bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1288: GLI2 is a significant determinant of HH-GLI pathway activaton in Ewing sarcoma
Authors: Christensen Laura , May William A. 
Published: August 2012

Abstract
Ewing Sarcoma is an aggressive bone and soft tissue malignancy of children, adolescents and young adults. Non-canonical activation of the Hedgehog-GLI pathway by the Ewing specifc EWS/FLI1 transcription factor has been shown to mediate important aspects of tumor phenotype. While evidence regarding the role of EWS/FLI1 in direct activation has been published, no one has yet investigated the role of other pathway components in Ewing tumors. Physiologically, GLI2 is the principal transcriptional activator of GLI1 and substantial amounts of GLI2 can be demonstrated in Ewing tumors and cell lines. So we hypothesized that GLI2 may also function in Ewing cells to help to regulate GLI1 and Hedgehog-GLI pathway activaton. Since GLI2 can be targeted by pharmacologic means, understanding its role in Ewing tumors is of potential significance. We demonstrate that GLI2 is expressed at significant levels in Ewing tumors. Furthermore, we show by overexpression studies, that GLI2 overexpression augments expression of both GLI1 and other pathway targets in Ewing cell lines. By using shRNA, we also demonstrate that knockdown of GLI2 expression has the expected effect of diminishing GLI 1 expression in Ewing lines. Finally, we show that treatment with GLI inhibitors also diminishes GLI2 activation of GLI1. Overall, these data indicate that GLI2 in Ewing cells exists in an activator state in Ewing cells and that pharmacologic means of targeting GLI2 may be an effective strategy for targeted therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1288. doi:1538-7445.AM2012-1288
Abstract 1304: Specific MUC1 isoforms function to regulate gene expression and tumor growth in pancreatic cancer
Authors: Grandgenett Paul M. , Bunt Stephanie K. , Mohr Ashley M. , Radhakrishnan Prakash , Hamada Tomofumi , Hollingsworth Michael A. 
Published: August 2012

Abstract
Cancer cells, especially adenocarcinomas, express aberrant forms of mucins, as compared to their normal cell counterparts. These aberrant forms arise as a consequence of transformation-related alterations in expression of mucin mRNAs including alternative splice forms, and deregulation of enzymes that post-translationally modify mucin core proteins. Previous work has established that MUC1 is overexpressed and differentially glycosylated in adenocarcinomas and that this overexpression is associated with aggressive forms of pancreatic cancer. Most studies have focused on the full-length MUC1 isoform that contains the VNTR and all seven exons, but alternative splicing of MUC1 yields a minimum of 30 isoforms, of which several have been linked to malignancy in ovarian, cervical, and breast cancer. We evaluated expression of MUC1 alternate splice forms in a series of isogenic clonal pancreatic cancer cell lines that exhibit different properties of morphological differentiation, tumor growth and metastasis. The results revealed significant variation in splice variant expression between these isogenic cell lines and has implicated an association between isoform expression and metastatic potential. The knockdown of specific splice variants and MUC1 isoform families in S2-007 pancreatic cancer cells suggested that individual isoforms show differential capacity for regulating expression of target genes and miRNAs, which in turn led to differences in tumor growth rate and metastatic potential. Specifically, the stable knockdown of all members of the MUC1 X-family significantly altered expression of miRNAs 193b and 320 and reduced tumor growth in a pancreatic cancer animal model. MUC1 X-family also affected expression levels of several genes associated with Gemcitabine resistance and both pro and anti-inflammatory pathways that are predicted to influence disease progression and tumor associated immunosuppression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1304. doi:1538-7445.AM2012-1304
Abstract 1421: Down-regulation of neuronal repressor gene REST inhibits tumor growth in Ewing's sarcoma
Authors: Zhou Zhichao , Kleinerman Eugenie 
Published: August 2012

