bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3352: The medulloblastoma oncogene Otx2 enhances migration and permits ectopic proliferation of neuronal progenitor cells of the cerebellum and brainstem
Authors: Wortham Matthew , Jin Genglin , Sun Julia Lailai , Bigner Darell D. , Yan Hai 
Published: August 2012

Abstract
Medulloblastoma is the most common malignant brain tumor in children. Despite a thorough understanding of the genetic underpinnings of this tumor, the pathogenesis of some variants of medulloblastoma, in particular the non-Shh/non-Wnt subtypes, is poorly understood. One of the most common genetic aberrations in non-Shh/non-Wnt medulloblastomas is copy number gain of the homeobox transcription factor OTX2. Here we have characterized mice engineered to ectopically express Otx2 in the hindbrain to identify the functional consequences of this subtype-specific genetic insult. Otx2 expression induced accumulation of proliferative hyperplasias in the cerebellar white matter and dorsal brainstem that were reminiscent of preneoplastic cells identified in other animal models of medulloblastoma. These hyperplasias were comprised of neuronal progenitor cells that had migrated away from their mitogenic niches. As animals reached adulthood, ectopic cells exited the cell cycle and differentiated, indicating that factors limiting proliferative lifespan prevented full transformation by Otx2. Comparison of the effect of Otx2 with activation of the Shh or Wnt pathways, which occur in distinct subtypes of medulloblastoma, revealed overlap of responsive cell types but distinct developmental processes involved. While activation of the Shh or Wnt pathways give rise to sustained proliferation of neuronal progenitor cells at their mitogenic niches, we found that Otx2 permitted or enhanced migration of these cells away from these niches and induced ectopic proliferation. These findings identify a role for Otx2 overexpression in altering spatiotemporal control of neuronal progenitor cell proliferation and implicate a relationship between the cells of origin of non-Shh/non-Wnt medulloblastomas and those of other medulloblastoma subtypes.
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 3352. doi:1538-7445.AM2012-3352
Abstract 3356: Development of a novel Wnt pathway antagonist antibody, OMP-18R5, that reduces tumor initiating cell frequency in breast cancer
Authors: Lewicki John , Axelrod Fumiko , Beviglia Lucia , Bond Christopher J. , Donigian Lucas , Fischer Marcus , Kapoun Ann M. , Sato Aaron , Satyal Sanjeev , Wang Min , Yen Wan-Ching , Hoey Timothy , Gurney Austin 
Published: August 2012

Abstract
The Wnt/beta-catenin pathway, which signals through the Frizzled (Fzd) receptor family and several co-receptors, is known to play a critical role in several major cancer types. Mutations in the signalling pathway occur in most cases of human colon cancer, and activation of Wnt signalling through various mechanisms has been reported in multiple major tumor types. We have developed a novel Wnt pathway antagonist antibody, OMP-18R5 which was initially identified by binding to Frizzled7, and subsequently found to also bind several other human FZDs through a conserved epitope within the extracellular domain. OMP-18R5 blocks Wnt binding and canonical signalling induced by multiple Wnt family members. In xenograft studies with minimally passaged human tumors, OMP-18R5 inhibited the growth of a broad range of tumor types and has been found to be particularly active in breast cancer. OMP-18R5 treatment reduced tumor growth and the frequency of tumor initiating cells in combination with pacilitaxel. Furthermore, we found that OMP-18R5 treatment can restore chemosensitivity in drug resistant breast tumors. Molecular analyses indicated OMP-18R5 inhibits the expression of EMT markers in breast tumors, thus providing additional evidence linking EMT with resistance to chemotherapy and cancer stem cells. In addition to combination activity with paclitaxel, OMP-18R5 treatment also resulted in increased anti-tumor activity in combination with trastuzumab in a Her2+ breast cancer model. These data suggest that OMP-18R5, which has recently entered Phase 1 clinical testing, may be useful in the treatment of various types of breast 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 3356. doi:1538-7445.AM2012-3356
Abstract 3362: Tumor initiating cells are sensitive to paclitaxel encapsulated in polymeric nanoparticles
Authors: Swaminathan Suresh Kumar , Toti Udaya , Panyam Jayanth 
Published: August 2012

