model of colorectal carcinoma (CRC). We sat up a physiological mouse model of CRC by orthotopic microinjection of HT29 colon cell, which mimics the natural history of human CRC. Indeed, primary colic tumors and pulmonary and hepatic distant metastases grew in mice. Furthermore, bioluminescence imaging was used to follow the outcome of luciferase expressing cancer cells. We showed that systemic treatment with human Vd1+ T lymphocytes could inhibit the growth of intracaecal HT29 tumors and led a substantial reduction of distant metastases. Our results are the first arguing for a crucial role of ?d T cells against CRC, specially in preventing the dissemination of colon cancer cells. Taken together, our results underline the role of of ?d T cells in theimmune response against colorectal cancer. Our findings put forward Vd2neg T cells as attractive candidates for novel anti-tumor immunotherapy protocols
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Pereira, Carolina Ruivo 1986. "Genomic profile of tumorgrafts identifies B2M as a novel tumor suppressor gene in lung cancer". Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/482055.
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El cáncer de pulmón es la forma más mortal de cáncer en el mundo. Recientemente, el estudio del perfil genómico a larga escala de tumores humanos ha impulsado el desarrollo de drogas que tienen como diana terapéutica genes alterados. Dado que las terapias dirigidas son escasas, el descubrimiento de nuevos genes implicados en cáncer de pulmón con relevancia clínica es crucial.
Por eso, este proyecto tuvo como base la secuenciación de exomas y transcriptomas de xenotransplantes de pulmón. La pureza tumoral alcanzada durante el injerto fue fundamental, sobre todo para identificar delecciones homocigóticas y amplificaciones génicas. El gen B2M (β2-microglobulina), encontrado inactivado en 5% de los tumores pulmonares, se caracterizó. Su pérdida genética se correlacionó con bajos niveles de infiltración intratumoral por linfocitos T citotóxicos. Además, la β2-microglobulina se asoció a supervivencia en pacientes tratados con agentes anti-PD1/PD-L1, evidenciando su rol potencial el predecir respuestas a inmunoterapias en neoplasias pulmonares.Lung cancer is the deadliest form of cancer worldwide. Recently, the large-scale genomic profiling of human tumors has fueled the development of efficient anticancer agents that target the activity of mutated genes. Given that directed therapies are still very scarce, the discovery of novel lung cancer-related genes with potential relevance within the clinical context is imperative. Thus, this project consisted on coupling high-throughput sequencing strategies (exomes and transcriptomes) with the use of lung tumorgrafts. The high tumor purity achieved through the engraftment was crucial, particularly to identify homozygous deletions and gene amplifications. The B2M gene (β2-microglobulin), found to be mutated in 5% of lung tumors, was characterized. Its genetic loss was correlated to lower cytotoxic T-cell intratumoral infiltration, probably impairing the immune-mediated tumor eradication. Moreover, β2-microglobulin was associated with survival in patients treated with anti-PD-1/PD-L1 agents, highlighting a potential role in predicting response to immunologically-based therapies in lung cancer.
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Djidja, M.-C., S. Francese, Paul M. Loadman, Chris W. Sutton, P. Scriven, E. Claude, M. F. Snel, J. Franck, M. Salzet i M. R. Clench. "Detergent addition to trypsin digest and Ion Mobility Separation prior to MS/MS improves peptide yield and Protein Identification for in situ Proteomic Investigation of Frozen and FFPE Adenocarcinoma tissue sections". Wiley, 2009. http://hdl.handle.net/10454/4565.
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noThe identification of proteins involved in tumour progression or which permit enhanced or novel therapeutic targeting is essential for cancer research. Direct MALDI analysis of tissue sections is rapidly demonstrating its potential for protein imaging and profiling in the investigation of a range of disease states including cancer. MALDI-mass spectrometry imaging (MALDI-MSI) has been used here for direct visualisation and in situ characterisation of proteins in breast tumour tissue section samples. Frozen MCF7 breast tumour xenograft and human formalin-fixed paraffin-embedded breast cancer tissue sections were used. An improved protocol for on-tissue trypsin digestion is described incorporating the use of a detergent, which increases the yield of tryptic peptides for both fresh frozen and formalin-fixed paraffin-embedded tumour tissue sections. A novel approach combining MALDI-MSI and ion mobility separation MALDI-tandem mass spectrometry imaging for improving the detection of low-abundance proteins that are difficult to detect by direct MALDI-MSI analysis is described. In situ protein identification was carried out directly from the tissue section by MALDI-MSI. Numerous protein signals were detected and some proteins including histone H3, H4 and Grp75 that were abundant in the tumour region were identified
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Melocchi, V. "A NOVEL APPROACH FOR THE IDENTIFICATION OF CANDIDATE DRIVER LESIONS IN BREAST CANCER BASED ON THE COMPARISON OF THE MUTATIONAL PROFILES OF A PRIMARY TUMOUR AND ITS MATCHED MAMMOSPHERES AND XENOGRAFT". Doctoral thesis, Università degli Studi di Milano, 2017. http://hdl.handle.net/2434/468649.