Abstract
Ewing's sarcoma is a peripheral primitive neuroectodermal tumors (PNET). The abnormal differentiation of neuronal stem cells may relate to tumorigenesis of Ewing's sarcoma. The RE1-silencing transcription factor (REST) is a neuronal repressor gene which regulates neuronal stem cell differentiation. The aim of this study is to investigate the role of REST in Ewing's sarcoma. Our results demonstrated that three human Ewing's sarcoma cell lines TC71, A4573 and SK-ES expressed high levels of REST. Six of seven tumor samples from patients with Ewing's sarcoma were shown REST positive. Transfection of EWS-FLI-1 into mesenchymal stem cells up-regulated REST expression. Down-regulation of EWS-FLI-1 using si-RNA inhibited REST expression in TC71 cells, suggesting EWS-FLI-1 fusion protein regulates REST expression in Ewing's sarcoma. The siRNA-REST stable transfected cell line was established to down-regulate REST expression in TC71 Ewing's sarcoma cells. In vivo experiments indicated that Ewing's sarcoma tumor growth was significantly inhibited in the mice injected with si-REST-TC71 cells compared to the mice injected with si-control cells. Down-regulation of REST inhibited cell proliferation and induced apoptosis in TC71 tumors. The immunohistochemical staining indicated that the tumor vessels and pericyte marker expression were reduced in si-REST tumor tissues. Inhibition of REST decreased the early neural differentiation marker MSX-1 expression and up-regulated the terminal neural differentiation marker β-Tubulin III (Tuj) expression. These data suggesting that neuronal repressor gene REST plays an important role in tumor development of Ewing's sarcoma. Inhibition of REST suppressed tumor growth and altered neuronal differentiation marker expression in Ewing's sarcoma. REST is a potential target for treatment of Ewing's sarcoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1421. doi:1538-7445.AM2012-1421
Abstract 1422: High FLT3 mRNA expression without FLT3-ITD in infants with acute myeloid leukemia
Authors: Shimada Akira , Yamada Miho , Yamashita Yuka , Yokozawa Toshiya , Tomizawa Daisuke , Kinoshita Akitoshi , Taga Takashi , Tawa Akio , Taki Tomohiko , Hayashi Yasuhide , Fujimoto Junichiro , Horibe Keizo , Adachi Souichi 
Published: August 2012

Abstract
Introduction: When compared to older patients, infants with acute leukemia exhibit high frequency of MLL gene rearrangement (MLL-R), and are known to have higher vulnerability to intensive cytotoxic therapy, such as hematopoietic stem cell transplantation (HSCT). In contrast to acute lymphoblastic leukemia (ALL) in infants, there have been a few reports on acute myeloid leukemia (AML) in infants including our group (A. Shimada et al, ASH 2011). We and other group reported that MLL-R had the clinical impact in infant ALL, however, not in infant AML. Infant ALL with MLL-R expressed high FLT3 mRNA, on the other hand, the importance of FLT3 mRNA remains to be obscure in infant AML. Patients: Forty four infants with AML, aged less than 1 year at diagnosis, registered in JPLSG AML-05 from 2006-2010. Patients with Down syndrome were excluded. The most frequent FAB classification type was M7 (18/44, 40.9%), followed by M5 (15/44, 34.1%), and M4 (4/44, 9.0%). Total 16 of 44 (36.4%) infant AML patients had MLL-R, 9 patients were detected by G-banding method, and other 7 patients were by FISH analysis or RT-PCR. There was not t(8;21), t(15;17) except for one inv(16) patient. Methods: FLT3 mRNA expression and internal tandem duplication (ITD) were analyzed in the first diagnostic bone marrow samples by RQ-PCR and PCR. Results: No patients had FLT3-ITD, however, higher FLT3 mRNA expression was found in MLL-R patients (n=16) (median 623,150 copies/μgRNA) compared with MLL-wild type (WT) (n=28) (median 25,105) (p&lt;0.005). This phenomenon was also observed in 12-23 months AML patients. Discussion: High FLT3 mRNA expression was reported in infant ALL with MLL-R and it can be a molecular target for FLT3 inhibitor. On the other hand, there was no report in infant AML. Our previous data suggested that SCT had the limited efficacy for infant AML, FLT3 inhibitor might be considered to be used for infant AML with MLL-R in future.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1422. doi:1538-7445.AM2012-1422
Abstract 1434: A mouse model of the most aggressive subgroup of human medulloblastoma
Authors: Kawauchi Daisuke , Robinson Giles , Uziel Tamar , Gibson Paul , Rehg Jerold , Gao Cuilan , Finkelstein David , Qu Chunxu , Pounds Stanley , Ellison David W. , Gilbertson Richard J. , Roussel Martine F. 
Published: August 2012