Abstract
Tumor initiating cells (TICs) represent a small fraction of tumor cells, and are considered to be key drivers of tumor growth, drug resistance and recurrence. TICs are highly resistant to conventional chemotherapy, possibly due to overexpression of drug efflux transporters and other protective mechanisms. Because drug resistance and tumor relapse are significant problems, approaches to eliminate TICs are urgently needed. Recent studies show that tumor populations that are depleted of TICs demonstrate a return of the TIC sub-population 1 suggesting the possibility of de-differentiation of non-TICs to TICs. We hypothesized that sustained delivery of a cytotoxic agent to the tumor population could potentially reduce TIC fraction and consequently increase the therapeutic effectiveness of chemotherapy. To test this hypothesis, we encapsulated paclitaxel, a microtubule stabilizing agent, in PLGA nanoparticles formulated using an FDA-approved polymer, poly (lactide-co-glycolide). Our previous studies have shown nanoparticles can sustain the intracellular delivery of encapsulated drugs like paclitaxel 2. The effectiveness of nanoparticle-encapsulated paclitaxel in reducing TIC fraction was investigated by standard cancer stem cell assays- mammosphere formation and anchorage-independent growth on soft agar in MCF-7, an ER+ luminal breast cancer cell line. Results obtained in these studies show that drug encapsulated PLGA formulations effectively decreased mammosphere formation and soft-agar colony formation when compared to free drug treatment. In mammosphere assays, paclitaxel solution treatment did not significantly affect the mammosphere formation relative to untreated controls, whereas paclitaxel loaded PLGA nanoparticles treatment decreased the number of mammospheres to 50 ± 33% of untreated controls. In soft-agar colony formation assay, paclitaxel solution treatment increased the number of colonies to 122 ± 10% of untreated controls. In contrast to this, paclitaxel loaded PLGA nanoparticles treatment decreased the number of colonies to 66 ± 8% of untreated controls. Future studies will investigate the effectiveness of these formulations on TICs in mouse models of breast cancer. References 1 Gupta, P. B. et al., Cell 146 (4), 633; Chaffer, C. L. et al., Proc Natl Acad Sci U S A 108 (19), 7950. 2 Patil, Y. B. et al., Biomaterials 31 (2), 358.
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 3362. doi:1538-7445.AM2012-3362
Abstract 3364: Calcium blockers decrease the bortezomib resistance in mantle cell lymphoma (MCL) via manipulation of tissue transglutaminase activities.
Authors: Jung Hyun-joo , Chen Zheng , Nami McCarty 
Published: August 2012

Abstract
Although bortezomib is clinically approved for the treatment of Mantle Cell Lymphoma (MCL), only limited effects have been demonstrated. To improve outcomes for bortezomib resistant patient groups, it is necessary to introduce the new therapeutic strategies. In this report, we utilized biochemical and molecular methodologies to demonstrate tissue transglutaminase (TG) activates downstream NF-kB signaling pathways. The signaling axis from TG to NF-kB could be a new therapeutic target to overcome bortezomib resistance in MCL. TG2 is a calcium-dependent protein crosslinking enzyme, and was reported to over-expressed in various cancer cells. MCL expressed elevated levels of TG2, and the modification of TG2 activities altered NF-κB expression and downstream signaling in MCL cells. When the TG2 signaling was inhibited via calcium blockers, the combination of a calcium blocker perillyl alcohol (POH) with bortezomib suppressed NF-κB expression and improved the cytotoxicity of bortezomib in MCL cells. Our study is the first to show the expression of TG2 and the contribution of TG2 to NF-κB signaling in MCL. TG2 inhibition can be an alternative target as anti-MCL therapy, and calcium blockers could be effective combinatory drugs with bortezomib to overcome the bortezomib resistance of MCL.
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 3364. doi:1538-7445.AM2012-3364
Abstract 3367: Breast cancer stem cell-like cells are sensitive to ionizing radiation: Role of ATM
Authors: Kim Seog-Young , Prochownik Edward V. , Lee Yong J. 
Published: August 2012

Abstract
The aim of this study was to determine the radiosensitivity of cancer stem (tumor-initiating) cells (CSC), which are known to be responsible for tumorogenicity and metastasis. We used breast cancer stem cell (CSC)-like MDA-MB231 and MDA-MB453 cell lines which were established by Dr. Edward V. Prochownik (Sajithlal et al., Stem Cells, 28:1008, 2010). Interestingly, these cells can proliferate without differentiation and have characteristics of tumor-initiating cells. CSC-like cells and their alternate subset non-CSC cells were exposed to α-rays (1.25-8.75Gy) and survival curves were determined by colony formation. A final slope, D0, of the survival curve for each cell line was determined to measure radiosensitivity. D0 of CSC-like MDA-MB453 cells and that of non-CSC MDA-MB453 cells were 1.16 Gy and 1.55 Gy, respectively. Similar results were observed in MDA-MB231 cells. We further examined whether CSC-like cells are relatively radiosensitive owing to different intrinsic factors including cell cycle distribution, free-radical scavengers and DNA repair. We observed that, unlike non-CSC cells, CSC-like cells have little/no sublethal damage repair and a low intracellular level of ATM. These results suggest that low DNA repair capability is responsible for the high radiosensitivity of these CSC-like cells.
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 3367. doi:1538-7445.AM2012-3367
Abstract 3370: DNA repair in glioma stem cell-mediated radiation resistance
Authors: Rivera Maricruz , Hjelmeland Anita , Rich Jeremy 
Published: August 2012