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The clinical management of breast cancer patients is complicated by the high genetic heterogeneity of this disease, which makes the standardization of treatments, the prediction of prognosis and therapy response, and the development of personalized therapies difficult. Nevertheless, the advent of high-throughput genomics screenings based on microarray or next-generation sequencing (NGS) technologies has greatly enhanced our understanding of the genomic landscapes underlying breast cancer development and progression. Such discoveries are now allowing clinicians to tailor therapies based on the molecular subtype of the tumour (luminal, basal and HER2).
NGS studies have also started to provide insights into the range of molecular profiles of tumour cells from the same tumour, and have shown that in some breast cancers a high level of intratumoral genetic heterogeneity exists. The findings from these studies support a scenario in which breast tumours can be either: i) monogenomic, comprised of a single clonal cell population; ii) or polygenomic, composed of several related clonal subpopulations. The co-existence of different cancer driver genetic lesions in polygenomic tumours might contribute to treatment failure in some cases, as relapse could be driven by the expansion of a subpopulation of cells intrinsically resistant to the therapy. Importantly, cancer genetic heterogeneity has been recapitulated in experimental settings using cancer stem cells (CSCs) xenografted in mouse models.
We hypothesized that the mutational events that drive the onset and progression of breast tumours lie within the CSC compartment. To explore this possibility, we analysed and compared the mutational profiles of a primary breast tumour and its matched mammospheres (source of CSC-derived population), patient-derived xenograft (PDX) and PDX-derived mammospheres using Whole Exome Sequencing (WES).
We setup a NGS approach to look for rare mutations in the primary tumour that may be present in the CSC compartment using low amounts of DNA input. We optimised an experimental protocol in which the genomic DNA (gDNA) of each sample was subjected to Whole Genome Amplification (WGA) prior to performing WES. This enabled us to obtain a sufficient amount of DNA (≥ 3 μg) to perform WES. We also introduced a filtering step in our analysis, based on the Xenome software, for PDX-derived samples to eliminate possible contamination from murine DNA.
Our study allowed us to characterize the genetic profiles of CSCs and to identify cancer-relevant mutations that could drive breast cancer onset and progression. We identified 15 candidate driver mutations in 11 genes that were enriched, in terms of mutation frequency, within primary tumour-derived mammospheres and the PDX. Together with these mutations, we identified 4 mutations in 4 genes, not enriched, but shared among all analysed samples, which likely represent “founder” mutations.
Based on our results, we will now endeavour to determine the clinical relevance of the candidate driver mutations identified in our study by determining their prevalence in independent patient cohorts. Having optimised the protocol for NGS of matched primary tumour, PDX and mammosphere populations, we will also extend our mutational analysis to additional breast tumours for the identification of more driver mutations and for the deconvolution of intratumoral genetic heterogeneity of breast cancer.
Understanding the driving mutational forces of breast tumours and relative mechanisms involved is paramount for the development of more effective therapeutic strategies.
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Vallerand, David. "Etude du stroma de tumeurs mammaires humaines xénogreffées et de modèles transgéniques murins". Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T001.
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La progression tumorale est un processus multi-étapes dépendant notamment des interactions entre les cellules cancéreuses et le stroma environnant. Le développement du cancer du sein implique une communication étroite entre les cellules épithéliales mammaires, les cellules inflammatoires, les myofibroblastes et les cellules endothéliales. Ainsi, le microenvironnement tumoral apparaît comme une cible de choix dans le traitement anti-tumoral. L’utilisation de modèles précliniques est une étape clé dans le développement et la validation de nouvelles thérapies. Néanmoins, peu d’études sont disponibles sur le rôle du stroma péri-tumoral dans ces modèles.Dans le but d’étudier le stroma péri-tumoral des modèles précliniques de cancers du sein, nous avons combiné une analyse par cytométrie en flux à une analyse par immunohistochimie afin d’identifier, puis de quantifier, les différentes populations stromales hématopoïétiques (lymphocytes, monocytes/macrophages, polynucléaires) et non hématopoïétiques (myofibroblastes, cellules endothéliales). Vingt et un modèles de xénogreffe de tumeurs humaines de cancers du sein ainsi que 2 modèles transgéniques (MMTV-PyMT et MMTV-ErbB2), ainsi que leurs allogreffes respectives, furent utilisés lors de ce travail.Les analyses des tumeurs humaines et murines ont montré un infiltrat stromal très hétérogène d’une tumeur à l’autre, avec pour composante majoritaire les macrophages. Un infiltrat important en polynucléaires a également été détecté dans les modèles de PDX, caractéristique d’une inflammation locale importante dans ces modèles. L’analyse phénotypique de macrophages a montré une expression variable de marqueurs M1 et M2 dans les modèles de PDX. Les macrophages issus de tumeurs murines transgéniques, spontanées ou