Abstract
Human medulloblastomas are molecularly classified into four major subgroups. Among them, the MYC-subgroup, the most aggressive and the least curable is characterized by amplification or overexpression of the c-MYC gene. While mouse models for the human SHH-subgroup have advanced the development of targeted treatments for this subgroup, the absence of a preclinical model for the MYC-subgroup has severely limited our understanding of its biology and treatment. We have now generated the first mouse model of MYC-subgroup medulloblastoma that faithfully recapitulate the transcriptome, histopathology, and clinical behavior of the human disease. This mouse model was generated by orthotopic transplantation of percoll-purified Myc-transduced cerebellar cells from postnatal day 6-7 Trp53-deficient mice into the cortices or the cerebellum of immunocompromised recipient animals. While &gt;2 x 105 cells from the mouse SHH-tumors are required to induce a tumor, 100 MYC-tumor cells were sufficient, suggesting that most MYC-tumor cells are tumor initiating cells. MYC-tumors can be passaged indefinitely as neurospheres that express markers associated with stem cells, including Prom1, Lgr5, Oct4, Nanog, and Sox2 and induce secondary medulloblastomas with similar characteristics as the primary tumors, after orthotopic transplant into the cortices of recipient mice. This novel medulloblastoma model should significantly advance our efforts to develop new therapeutic modalities and to determine the origin of this deadly childhood cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1434. doi:1538-7445.AM2012-1434
Abstract 1480: Regulation of ovarian tumor growth and stromal cell infiltration by the HU177 biomechanical ECM switch
Authors: Ames Jacquelyn Joan , Caron Jennifer M. , Contois Liangru , Vary Calvin , Friesel Robert , Liebes Leonard , Brooks Peter C. 
Published: August 2012

Abstract
Accumulating evidence indicates that the malignant behavior of tumors depends not only on tumor cells themselves, but also on the stromal cells that comprise the malignant tumor mass. Experimental findings suggest that stromal cells such as cancer-associated fibroblast (CAF) may play important roles in promoting tumor growth and metastasis as well as regulating the efficacy of certain chemotherapeutic drugs. However, developing novel clinical strategies that selectively and simultaneously impacts tumor and stromal cells remains challenging. Alterations in the integrity and molecular composition of the extracellular matrix (ECM) are hallmarks of tumor progression. Our previous studies have shown that structural remodeling of the ECM can result in localized triggering of what we have termed “biomechanical ECM switches” or changes in the three-dimensional structure of pre-existing ECM molecules. A humanized antibody (TRC093/D93) specifically directed to the HU177 cryptic collagen epitope that is selectively exposed following triggering of a biomechanical ECM switch has been developed, and a human phase-I clinical trial was recently completed with encouraging results. Here we provide evidence that the HU177 biomechanical ECM switch is triggered within human ovarian tumors resulting in the exposure of the HU177 cryptic collagen epitope. The relative exposure of the HU177 cryptic site was significantly (P&lt;0.05) enhanced in biopsies of malignant ovarian tumors as compared to benign ovarian lesions. Selective targeting of the HU177 cryptic collagen epitope by Mab D93 significantly (P&lt;0.05) inhibited SKOV-3 tumor growth by approximately 70% as compared to controls. Tumors from these mice exhibited reduced angiogenesis, elevated levels of apoptosis and a significant reduction in infiltration of alpha smooth muscle cell actin (αSMC-actin) positive stromal fibroblasts. Importantly, while Mab D93 inhibited SKOV-3 tumor cell adhesion to denatured collagen type-I and enhanced the expression of the cyclin dependent kinase inhibitor P27KIP1, it also selectively inhibited (80%) fibroblast migration on denatured collagen type-I that was induced by either FGF-2 or SKOV-3 condition medium. Collectively these studies provide evidence that specific targeting of the HU177 cryptic collagen epitope may represent a highly selective strategy to inhibit ovarian tumor growth in part by limiting stromal cell invasion.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1480. doi:1538-7445.AM2012-1480
Abstract 1486: The contribution of stromal caveolin-1 to breast cancer metastasis
Authors: Burrows Allan D. , Restall Christina , Sloan Erica K. , Anderson Robin L. 
Published: August 2012