Abstract
Glioblastoma multiforme is the most common type of primary brain cancer in adults and has a 14-month median survival after diagnosis. This low survival is due to resistance to the currently available therapies, which include surgery, radiation, chemotherapy, and anti-angiogenic drugs. Resistance to chemotherapy and radiation in these tumors has been linked to a subgroup of highly tumorigenic cells, called glioblastoma stem cells (GSCs), that resemble normal neural progenitor cells. GSCs have the ability to self-renew, differentiate into various lineages, and re-propagate the tumor, making GSCs an attractive target for treatment. Radiation-treated GSCs retain their tumorigenic capacity and have decreased apoptosis compared to non-GSCs. In addition, GSCs have enhanced DNA damage response activation and faster DNA double-stranded break (DSB) resolution relative to non-GSCs after exposure to ionizing radiation (IR). Exposure to low dose radiation induces DSBs, which are repaired by either non-homologous end joining (NHEJ) or homologous recombination (HR). Targeting key proteins involved in HR, such as RAD51, has been shown to reduce glioma cell viability. We are investigating the molecular mechanisms by which DNA repair mediates radiation resistance in GSCs, with some lead candidates identified. Based on a DNA repair gene array, several candidates were identified to be preferentially expressed in GSCs. Current work is focusing on targeting these genes and elucidating their role in radiation resistance.
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 3370. doi:1538-7445.AM2012-3370
Abstract 3371: Targeting glioblastoma stem cell pathways through phage display screening
Authors: Liu James K. C. , Wu Qiulian , Rich Jeremy N. 
Published: August 2012

Abstract
Glioblastomas are the most common and lethal primary brain tumor with conventional therapy offering only palliation. Their resistance to radiotherapy and chemotherapy has been hypothesized to be due in part to the therapeutic resistance of cancer stem cells (CSCs), a subpopulation of cancer cells functionally defined by the ability to self renew and propagate tumors. Development of effective and safe anti-CSC therapeutics will require a selective targeting of CSCs without disruption of normal stem cell maintenance. As phage display technology has been used in cancer to identify, target, and image tumor cells, we employed phage display technology to identify novel proteins specific to the functioning of brain tumor stem cells. A M13 bacteriophage peptide library consisting of 109 different combinations of 7 amino acid long peptide sequences was screened for binding to functionally validated CSCs in both in vitro and in vivo settings. In vitro screening was performed against CSCs isolated from human glioblastoma tumors grown in culture following negative selection on non-CSCs. In parallel, in vivo screening was also performed by injecting the random phage library into immunocompromised mice with either subcutaneous or intracranially xenografted glioblastoma cell lines. The xenografted tumors were resected and divided into stem and non-stem cells prospectively. Phage peptides bound to CSCs were collected in order to isolate peptide sequences that selectively target the CSC subpopulation. In silico analysis of the recovered peptide sequences from both screens using a protein BLAST search revealed several novel proteins that may play an important role in the maintenance and functioning of glioblastoma CSCs. Gene expression analysis showed that several of these genes are preferentially upregulated in glioma CSCs when compared to their non-stem counterparts, suggesting these genes may play a vital role in the unique functions of CSCs and be used to target and image CSCs. These studies validate phage display screening as a method to discover novel proteins and pathways that permit interrogation of CSCs.
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 3371. doi:1538-7445.AM2012-3371
Abstract 3374: Characterizing a new population of adult mouse submandibular gland stem cells
Authors: Xiao Nan , Lin Yuan , Diehn Maximilian , Le Quynh-Thu 
Published: August 2012