allogreffées, présentaient quant à eux un profil majoritairement M1. L’étude transcriptomique de macrophages triés, a permis à la fois de valider les résultats obtenus au niveau protéique mais a également mis en évidence des différences majeures dans l’expression de nombreux gènes, impliqués dans des voies de signalisation variées telles que la croissance tumorale, l’invasion et la métastase.Cette étude nous a permis de mettre en évidence le rôle de la tumeur sur son microenvironnement. En effet, celle-ci est à la fois capable d’attirer un panel de cellules stromales qui lui et propre et ensuite de l’activer de façon spécifiqueTumor development is a multi-step process influencing by interactions between tumor cells and surrounding stroma. Breast cancer development involves a high level of communication between mammary epithelial cells, inflammatory cells, myofibroblasts and endothelial cells. So, the tumoral microenvironment appears as a prime target for anti-tumoral treatment. The use of preclinical models is a critical step in development and validation processes of new therapies. Nevertheless, the role of stroma in these models is poorly understood.In order to evaluate stromal cell populations in breast cancer preclinical models, we combined flow cytometry analysis and immunohistochemistry to identify, and then quantify, various stromal populations as hematopoietic cells (lymphocytes, monocytes/macrophages, polymorphonuclear leukocytes) and non-hematopoietic cells (myofibroblasts, endothelial cells). Twenty-one breast cancer patient-derived xenografts as well as 2 transgenic mouse models (MMTV-PyMT and MMTV-ErbB2), and their respective allografts, were studied.Analysis of human and murine tumors showed a strong heterogeneity between tumors regarding infiltrating stroma-cells, with a high proportion of macrophages. A significant amount of polymorphonuclear leukocytes was also detected in PDXs, indicating a local inflammation in these models. The phenotypic analysis of macrophages showed a variable expression of M1 and M2 markers in PDXs. Macrophages infiltrating transgenic mouse tumors, spontaneous or allografted, were mainly M1. Transcriptomic analyses of sorted macrophages, allowed us to validate previous results but also highlighted major differences in the expression of numerous genes implicated in various pathways as tumor growth, invasion and metastasis.Finally, this study highlighted the impact of tumor cells on their surrounding stroma. Indeed, we demonstrate that cancer cells are able to attract a specific panel of stromal cells and activate them in a specific way
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Dobosz, Michael [Verfasser], Vasilis [Akademischer Betreuer] Ntziachristos i Hans-Jürgen [Akademischer Betreuer] Wester. "The application of in vivo and ex vivo multispectral epi-fluorescence imaging for the preclinical discovery and development of monoclonal antibodies in tumor xenograft models / Michael Dobosz. Betreuer: Vasilis Ntziachristos. Gutachter: Hans-Jürgen Wester ; Vasilis Ntziachristos". München : Universitätsbibliothek der TU München, 2014. http://d-nb.info/1080903682/34.
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Dobosz, Michael Verfasser], Vasilis [Akademischer Betreuer] Ntziachristos i Hans-Jürgen [Akademischer Betreuer] [Wester. "The application of in vivo and ex vivo multispectral epi-fluorescence imaging for the preclinical discovery and development of monoclonal antibodies in tumor xenograft models / Michael Dobosz. Betreuer: Vasilis Ntziachristos. Gutachter: Hans-Jürgen Wester ; Vasilis Ntziachristos". München : Universitätsbibliothek der TU München, 2014. http://d-nb.info/1080903682/34.
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Göhrig, Andreas. "The role of the axon guidance molecule Slit2 in pancreatic cancer". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2015. http://dx.doi.org/10.18452/17202.
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Lokale Invasion und Ausbreitung von Tumorzellen entlang von Nerven und Gefäßen limitieren den Erfolg kurativer Therapien von Patienten mit Pankreaskarzinom (PDAC). Der axon guidance Faktor Slit2 und seine Robo-Rezeptoren steuern die Navigation von Nerven und Gefäßen sowie die Motilität von Epithelzellen. Sie stellen somit attraktive Regulatoren der klinisch bedeutsamen Ausbreitungswege des PDAC dar. Zielsetzung der vorgelegten Arbeit war die Charakterisierung der Expression von Slit2 im PDAC und seiner Funktion für Tumorwachstum und -ausbreitung. Quantitative Analysen belegten eine deutliche Reduktion der Slit2 mRNA Expression in humanen PDAC Proben im Vergleich zu gesundem Gewebe. Zudem korrelierten Slit2 mRNA-Werte unterhalb des Medians mit einer höheren Inzidenz lymphatischer Metastasierung und einem gesteigerten Prozentsatz befallener Lymphknoten. Die Slit2-Rezeptoren Robo1 und 4 wiesen hingegen vergleichbare Immunreaktivität im Tumor und gesundem Gewebe auf, wobei eine differentielle Lokalisation in Epithelien, Nerven und Gefäßen zu beobachten war. Die Re-Expression von Slit2 in Slit2-defizienten Zelllinien führte zu einer Hemmung der gerichteten Migration und Invasion. Der Robo1-Rezeptor knockdown hingegen stimulierte die Motilität von Tumorzellen mit endogener Slit2 Expression. Slit2-konditioniertes Medium aus Tumorzellen hemmte die Lamellipodienbildung und die Migration von Endothelzellen. In orthotopen humanen Xenograft-Modellen und einem murinen, syngenen Tumormodell reduzierte die Re-Expression von Slit2 in PDAC Zellen Tumorwachstum, Invasion, Metastasierung und Angiogenese. Zudem verminderte die Induktion von Slit2 in PDAC Zellen deren gerichtete Migration entlang aussprießender Neuriten in einem ex vivo Model. Die