Abstract
In a previous study, our group has shown that the expression of caveolin-1 (CAV1) in normal tissue surrounding a primary breast cancer is a powerful prognostic indicator of subsequent metastatic disease. Whilst reports linking expression of CAV1 within breast tumour cells to clinical outcome have not led to any clear conclusions, our finding of a strong positive correlation between loss of CAV1 expression in breast tumour stroma and poor prognosis (p&lt;0.0001) (Sloan et al, 2009, AJP 174: 2035-2043), is novel and exciting as it offers the potential of a reliable prognostic indicator of metastatic disease. Tumours arising from non- or weakly metastatic mammary cells grow at a faster or similar rate when co-injected with CAV1 null mammary fibroblasts. In contrast, co-injection with CAV1 expressing mammary fibroblasts has a suppressive effect on tumour growth. To mimic this phenotype observed in vivo, 3D co-culture assays are being developed, and although they have demonstrated a positive effect of fibroblasts on tumour cell migration and proliferation, no stromal CAV1 specific effect has been observed. To further understand the consequences of the loss of stromal CAV1, profiling of CAV1 expressing and null mouse mammary fibroblasts was conducted using cytokine arrays and cDNA microarrays. Differences in the secretion of known CAV1 associated cytokines such as RANTES, Gas6 and IL-6 were observed, with no significant changes in their expression. Based on these findings, CAV1 may be contributing directly to the progression of breast cancer and thus provide the basis of a stromal targeted therapy. An understanding of the mechanism by which CAV1 expression is lost from host cells, and how this loss leads to progressive disease, could allow a therapy that restores or substitutes for CAV1 activity in stromal cells or that targets the key cytokines involved in this paracrine signalling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1486. doi:1538-7445.AM2012-1486
Abstract 1524: M402, a novel heparan sulfate mimetic, inhibits pancreatic tumor growth and desmoplasia potentially via sonic hedgehog signaling in an orthotopic mouse model
Authors: Chu Chia Lin , Long Alison , Honan Christopher M. , Duffner Jay , Avery William , D'Alessandro Josephine , Kishimoto Takashi K. , Schultes Birgit C. 
Published: August 2012

Abstract
One of the hallmarks of pancreatic ductal adenocarcinoma (PDAC) is extensive desmoplasia in the surrounding tumor microenvironment that prevents delivery of chemotherapeutics (such as gemcitabine). Dysregulation of sonic hedgehog (SHH, a heparin-binding morphogen), has been implicated in pancreatic cancer tumorigenesis. We have rationally designed a heparan sulfate mimetic, M402, that has previously been shown in animal studies to reduce metastatic seeding through disruption of several key heparin-binding growth factors (including FGF2, VEGF, SDF-1α and P-Selectin). We hypothesized that M402, alone or in combination with gemcitabine, could potentially modulate tumor-stroma interactions in an orthotopic pancreatic cancer model (Capan-2 cell line) which secretes SHH and displays a desmoplastic response in vivo. Capan-2 human adenocarcinoma cells (∼1x106 cells) were injected into the pancreata of immunodeficient mice (Nu/Nu CD-1). M402 (10-40 mg/kg/day) or saline treatment commenced on Day 4 or 32. Gemcitabine (30-60 mg/kg, twice weekly, IP) treatment commenced between Weeks 3-6. At the termination of each study (Week 8), gross anatomical observations were made of the primary pancreatic tumor and metastatic lesions in the surrounding tissues including the spleen, intestines and liver. Gemcitabine was increasingly less effective when started at later time points, but still reduced the primary tumor weight by 60-70% (at 30-45 mg/kg) when treatment was started at week 5. While the addition of M402 to gemcitabine showed some additive effect on primary tumor burden, metastasis, invasion, and surrounding fibrotic lesions appeared particularly impacted by the combination treatment. M402 was also effective as monotherapy showing a dose-dependent reduction in primary tumor weight and fibrotic lesions. Immunohistochemical and qPCR analyses showed reduced fibrosis and SHH signaling with M402 and gemcitabine combination treatment. These results demonstrate that M402 can modulate tumor-stroma interactions involved in the desmoplastic response in a murine model of pancreatic cancer and provide a rationale for the clinical investigation of M402 as a potential anti-desmoplastic agent in pancreatic cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1524. doi:1538-7445.AM2012-1524
Abstract 1528: Cooperative cross-talk between neuroblastoma subtypes confers resistance to anaplastic lymphoma kinase inhibition
Authors: Chan Andrew M. , Yan Xiaocai , Kennedy Colin R. , Tilkens Sarah B. , Wiedemeier Olena , Guan Hong , Park Jong-In 
Published: August 2012

