bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4196: Successful establishment of human rhabdomyosarcoma xenografts in a human-adapted mouse model
Authors: Seitz Guido , Pfeiffer Matthias , Warmann Steven W. , Handgretinger Rupert , Leuschner Ivo , Fuchs Jörg , Armeanu-Ebinger Sorin 
Published: February 2011

Abstract
Purpose:
The outcome of patients with advanced stage rhabdomyosarcoma is still sobering. Treatment results cannot be improved by conservative treatment options. Therefore, novel treatment approaches such as immunotherapy need to be evaluated in human-adapted animal models. The aim of this study was to develop a humanized mouse model of childhood rhabdomyosarcoma as a basis for studies of immunotherapeutic approaches.
Methods:
NOD/LtSz-scid IL2R gamma null mice were used for all experiments (n =14). Animals underwent subletal irradiation (1 × 300cGy). Afterwards, transplantation of human CD34+-cells (1.000.000 cells per animal i.v.) was carried out. Eight weeks after transplantation, subcutaneous xenotransplantation of human alveolar (Rh30) and embryonal rhabdomyosarcoma (RD) cell lines was carried out. Engraftment of human cells was assessed in peripheral blood at day 21 and at day 55 of the experiment. Animals were sacrified and tumors were resected 93 days after CD34+-transplantation.
Results:
Successful engraftment of human cells with establishment of a human immune system was observed in 12 of 14 animals. B-cells and T-cells were mostly detected in the peripheral blood. There were only a few monocytes and nearly no NK-cells. Xenotransplantation of alveolar RMS resulting in subcutaneous tumor growth was feasible in 7 animals. Xenotransplantation of embryonal RMS was performed in 5 animals and led to tumor growth in 1 animal. Histological work up showed either alveolar or embryonal RMS cells with central necrosis.
Conclusion:
For the first time, we developed a xenotransplantation model of human rhabdomyosarcoma in a humanized mouse model. Establishment of subcutaneous tumor xenografts was more effective in alveolar subtype. This model will serve as basic research tool for further analysis of novel immunotherapeutic approaches in solid pediatric tumors.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4196.
Abstract 4197: Mouse xenograft models of human soft tissue sarcomas
Authors: Sicinska Ewa , Moss Samuel , Brito Joseph , Priolo Carmen , Finn Stephen , Wagner Andrew , Demetri George , Loda Massimo 
Published: February 2011

Abstract
Sarcoma represents a class of tumors arising from mesenchymal tissue. New approaches that target sarcoma-specific molecular alterations hold a promise of more effective therapies. Currently available sarcoma models do not accurately resemble relevant properties of the human disease and very often are inadequate for predicting the efficacy of investigational drugs in preclinical settings. Thus, in order to test novel targeted therapies, it is essential to develop in vivo models of sarcomas.
To this end, we have created a panel of well-characterized xenografts of primary human sarcomas that represent a spectrum of histotypes. Specifically, we transplanted intact human sarcomas under the skin of immunodeficient mice. We then compared the morphologic, phenotypic, and genetic characteristics of the tumor tissues before and after implantation in recipient mice.
To date, we have implanted into Nu/Nu recipients tumor tissue fragments from 32 gastrointestinal stromal tumors (GIST) 10 dedifferentiated liposarcomas and 6 leiomyosarcomas. Successful tumor growth was detected in 86% cases of GIST, 44% of liposarcomas and 33% of leiomyosarcomas. Upon serial transplantation, 35% of GISTs, 44% of liposarcomas and 33% of leiomyosarcomas have grown beyond passage F3. Histological analysis of the primary tumors and corresponding xenografts revealed that morphology and immunophenotype (c-Kit status for GISTs, MDM2 for liposarcomas, Smooth Muscle Actin for leiomyosarcomas) was retained throughout all passages. Moreover, all major genetic abnormalities present in the primary tumors were retained in the xenografts, as revealed by genome-wide Single Nucleotide Polymorphism (SNP) array analyses.
Our results show that this approach can be used to generate animal models that faithfully reproduce characteristics of human intact tumors. These models can be used for in vivo preclinical drug testing, diagnostic and prognostic molecular markers discovery, and for identification of molecular mechanisms of drug resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4197.
Abstract 4198: Characterization of basal cell carcinoma (BCC) allograft in comparison with spontaneous murine BCCs
Authors: Wang Grace Y. , So Po-Lin , Libove Eileen , Epstein Ervin H. 
Published: February 2011