vorliegenden Daten weisen Slit2 die Funktion eines Tumorsuppressors im duktalen Pankreaskarzinom zu. Ein Verlust der Slit2-Robo Aktivität könnte somit Metastasierung und neuronale Invasion fördern und einen aggressiveren Phänotyp begünstigen.Early dissemination of pancreatic ductal adenocarcinoma (PDAC) via vascular routes and neural invasion limits curative therapy, suggesting a central role for the interaction of tumor cells with blood vessels and nerves in the tumor stroma. Slit2 and its Robo receptors constitute a system of guidance cues that function in axon guidance, angiogenesis and epithelial morphogenesis, respectively. Here, we studied the expression of Slit2 in PDAC and its function for tumor growth and dissemination. Slit2 mRNA expression was reduced in specimens of human PDAC as compared to non-transformed pancreas and low Slit2 mRNA expression correlated with a higher incidence and a higher extent of lymphatic metastasis. In contrast, the Slit2 receptors Robo1 and Robo4 were uniformly present in clinical samples of PDAC and healthy pancreas and displayed differential localization on epithelial tumor cells, nerves and tumor vasculature. Stable or inducible re-expression of Slit2 in Slit2-deficient PDAC cell lines inhibited directed migration and invasion. Conversely, Robo1-knockdown stimulated the motility of PDAC cells with endogenous Slit2 expression. Tumor cell derived Slit2, furthermore, suppressed lamellipodia formation and migration of primary endothelial cells. In vivo studies in orthotopic human xenograft and mouse syngeneic pancreatic cancer models revealed that re-expression of Slit2 in PDAC cells inhibited tumor growth, invasion, metastasis and angiogenesis. In addition, induction of Slit2 in PDAC cells impaired the unidirectional migration along outgrowing neurites in ex vivo co-cultures of tumor cells and dorsal root ganglia. These data provide evidence for a functional role of Slit2 as a tumor suppressor in human PDAC. A loss of Slit2-Robo activity as observed in human PDAC samples, might consequently promote metastasis and neural invasion and favors a more aggressive phenotype.
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Nguyen, Phu Hung. "Caractérisation et ciblage des cellules souches cancéreuses dans l’adénocarcinome gastrique". Thesis, Bordeaux, 2015. http://www.theses.fr/2015BORD0052/document.
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Les cellules souches cancéreuses (CSC) représentent une sous-population de cellules tumorales à l’origine de l’hétérogénéité et de la croissance tumorale. Les CSC sont plus résistantes aux traitements, et à l’origine de la rechute et des métastases. L’identification des CSC constitue actuellement un enjeu majeur dans le développement de nouvelles thérapies ciblées pour inhiber la croissance tumorale et éradiquer le cancer. Dans ce travail, nous avons cherché à identifier, caractériser, et cibler les CSC dans l’adénocarcinome gastrique. Des modèles murins de xénogreffe de tumeurs primaires de patients atteints d'adénocarcinome gastrique hors cardia de types intestinal et diffus ont été développés, ainsi qu’un modèle de tumorsphere in vitro afin d’évaluer les capacités tumorigéniques de sous-populations tumorales. Nous avons identifié CD44 et l'aldéhyde déshydrogénase (ALDH) comme marqueurs d’enrichissement des CSC dans les 2 types d’adénocarcinomes gastriques, l’ALDH représentant un marqueur plus spécifique que CD44. Nous avons ensuite étudié l'effet de l’acide rétinoïque tout trans (ATRA), et nous avons montré que l'ATRA inhibe la formation et la croissance des tumorspheres in vitro ainsi que la croissance tumorale in vivo. Cet effet de l’ATRA passe par l’inhibition de l’expression des marqueurs souches et des capacités d'auto-renouvèlement des CSC. En conclusion, CD44 et ALDH sont des marqueurs de CSC dans les adénocarcinomes gastriques hors cardia de types intestinal et diffus, et le traitement par l’ATRA constituerait une stratégie commune de traitement pour cibler spécifiquement les CSC et inhiber la croissance tumorale dans ces deux types de cancer gastriqueCancer stem cells (CSCs) are a subpopulation of tumor cells at the origin of the heterogeneity and growth of tumors. CSCs are more resistant to treatment, and are responsible for relapse and metastasis. The identification of CSCs is a major challenge for the development of new targeted therapies to inhibit tumor growth and eradicate cancer. In this work, we aimed to identify, characterize, and target CSCs in gastric adenocarcinoma. Mouse models of primary tumor xenografts from intestinal and diffuse type non-cardia gastric adenocarcinomas from patients were developed, as well as an in vitro tumorsphere assay, to assess the tumorigenic capacity of subpopulations of tumor cells. We identified CD44 and aldehyde dehydrogenase (ALDH) as CSC enrichment markers in the two types of gastric adenocarcinoma, ALDH representing a more specific marker than CD44. We then studied the effect of All-trans retinoic acid (ATRA), and showed that it inhibited the formation and growth of tumorspheres in vitro and tumor growth in vivo. This effect of ATRA is due to the inhibition of stem marker expression and the self-renewal capacity of CSCs. In conclusion, CD44 and ALDH are effective CSC markers in intestinal and diffuse type non-cardia gastric adenocarcinomas, and treatment with ATRA provides a common treatment strategy to specifically target CSCs and inhibit tumor growth in both subtypes of this gastric cancer
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Prudent, Renaud. "Identification et caractérisation d’inhibiteur de la protéine-kinase CK2". Grenoble 1, 2009. http://www.theses.fr/2009GRE10260.