Abstract
Xerostomia or dry mouth is a hyposalivation condition that leads to difficulty in speaking, eating, mucosal pain, and enhanced risk of dental and mandibular infection. It can be due to damage of salivary gland nervous system, medications, systematic diseases such as diabetes and Sjogen's syndrome, and radiotherapy (RT) for head and neck cancer. Current available treatments are ineffective due to limited residual glandular function. Stem cell transplantation therapy may be a very promising future direction in treating this severe condition. Using fluorescence-activated cell sorting (FACS) method, we have successfully identified a new population of stem cells from adult mouse submandibular gland. Among all the populations of cells evaluated, the c-Kit+/Sca1+/CD24+/lin− cells generated the highest number of salispheres when cultured in vitro, at least 4 folds more than c-Kit+ or Sca1+ only cells. The c-Kit+/Sca1+/CD24+/lin− cells also expressed significantly higher level of embryonic salivary stem cell marker keratin 5 (CK5) and the basolateral secretory duct maker keratin 14 (CK14), when compared to the CD24+/lin− epithelial cell population. MTT assay showed salispheres derived from c-Kit+/Sca1+/CD24+/lin− population exhibited 10 folds higher enzyme activity than control populations. These spheres continued to express stem cell markers c-Kit and Sca1 after Day 21 and proliferate (Ki67 staining) actively after 14 days in vitro. In addition, these salispheres differentiated into functional acinar cells, indicated by a-amylase staining. More importantly, the dissociated 1st generation of salispheres was capable of generating 2nd salispheres in vitro, indicating the self-renewal property of the these cells. In conclusion, we have identified a subpopulation of adult salivary gland cells that exhibit stem cell properties. Future work will focus on (1) gene expression studies to further elucidate the molecular characteristics of these cells and (2) confirming their renewal capacity in vivo via transplantation studies.
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 3374. doi:1538-7445.AM2012-3374
Abstract 3376: Cord blood stem cells revert EMT to MET in glioma stem cells by downregulating synergistic transcriptional activation of Sox2 and Twist1
Authors: Velpula Kiran Kumar , Dasari Venkata Ramesh , Tsung Andrew J. , Dinh Dzung H. , Rao Jasti S. 
Published: August 2012

Abstract
The dynamic nature of cancer stem cells that underlie metastasis or their ability to switch between different cellular identities, as in epithelial to mesenchymal transition and mesenchymal to epithelial transition has profound implications for cancer therapy. The functional relationship between molecules involved in cancer cell stemness and metastasis is not clear. In this regard, our studies on human glioblastoma tissue grade IV specimens showed significant expression of Twist1 and Sox2, known mesenchymal and stemness related markers, respectively, indicating their association with glial tumorigenesis and metastasis. The glioma stem cells obtained from CD133+ cells demonstrated increased expression of Twist1 and Sox2 accompanied by significant increase in the mesenchymal markers such as N-cadherin, vimentin and β-catenin. Our studies on glioma stem cells treatment with human umbilical cord blood derived mesenchymal stem cells, showed down regulation of Twist1 and Sox2 proteins, apart from other mesenchymal stem cell markers. Based on the in vitro experiments and in vivo intracranial xenograft mouse model studies we elucidated the potential therapeutic role of hUCBSC in suppressing glioma cancer stemness by the induction of mesenchymal to epithelial transition.
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 3376. doi:1538-7445.AM2012-3376
Abstract 3377: Oncolytic herpes simplex virus treatment of malignant peripheral nerve sheath tumor (MPNST) cancer stem-like cell orthotopic tumor model
Authors: Antoszczyk Slawomir J. , Rabkin Samuel D. 
Published: August 2012

Abstract
Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft tissue sarcomas arising in peripheral nerves that often occur in patients with neurofibromatosis type 1 (NF1) and have an extremely poor prognosis. Therapy consists of surgery followed by radiation and/or chemotherapy, which are generally of limited efficacy. Cancer stem cells are a subpopulation of tumor cells with stem cell like properties that are thought to be important in tumor progression, resistance to therapy, and metastasis. We have isolated MPNST cancer stem-like cells (MSLCs) from a human MPNST cell line by non-adherent sphere-culture in neurosphere media with EGF and bFGF (without serum). Implantation of the MSLCs in the sciatic nerve generates an orthotopic MPNST model in athymic mice. As the tumors grow, mice develop neurologic deficits that are quantified using a neurologic scoring system and externally measurable masses. As a novel therapeutic strategy we are using oncolytic herpes simplex virus (oHSV) vectors, which replicate in and kill tumor cells but not normal tissue. Tumor selectivity is engendered by mutating viral genes that make virus replication non-permissive in ‘normal’ cells, while retaining permissivity in cancer cells. For these studies, we used G47α, a multi-mutated oHSV with deletions in the α34.5 and ICP47 genes and an inactivating LacZ insertion in the ICP6 gene. G47α is very efficacious in many tumor models and is currently in clinical trial for glioblastoma. G47α was able to infect and spread in MSLCs in vitro and MSLC-derived tumors in vivo. Treatment of established MSLC-derived sciatic nerve tumors with a single intratumoral injection of G47α significantly prolonged survival of mice and reduced neurologic deficits. There was no difference in survival between mice treated with 2 x 10^5 pfu versus 2 x 10^6 pfu, although the mice receiving the higher virus dose had significantly higher neurologic score (less deficit). We describe a new preclinical MPNST model generated by implantation of human MSLCs into the sciatic nerve of immune-deficient mice. Treatment of established tumors by oHSV G47α is highly efficacious. These preclinical studies suggest that oHSV should be considered for the treatment of patients with MPNST.
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 3377. doi:1538-7445.AM2012-3377