Abstract
Small molecule inhibitors against Hedgehog (HH) activity have become one of the hottest targets in cancer drug development. This is because HH pathway has been found to play a role in possibly as many as 30% of all human malignancies, including basal cell carcinoma (BCC), medulloblastoma, rhabdomyosarcoma, pancreatic, gastrointestinal, ovarian, and prostate cancers, some leukemias, and multiple myeloma. Ptch 1+/− mice develop BCCs after UV or ionizing radiation and provide an excellent model system for investigating the HH regulatory system, studying the effect of HH in cancer biology, and evaluating tumor intervention therapies. However, there are intrinsic limitations to the use of autochthonous mouse tumors to investigate therapeutic interventions, including inter-tumor variability and long tumor latency, necessitating the enrolling of numerous mice to assess the efficacy of any intervention. One approach to circumventing these problems is to use tumor allografts. In the present study we aimed to develop BCC tumor allografts, which have not previously been established successfully, and to compare their histology, growth rate, vasculature, and sensitivity to drug treatment with that of their parental tumors. We injected single cell suspensions derived from primary murine BCCs into multiple NOD/SCID mice and compared allograft histology (H&E) and immunophenotype (Ki67, Gli1 and CD31) with that of the parental tumors. We found that allografts generated from the same spontaneous tumor were relatively similar to one another and reproduced the histology of the parental tumor, exhibiting either an infiltrative subtype or a nested structure resembling infiltrative/trichoepithelioma or nodular human BCC subtypes respectively. Consistent with their faster growth rate, allograft tumors showed greater Ki67 staining than did primary tumors. However, allografts expressed slightly reduced Gli1 levels. Similar vascular distribution was observed in both tumor models. Finally, we tested the tumor allograft sensitivity to HH inhibitor treatments.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4198.
Abstract 4200: Transgenic mice overexpressing a Claudin-6 tail deletion mutant are resistant to tumor formation
Authors: Turksen Kursad , Arabzadeh Azadeh , Troy Tammy-Claire 
Published: February 2011

Abstract
Morphological and physiological observations suggest that the tight junction (TJ)-based permeability barrier is modified/disrupted during tumorigenesis. It is now also widely recognized that the Claudin (Cldn) family of four tetraspan transmembrane proteins is crucial for tight junction assembly and permeability barrier function. However, the detailed roles of the Cldn cytoplasmic tail and extracellular loop domains in these processes or their dysfunction in tumorigenesis are not yet understood. We recently demonstrated that the tail domain of Cldn6 is crucial for membrane targeting and epidermal permeability barrier (EPB) formation, by forced expression of a Cldn6 tail deletion mutant (CDelta187) via the involucrin (Inv) promoter in the suprabasal compartment of the mouse epidermis. Even though a functional barrier formed, Inv-CDelta187 mice displayed histological and biochemical abnormalities in the epidermal differentiation program leading to a thickening of the epidermis after 1 week of age that persisted throughout life. Notably, a significant amount of not only Cldn6, but also Cldn10, Cldn11, and Cldn18 remained cytoplasmically localized and the protein-unfolding pathway was activated in transgenic epidermal cells. Using a well-established two-stage chemical carcinogenesis model, we are now investigating the temporal and spatial changes in expression of these and other (Cldn1, Cldn12) Cldns that we have previously demonstrated to be important in epidermal differentiation and tumorigenesis in CDelta187 versus wild type (WT) mice. METHODS: The lower dorsal backskin of mice was treated topically with 7,12-dimethylbenz(a)anthracene (DMBA; 0.25 mg/ml in acetone) and following a 10-day incubation period, 12-O-tetradecanoyl-phorbol-13-acetate (TPA; 25 microg/ml in acetone) was applied three times a week to the same area. Backskin samples were dissected 2, 4, 6, 8 and 12 weeks after the initiation of the experimental protocol and immunohistochemistry was performed on sections using antibodies against the following: Cldn1, Cldn6, Cldn11, Cldn12, Cldn18, Ki67 (proliferation marker) and CD3 (immune infiltration marker). Strikingly, epidermal tumor formation was inhibited in CDelta187 as compared to WT animals. This is the first demonstration that alterations in Cldn structure and homeostasis may play a protective role against DMBA/TPA-induced skin tumors. Further investigation into the molecular mechanisms underlying this protective function is underway. Supported by CIHR
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4200.
Abstract 4204: Essential role of odontoblastic Smad4 in suppressing multiple keratocystic odontogenic tumors in mice
Authors: Gao Yuanrong , Yang Guan , Weng Tujun , Du Juan , Wang Xuejiu , Zhou Jian , Wang Songlin , Yang Xiao 
Published: February 2011