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De nombreuses observations établissent un lien entre la dérégulation de la protéine kinase CK2 et certains cancers. Une activité élevée de CK2 dans certains cancers est un marqueur de mauvais pronostique. CK2 favorise la progression tumorale en régulant de nombreux oncogènes et suppresseur de tumeurs, ainsi qu’en protégeant des protéines anti-apoptotiques du clivage par les caspases. En conséquence, CK2 a émergé comme une cible thérapeutique et son inhibition pharmacologique représente une stratégie prometteuse. A l’instar d’autres protéine-kinases, des inhibiteurs ATP-compétitifs de CK2 ont déjà été identifié. Cependant, leur efficacité est variable, ce qui a conduit au développement de stratégies alternatives pour inhiber cette enzyme multi-protéique. Par criblage de chimiothèques à l’aide de CK2a recombinante, j’ai identifié des composés ciblant le site de fixation de l’ATP de la kinase ou un exosite. Ces composés ont été caractérisé structuralement par radiocristallographie aux rayons X ou par diffusion de rayons X aux petits angles (SAXS). Ces composés ont également été testés dans un test rapporteur de l’activité CK2 cellulaire. Certains inhibiteurs sont actifs sur CK2 dans des cellules vivantes. Deux composés (un ATP-compétitif et un allostérique) démontrent une activité anti-tumorale dans des tests de régression de xénogreffes tumorales dans des modèles murins. Ainsi, ces travaux ont conduit à l’identification des premiers inhibiteurs allostériques de CK2. Ceci montre que cibler CK2 hors du site de fixation de l’ATP est une alternative viable qui permettra d’exploiter de nouveaux mécanismes d’action et d’envisager de nouvelles opportunités thérapeutiquesExperimental evidence supports the view that disregulated Protein kinase CK2 is linked to cancers. Elevated CK2 activity in human cancer is an unfavorable prognostic marker. CK2 enhances progression of oncogenesis by regulating various oncogenes, tumor suppressor proteins and protecting anti-apoptotic proteins from caspase-mediated cleavage. Consequently, CK2 has emerged as a therapeutic target and its pharmacological inhibition appears as a promising strategy. Similar to other protein kinases, numerous ATP competitive inhibitors have been identified. However, they display variable effectiveness. Recently, alternative strategies to inhibit this multi-subunit enzyme have been revealed. Screening of chemical libraries using recombinant CK2a could identify compounds that target either the ATP binding site or exosites. These compounds were structurally characterized by analyzing CK2a-inhibitor complexes by means of X-ray structure crystallography or Small-Angle X-ray Scattering (SAXS). These compounds were also evaluated in a novel CK2 cellular activity assay. Several chemically unrelated inhibitors were found to be potent CK2 inhibitor in living cells. Two compounds (ATP-competitive and allosteric, respectively) showed anti-tumor activity, when tested in murine tumor xenograft regression assays. Taken together, this work leads to the identification of the first allosteric inhibitors of CK2, highlighting a new mode of inhibition of CK2. It also demonstrates that targeting an exosite on CK2 is a viable alternative to ATP-competitive inhibitors. This promises new opportunities by exploiting these new mechanisms of action
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Colombo, Pierre-Emmanuel. "Nouveaux vecteurs polymères et modèles expérimentaux en vue de la délivrance intrapéritonéale prolongée d’agents anti tumoraux dans le traitement des cancers de l’ovaire". Thesis, Montpellier 1, 2012. http://www.theses.fr/2012MON1T003.
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Le cancer de l'ovaire est la première cause de décès par cancer gynécologique. Cette thèse avait pour objectif la prospection de nouvelles solutions thérapeutiques fondées sur la délivrance prolongée d'agents anti tumoraux à l'aide de systèmes macromoléculaires de synthèse. L'un des obstacles majeurs était la disposition d'un modèle de tumeur pertinent chez l'animal. Après un examen bibliographique des connaissances acquises, le deuxième chapitre examine le potentiel d'un panel de xénogreffes dérivées de tumeurs ovariennes humaines directement greffées chez la souris immunodéprimée. Il est montré que les principales caractéristiques phénotypiques et moléculaires des tumeurs originales sont maintenues au niveau des greffes. Les résultats traduisent la présence d'une hétérogénéité intra-tumorale et d'une oligoclonalité au niveau des tumeurs primaires. L'ensemble confirme l'importance du choix du modèle tumoral pour l'évaluation de nouveaux traitements et l'étude des mécanismes aboutissant aux rechutes de la maladie et au développement d'une chimiorésistance. Un troisième chapitre traite l'exemple d'un système de délivrance prolongée fondé sur le couplage d'un agent antitumoral modèle, la doxorubicine, associé de diverses manières à un vecteur macromoléculaire biorésorbable, le poly(L-lysine citramide). Le premier conjugué obtenu par couplage direct sur le vecteur étant trop stable, divers systèmes ont été conçus pour obtenir la libération souhaitée. L'utilisation d'un bras espaceur clivable de type ester-hydrazone a fourni le meilleur résultat. Pour pallier la complexité de ces conjugués, une stratégie innovante fondée sur le piégeage de la doxorubicine dans une gélatine artificielle à base de poly(N-acryloyl glycinamide) est prospectée qui devrait permettre l'utilisation simultanée de plusieurs principes actifs piégés temporairement par voie physique dans un gel adhésif et fournir des solutions mieux adaptées aux contraintes cliniques des traitements intrapéritonéauxOvarian carcinoma