Abstract
Neuroblastoma is a pediatric solid tumor that can be stratified into stroma-rich and stroma-poor histological subgroups. The stromal compartment of neuroblastoma is composed mostly of Schwann cells and they play critical roles in the differentiation, survival and angiogenic responses of tumor cells. In certain neuroblastoma cell lines, the coexistence of neuroblastic N-type and substrate-adherent S-type is frequently observed. One such cell line, SK-N-SH, harbors a F1174L oncogenic mutation in the Anaplastic Lymphoma Kinase (ALK) gene. Treatment of SK-N-SH with an ALK chemical inhibitor, TAE684, resulted in the outgrowth of S-type cells that expressed the Schwann cell marker, S100α6. Nucleotide sequencing analysis of these TAE684-resistant (TR) sublines revealed the presence of the ALK F1174L mutation suggesting their tumor origin, although ALK protein was not detected. Consistent with these findings, TR cells displayed ∼9-fold higher IC50 values than N-type cells. Also, unlike N-type cells, TR cells have readily detectable phosphorylated STAT3 but weaker phosphorylated AKT. Under co-culture conditions, TR cells conferred survival to N-type cells against the apoptotic effect of TAE684. Co-cultivation also greatly enhanced the overall phosphorylation of STAT3 and its transcriptional activity in N-type cells. Finally, conditioned medium from TR clones enhanced cell viability of N-type cells and this effect was Phosphatidylinositol 3-Kinase-dependent. Taken together, these results demonstrate the ability of tumor-derived S-type cells in protecting N-type cells against the apoptotic effect of an ALK kinase inhibitor through upregulating pro-survival signaling. This project was supported by MACC funds, Advancing a Healthier Wisconsin, Wisconsin Breast Cancer Showhouse (O.W.), NIH CA133669 (H.G. and A.M.C.) and the Children's Research Institutes of the Children's Hospital of Wisconsin.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1528. doi:1538-7445.AM2012-1528
Abstract 1535: Intratumoral chitosan/interleukin-12 immunotherapy reduces breast cancer metastasis
Authors: Vo Jimmy Nhu 
Published: August 2012

Abstract
Interleukin-12 (IL-12) is a potent antitumor cytokine that exhibits significant clinical toxicities after systemic administration. Local delivery of IL-12 has been shown to significantly reduce this threat. Our lab has recently shown that local delivery of IL-12 with the biopolymer chitosan can eliminate aggressive murine tumors while minimizing the chances for toxicity. In addition to eliminating the tumors, our lab has demonstrated that local chitosan/IL-12 immunotherapy can lead to the activation and expansion of CD8+ T cells and natural killer cells, increased production of interferon-gamma, and activation of dendritic cells that can recognize and attack these tumor cells. This immune response was evaluated for efficacy in preventing tumor metastasis. Mice bearing 4T1 tumors were treated with DPBS, IL-12, chitosan, or chitosan-IL-12 prior to surgical resection of the primary tumor. Survival analysis returned survival rates of 0%, 25%, 0%, and 40% respectively. In a separate study, lungs were examined for metastatic nodules revealing that mice treated with chitosan/IL-12 displayed significantly fewer nodules than other treatment groups. Based on the data obtained thus far, chitosan/IL-12 shows promising potential as an immunotherapy to reduce metastatic disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1535. doi:1538-7445.AM2012-1535