Abstract
Keratocystic odontogenic tumors (KCOT) are cystic epithelial neoplasias with a high recurrence rate. However, the molecular mechanisms underlying the initiation and progression of KCOTs are still largely unknown. Here, we show that specific ablation of Smad4 in odontoblasts unexpectedly resulted in spontaneous KCOTs in mice. The mutant mice exhibited malformed teeth characterized by fractured incisors and truncated molar roots. These abnormalities were mainly caused by disrupted odontoblast differentiation that led to irregular dentin formation. The cystic tumors arising from the reactivation of epithelial rests of Malassez (ERM), in which Smad4 remained intact, proliferated and formed stratified and differentiated squamous epithelia which exhibited a dramatic up-regulation of Hedgehog signaling. Odontoblasts which are responsive to TGF-β/BMP signals may produce signal molecules to inhibit the activation of ERM. Indeed, we observed a down-regulation of BMP signals from Smad4 mutant odontoblasts to adjacent Hertwig's epithelial root sheath (HERS). Intriguingly, KCOTs frequently emerged from Smad4-deficient ERMs in the keratinocyte specific Smad4 knockout mice, suggesting a novel mechanism that reciprocal TGF-β/BMP signaling between odontoblasts and HERS were required for tooth root development and suppression of KCOT formation. These findings provide insight into the genetic basis underlying KCOTs and important implications for new directions in KCOT treatments.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4204.
Abstract 4207: Pharmacodynamic comparisons of novel cryobiopsy instrumentation compared to standard techniques through comparative oncology modeling
Authors: Paoloni Melissa C. , Mazcko Christina , DiPaolo Tiziano , Parchment Ralph , Kinders Robert , Tomaszewski Joseph , Khanna Chand 
Published: February 2011

Abstract
The development of novel and targeted cancer drugs requires innovative clinical trial designs to define drug (pharmacokinetic) and host (pharmacodynamic) relationships early in the development process. For most new cancer agents there is increased emphasis on pharmacodynamic (PD) endpoints measured in tumor and surrogates as biomarkers of response. Accordingly, novel tissue collection procedures and instruments are needed to ensure that PD endpoint assessments are representative of their actual in vivo “state”. The Cassi Rotational Core Biopsy Device (Cryobiopsy) (Sanarus Medical, Inc, Pleasanton, California) is a biopsy instrument capable of incisional tissue collection and simultaneous freezing. In rodent xenograft models it demonstrated superiority in consistency for tumor analyte detection compared to traditional biopsy techniques. Whether this value would translate to the clinical setting was unknown. Use of naturally occurring cancers in pet dogs provides a model system to validate and optimize instrumentation techniques prior to use in human trials. A prospective clinical trial in dogs with lymphoma was conducted through the National Cancer Institute-Comparative Oncology Trials Consortium (NCI-COTC) to 1) determine if Cyrobiopsy provides sample quality advantages over conventional tru-cut, and open biopsy procedures, and 2) validate a “practice setting” Cryobiopsy Standard Operating Procedure (SOP) that could be followed by multiple users providing consistent high-quality biopsy samples. Ten dogs with newly diagnosed lymphoma enrolled. Cryobiopsy and tru-cut samples were collected in each patient from two lymph nodes in three planes via alternating techniques. A whole lymph node was then removed via excisional biopsy from the same dog. No adverse events were reported with Cryobiopsy or standard biopsy methods. The SOP for cryobiopsy collection of tissues was successfully implemented in a relevant clinical setting. Cryobiopsy collected samples successfully preserved target phospho-proteins (p-AKT: tAKT, p-ERK: tERK, p-MEK: tMEK) collected from tumor tissue. No difference in phospho-protein detection by Western was seen across biopsy techniques. In conclusion, this effort highlights the utility of the comparative approach to model medical device evaluation and PD biomarker assay validation in the clinical theatre.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4207.
Abstract 4208: Constitutive activation of Wnt/beta-catenin signaling induces uterine developmental defects
Authors: Wang Yongyi , Smits Ron , Franken Patrick , Jia Yundan , Grootegoed J. Anton , Burger Curt W. , Fodde Riccardo , Blok Leen J. 
Published: February 2011