is the most lethal gynecologic malignancy. The aim of this PhD thesis was to develop new therapeutic approaches based on novel synthetic macromolecular drug delivery systems for intraperitoneal chemotherapy. These objectives were limited by the requirement of reliable tumor models for experimental studies. After a concise review of knowledge published in the literature, the potential interest of the establishment of a collection of tumor grafts derived from samples of human tumors is examined in a second chapter. Data show that the major phenotypic and genotypic features of the original tumors are maintained in the xenografts. They also confirm the importance of this tumor model to test new drugs and to analyze intratumoral heterogeneity and oligoclonality in primary ovarian carcinoma. The collection will be also helpful to study the mechanisms leading to disease recurrences and resistance to chemotherapies. An example of drug delivery system based on the different associations of a model chemotherapeutic drug (doxorubicin) with a bioresorbable macromolecular vector, namely poly(L-lysine citramide), is addressed in a third chapter. Direct amid linkage in the first conjugate was too stable with respect to antitumoral cytotoxicity desired after in vivo administration and different systems were generated subsequently to increase drug release in tumor deposits. The best results were obtained with a hydrazone cleavable spacer containing an ester group. To overcome the complexity of these conjugates, a novel strategy based on doxorubicin entrapment in a synthetic gelatin made of (poly(N-acryloyl glycinamide) is developed. This strategy should allow physical temporary entrapment of different drug molecules in a adhesive gel and could provide new solutions to the therapeutic challenges of intraperitoneal administration
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Coussy, Florence. "Identification de nouvelles thérapeutiques ciblées dans le cancer du sein à l’aide d’un large panel de tumeurs humaines xénogreffées". Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS560.
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Le cancer du sein triple négatif (CSTN) représente 10-15% des cancers du sein. Son pronostic est sombre en particulier face à la rareté des thérapies ciblées adaptées à ce sous type. Sa complexité de prise en charge est directement liée à sa grande hétérogénéité tant au niveau moléculaire que morphologique.Dans ce contexte, nous avons développés des modèles de Patient Derived Xenograft (PDX) issus de CSTN. Ce modèle, robuste, a la particularité de retenir les caractéristiques (histologiques, génotypiques mais aussi phénotypiques) des tumeurs observées chez les patients.Dans notre cohorte de 61 PDX de CSTN, nous avons confirmé l’hétérogénéité anatomopathologique et génomique de ce sous type. Les différentes anomalies moléculaires mises en évidence sont de faible fréquence (<10%) mais 88% de nos modèles ont une altération potentiellement ciblables et plus de la moitié ont au moins 2 altérations ciblables. Nous nous sommes particulièrement intéressés à 2 sous types de CSTN : (i) le sous -type LAR (Luminal Androgen Receptor) dont nous avons décrit les premiers modèles de PDX : ces modèles présentent des altérations fréquentes de la voie PI3K ainsi que des réponses majeures aux inhibiteurs de cette voie ; (ii) le sous type métaplasique, dont 4 de nos 9 modèles présentent une double altération genomique dans les voies PI3K et RTK-MAPK ainsi que des réponses complètes et durables à la combinaison d’inhibiteurs de PI3K et de MAPK.Dans les autres sous-types de CSTN, nous avons également mis en évidence des taux de réponse importants aux inhibiteurs de la voie PI3K et MAPK. Les biomarqueurs de réponse à ces différentes thérapies ciblées testées sont en cours d’étude en particulier par intégration des données génomique et protéique de nos modèlesTriple negative breast cancer (TNBC) accounts for 10-15% of breast cancers. Its prognosis is worse, particularly due to the rarity of targeted therapies adapted to this subtype. Its complexity of management is directly related to its high heterogeneity, both at the morphological and genomical levels.In this context, we developed Patient Derived Xenograft (PDX) models from TNBC. This robust model has the specificity of retaining the characteristics (histological, genotypic but also phenotypic) of the tumors observed in patients.In our cohort of 61 PDXs of TNBC, we confirmed the anatomopathological and genomical heterogeneity of this subtype. Majority of targeted alterations are of low frequency (<10%) but 88% of our models harbour a potential targetable alteration and more than half have at least 2 targetable alterations. We were particularly interested in 2 subtypes of TNBC: (i) the LAR subtype for which we have described the first PDX models: these models present frequent alterations of the PI3K pathway as well as major responses to PI3K inhibitors; (ii) the metaplastic subtype, of which 4 of our 9 models show double alterations in the PI3K and RTK-MAPK pathways and complete and durable responses to the combination of PI3K-MAPK inhibitors.In the other CSTN subtypes, we have also demonstrated significant response rates to PI3K and MAPK inhibitors. Biomarkers of response to these various targeted therapies tested are being studied, in particular by integrating the genomic and protein data from a higher number of PDX models
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Hoffmann, Corinna. "Vorklinische Untersuchungen zur Wirkung einer Tumorvakzine in der Therapie Human Papillomvirus-assoziierter Tumorerkrankungen". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2012. http://dx.doi.org/10.18452/16558.
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Neuartige Vakzinierungsstrategien zur Aktivierung einer Tumor-spezifischen zellulären Immunantwort sind vielversprechende Ansätze zur Therapie von Tumoren, insbesondere Human Papillomvirus (HPV)-assoziierte Tumore. Bisherige HPV-Impfstudien zeigen zwar die Aktivierung einer spezifischen zellulären Immunantwort, eine Tumorreduktion bleibt jedoch aus. Um diesen Effekt auf Immunzellebene zu definieren, wurde die Wirkung der HPV-Vakzine Ad p14 im Mausmodell und an Untersuchungsmaterial humaner Tumore analysiert. In Mäusen bildeten sich HPV+ TC1-Tumore einer frühen Entwicklungsphase nach Vakzinierung zurück. Tumore einer späten Entwicklungsphase wuchsen dagegen in zwei Intervallen aus. Immunologische Eigenschaften der Tumorzellen blieben dabei unverändert. Unterschiede zeigten sich in den Frequenzen Tumor-infiltrierender Lymphozyten; in progressiven Phasen wurden nur CD4+ T Zellen nachgewiesen, in Regressionsphasen zusätzlich zytotoxische CD8+ T Zellen. Immunmodulatoren, wie Interferon alpha oder DTA-1, einem Antikörper für den Glucocorticoid-induzierten Tumornekrosefaktor-Rezeptor, unterstützten die Wirkung der Vakzine; letzterer erhöhte die Anzahl zytotoxischer CD8+ T Zellen und führte zur Abstoßung der TC1-Tumore. HPV+ Tumorgewebe des Menschen, wie auch ihre Vorstufen, zeigten im Vergleich zu anderen Tumoren, wie Bronchial oder Kolonkarzinomen einen signifikant höheren Anteil an CD4+ und CD8+ T Zellen und an Forkhead Box P3+ regulatorischen T Zellen. Die Ergebnisse deuten darauf hin, dass die immunologischen Abläufe bei der Entwicklung HPV-assoziierter Tumore mit denen vorangeschrittener chronischer Erkrankungen vergleichbar sind, in denen sich CD4+ und CD8+ T Zellantworten erschöpfen während sich gleichzeitig immunsuppressive Mechanismen verstärken. Um die Entwicklung von Impfstoffen zur Therapie HPV-assoziierter Tumore zu verbessern sollten diese Mechanismen ausführlicher betrachtet werden.Novel vaccination strategies, activating cellular tumour specific immune responses represent a promising approach for the treatment of cancer. Especially featured for these treatments are tumours evolving from chronic human papillomavirus (HPV) infections. But current strategies have not yet proved efficacious for complete tumour regression. Addressing cellular immunological aspects of tumour vaccination, this work focused on effects of HPV vaccine Ad p14 in mice and in samples of human tumours. In mice vaccination resulted in complete regression of early stage murine HPV+ TC1 tumours. Late stage TC1 tumours increased discontinuously. During that process, TC1 cells preserved their immunological characteristics. But frequencies of tumour-infiltrating lymphocytes varied; in progressing tumours only CD4+ T cells occurred, in temporary regressing tumours also CD8+ T cells were detected. Immune modulators, like interferon alpha or glucocorticoid-induced tumour necrosis factor receptor targeting antibody DTA-1 aggravated the effects of vaccination; latter raised cytotoxic CD8+ T cell numbers and resulted in complete tumour regression. Human HPV+ tumours as well as HPV+ precancerous stages revealed numbers of CD4+ and CD8+ T cells and especially of forkhead box P3+ regulatory T cells that were significantly increased compared to melanoma, bronchial or colon carcinoma. To assist further analysis of human HPV-associated cervical cancer and facilitate studies on therapeutic approaches, a humanized mouse model was established. The present work points to immunological exhaustion in the development of HPV-related tumours comparable to chronic diseases where CD4+ and CD8+ T cells exhaust and immunosuppression by regulatory T cells increases at the same time. For the development of appropriate strategies to enhance efficacy in HPV-associated tumour therapy, further knowledge of mechanisms involved in specific T cell activation, T cell exhaustion and immunosuppression is necessary.
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Halvorsen, Stefan. "Large-scale single-cell transcriptomics of osteosarcoma reveals extensive and different heterogeneity in primary tumors versus murine xenograft model". Thesis, 2016. https://hdl.handle.net/2144/17001.
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Heterogeneity within tumors has long been studied as a potential confounding factor for effective therapies, with recent studies pointing to heterogeneity resulting in distinct clonal subtypes, each with varying degrees of fitness and metastatic potential. Studies of heterogeneity have previously been limited to microscopy observations, immunohistochemistry, and flow cytometry. Recently, however, it has become possible to examine heterogeneity at a previously unexplored level: the transcriptome of individual cells.
Osteosarcomas have been known to be highly heterogeneous, so we have selected osteosarcoma as our primary tumor to study as a proof-of-concept. Additionally, we have elected to create a murine patient derived xenograft (PDX) model from a primary osteosarcoma tumor and examine differences between the primary tumor and resulting xenograft at the single-cell level. Through this, we hope to better understand tumor heterogeneity and add to the current discussion in the scientific community regarding the relevance of PDX models for testing promising new therapies and personalized medicine.