Abstract
Background: Wnt/beta-catenin signaling plays a regulatory role in uterine development and function. To study this role of Wnt/beta-catenin signaling during embryogenesis in more detail, we employed an AmhR2 promoter-driven C-recombinase (Jamin et al., 2002) to conditionally inactivate the Apc gene in mesenchymal cells surrounding the müllerian duct. As a consequence of Apc inactivation, defects in the destruction complex are expected to result in the intracellular accumulation of beta-catenin and the subsequent constitutive activation of canonical Wnt signaling.
Methods: [Apc15Lox/15lox;AmhR2-Cre] conditional Apc knockout mice were generated. Cre expression and AmhR2 promotor activity was verified by staining for beta-galactosidase activity in [AmhR2-LacZ] and [AmhR2-Cre;ROSA26-LacZlox] reporter mice. Furthermore, recombination of the Apc gene was verified for different laser micro-dissected regions of the uterus, from 8-week-old mice, by PCR. Uterine defects were examined by immunohistochemical staining for various uterine markers.
Results: It was observed that the Cre-mediated Apc gene deletion mainly took place in the myometrial layers of the uterus. Recombination in the stroma and epithelium of the lumen and glands was low. Microscopically, the affected mice showed a significant reduction in the number of glands and a somewhat disorganized stroma. The main defects, however, were observed in the myometrial layer of the uterus, where clear disorganization of muscle fibres and in 50% of cases visible loss of musculature was apparent. As a consequence of these defects, the mice displayed reduced litter sizes and some mice were incapable of normal delivery.
Conclusion: AmhR2-Cre driven embryonic knock-down of Apc results in a defect of the myometrial layer of the uterus. Effects on the endometrium were observed to be less profound.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4208.
Abstract 421: Dystroglycan glycosylation status predicts Gleason grade and influences prostate tumor growth
Authors: Esser Alison K. , Weydert Christine J. , Meier Melissa M. , de Bernabe Daniel Beltran-Valero , Smith Brian J. , Cohen Michael B. , Campbell Kevin P. , Henry Michael D. 
Published: February 2011

Abstract
Dystroglycan, an extracellular matrix receptor, is expressed in many tissues including muscle, neural, adipose and epithelial where its function includes roles in polarity, basement membrane formation and tissue morphogenesis. Loss of dystroglycan expression has been shown in many epithelial cancers including prostate cancer yet the underlying mechanism remains unclear. Here, we investigate the role of DG in prostate cancer progression. We show that staining for the extracellular αDG subunit with the glycosylation-sensitive IIH6 anti-αDG antibody as well as the transmembrane βDG subunit are independent predictors of Gleason score in clinical prostate cancer specimens. In addition, increased αDG glycosylation due to expression of LARGE, a putative glycosyltransferase, in prostate cancer cell lines results in decreased tumor growth in prostate cancer xenografts. We determined that this reduction in growth is specific to the effect of LARGE on dystroglycan. Therefore our work has shown that the extent of αDG glycosylation predicts Gleason scores in prostate cancer and that LARGE dependent glycosylation of αDG regulates tumor growth.
This work is supported by a grant from the National Institutes of Health R01-CA130916
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 421.
Abstract 4210: Gsta4 modifies susceptibility to skin tumor development in mice and humans
Authors: Abel Erika L. , Angel Joe M. , Riggs Penny K. , Langfield Laura , Jiang Anna , Carbajal Steve , Lo Herng-Hsiang , Person Maria , Awasthi Yogesh , Wang Li-E , Strom Sara , Wei Qingyi , DiGiovanni John 
Published: February 2011

Abstract
The incidence of non-melanoma skin cancer (NMSC) is equivalent to that of all other human cancers combined, and genetic factors contribute to risk of the disease. Using genetic crosses of skin tumor promotion sensitive DBA/2 mice with relatively resistant C57BL/6 mice, loci that modify susceptibility to tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) have been mapped to chromosomes (chr) 1, 2, 9, and 19. Here, we show that Glutathione S-transferase alpha 4 (Gsta4), which maps to skin tumor promotion susceptibility locus Psl1.2 on chr 9, was expressed at significantly different levels in the epidermis of C57BL/6 versus DBA/2 mice following treatment with diverse promoting agents. Gsta4 expression was dramatically upregulated in the epidermis of C57BL/6 mice, but not DBA/2 mice, following treatment with TPA, okadaic acid, chrysarobin, or ultraviolet light. Gsta4 deficient mice were more susceptible to skin tumor development in the two-stage skin carcinogenesis protocol providing compelling evidence that Gsta4 underlies the effect of Psl1.2 on susceptibility to skin tumor promotion by TPA. A number of polymorphisms were detected in the putative promoter region of Gsta4 in C57BL/6 versus DBA/2 mice, and ongoing studies are addressing the genetic basis of strain-specific expression of Gsta4 during tumor promotion. Finally, inheritance of polymorphisms in GSTA4 was associated with risk of NMSC in human populations, further supporting Gsta4/GSTA4 as a gene that modifies susceptibility to skin tumor development. Supported by NIH grant ES016623.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4210.