Through our examination of single-cell heterogeneity in osteosarcomas, we have confirmed the extensive heterogeneity previously reported, but this time at the level of mRNA. The osteosarcomas were so hetereogeneous that our resulting dataset of over 1,000 cells still did not have enough resolution to generate highly differentiated and separate groupings of cells. Upon examining inter-tumor heterogeneity, we observed the cells from different tumors to generally cluster separately. However, there were certain populations of cells from all tumors that clustered together. We also generated a PDX model and sequenced the resulting tumor, observing markedly reduced heterogeneity as compared to the original primary tumor. Importantly, the cells from the PDX model clustered within the larger group of cells from the original tumor, lending credence to the theory of clonal selection.
This work presents evidence of extensive intra- and inter-tumor heterogeneity at the mRNA level within osteosarcoma tumors. This heterogeneity requires further single cell sampling to shed light on the biology of tumor diversity. Further, this heterogeneity is significantly reduced in a generated murine PDX model. This difference should serve as a potential warning about additional factors to take into account when evaluating therapies in PDX models, and suggests that further studies examining cause and effect of this observed heterogeneity are warranted.
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Chung, Caroline. "Imaging Biomarkers of Response to Radiation and Anti-angiogenic Agents in Brain Tumors". Thesis, 2011. http://hdl.handle.net/1807/27330.
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There is mounting evidence to support combined therapy with radiation (RT) and antiangiogenic agents (AA) for the treatment of brain tumors. However, the therapeutic benefit of this combined treatment hinges on the specific dose, schedule, and duration of each treatment. Early biomarkers that reflect tumor physiological responses provide key information that could guide these aspects of treatment. Pre-clinical tumor models are invaluable tools for identifying potential biomarkers, their optimal timing for measurement and their ability to guide therapy in clinical translation. This thesis demonstrates the feasibility and potential of serial MRI to guide the design, delivery and measure of early response to combined AA and RT in a murine intracranial glioma model. We identified promising biomarker changes reflecting early treatment response that may ultimately facilitate individualized spatio-temporal delivery of radiotherapy (RT) and anti-angiogenic agents (AA) for brain tumors.
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Jekerle, Veronika. "Investigations of combined strategies to reverse P-glycoprotein- and BCRP-mediated multidrug resistance in human ovarian cancer cells and xenograft tumors /". 2006. http://www.gbv.de/dms/bs/toc/522576931.pdf.
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Jekerle, Veronika [Verfasser]. "Investigations of combined strategies to reverse P-glycoprotein- and BCRP-mediated multidrug resistance in human ovarian cancer cells and xenograft tumors / vorgelegt von Veronika Jekerle". 2006. http://d-nb.info/981409806/34.
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Sobhanifar, Solmaz. "Fluorescence imaging of tumour hypoxia in xenograft tumour models". Thesis, 2004. http://hdl.handle.net/2429/16229.
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Hypoxic cells in solid tumours are known to resist radiotherapy as well as forms
of chemotherapy. Hypoxia is also believed to promote tumour aggressiveness and
metastasis. It is therefore important to develop a practical method to identify hypoxic
tumour cells in order to assess which patients could benefit from hypoxic cell-targeted
therapies.
The goal of this study was to develop an immunohistochemical approach to the
detection of hypoxia in xenograft models that may be applied to clinical samples. The
hypotheses to be tested were that areas of chronic or transient hypoxia could be
distinguished based on specific patterns of hypoxia markers, and that HIF-1α could be
comparable as a hypoxia marker to pimonidazole. The objectives were: 1) to characterise
the kinetics of development under anoxia and loss upon reoxygenation of the exogenous
hypoxia marker pimonidazole and the endogenous hypoxia marker HIF-1α, 2) to use
quantitative fluorescence image analysis to compare patterns of pimonidazole binding
and HIF-1α expression in WiDr, SiHa and M006 human tumour xenografts, and to
measure marker response under various oxygen- breathing conditions, and 3) to compare
hypoxia marker patterns in xenograft tumours with patterns observed in cervical cancer
biopsies.
HIF-1α and pimonidazole colocalised in regions distant from blood vessels;
perinecrotic regions however showed pimonidazole binding but no HIF-la expression.
This lack was not a result of anoxia but likely a result of glucose and serum starvation.
With time after pimonidazole administration, the extent of colocalisation with HIF-1α
was reduced from 60% at 90min to 7% at 48hr, consistent with the movement of
pimonidazole-labelled cells into necrosis. Patterns of HIF-1α and pimonidazole binding
in clinical samples confirmed the dissociation between the markers when pimonidazole
was administered 24hr before tumour excision. Overall our xenograft results indicated
HIF-1α to be a reliable indicator of tumour hypoxia; however, it over-estimated
radiobiological hypoxia (<1% O2) and was not expressed in the most hypoxic regions of
tumours. The kinetics of marker development and loss, and occasional regions
expressing one but not the other marker indicated that HIF-1α in combination with
pimonidazole has the potential to measure the presence of transient hypoxia.Medicine, Faculty of
Medicine, Department of
Experimental Medicine, Division of
Graduate