bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 143: CD24 induced miR-21 regulation is mainly mediated through Src, and both (CD24, Src) are post-transcriptionally downregulated by miR-34a
Authors: Muppala Santoshi , Mudduluru Giridhar , Leupold Jöerg H. , Sleeman Jonathan P. , Allgayer Heike 
Published: August 2012

Abstract
Cancer is a complex disease and multi step process evolving from malfunctions of complex molecules and their networks which regulate this process. Understanding these networks will be essential to combat cancer. In this study, we focussed on key players in such networks. CD24, Src and miR-21 have been described as adverse prognostic markers in a panel of malignancies. CD24 interacts and co-localizes with Src in lipid rafts. Pdcd4 and miR-34a have been described as tumor suppressor genes which are down regulated in different tumor types. In a series of colon and breast cancer cell lines, we found that CD24 activates Src and inducing the activation of c-Jun and expression of c-Jun and c-Fos. Furthermore, we show here that it regulates the promoter activity of miR-21 and its expression, which leads to inhibition of miR-21 targeted tumor suppressor genes. Similar results were found for constitutively active src. Co-transfection of a CD24 expression construct and an si-RNA silencing of Src showed that CD24 mediated upregulation of miR-21 is mediated through Src. Taken together, our results suggest that CD24 expression upregulates miR-21 in a Src dependent manner. Furthermore, we found that miR-34a targets the CD24- and Src-3′UTR as shown by luciferase assays performed either with wild type or mutated miR-34a seed sequences within these 3′UTRs. MiR-34a post-transcriptional inhibition of CD24 and Src downregulated the activation of c-Jun and expression of c-Jun and c-Fos, inhibited miR-21 promoter activity and expression, and induced the expression of tumor suppressor genes Pdcd4 and PTEN significantly (p=0.05). Furthermore, miR-34a inhibited Src induced colony formation, migration and invasion. Our results revealed complex networking between essential players in the progression of solid tumors especially colorectal cancer. These findings could help to focus new therapeutic approaches to overcome this and further solid cancer entities.
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 143. doi:1538-7445.AM2012-143
Abstract 1446: Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem
Authors: Grammel Daniel , Warmuth-Metz Monika , von Bueren André , Kool Marcel , Pietsch Torsten , Kretzschmar Hans , Rowitch David , Rutkowski Stefan , Pfister Stefan , Schüller Ulrich 
Published: August 2012

Abstract
Medulloblastoma is a malignant brain tumor of childhood that comprises at least four molecularly distinct subgroups. We have previously described that cerebellar granule neuron precursors may give rise to the subgroup with a molecular fingerprint of Sonic hedgehog (Shh) signaling. Other recent data indicate that precursor cells within the dorsal brain stem may serve as cellular origins for Wnt-associated medulloblastomas. In order to see whether Shh-associated medulloblastomas are also able to develop in the dorsal brainstem, we analyzed two lines of transgenic mice with constitutive Shh signaling in hGFAP- and Math1-positive brainstem precursor populations, respectively. Our results show that in both of these lines, medulloblastomas arise from granule neuron precursors of the cochlear nuclei, a derivative of the auditory lower rhombic lip. This region is distinct from derivatives of precerebellar lower rhombic lip where medulloblastoma arise in mice with constitutive-active Wnt signaling. With respect to their histology and the expression of appropriate markers, Shh tumors perfectly resemble the human counterparts. Moreover, we find that in a series of 63 human desmoplastic medulloblastomas, 19 (30%) have a very close contact to the cochlear nuclei on MRI imaging. In conclusion, we suggest that precursors of the rhombic lip which may either develop into cerebellar or into cochlear granule neurons, may give rise to Shh-associated medulloblastoma.
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 1446. doi:1538-7445.AM2012-1446
Abstract 1457: Valproic acid enhances radiation therapy by protecting normal hippocampal neurons and sensitizing malignant glioblastoma cells
Authors: Sweeney Kyle , Bhave Sandeep , Hu Rong , Fong Jerry , Hallahan Dennis , Thotala Dinesh Kumar 
Published: August 2012

Abstract
Neurocognitive deficits are devastating sequelae that follow cranial irradiation in patients with medulloblastoma and leukemia. Valproic acid (VPA) has been used effectively as a neuroprotector in various neurological insults. In the present study we demonstrate that VPA could be used to protect hippocampal neurons from the damaging effects of radiation. The effect of VPA pretreatment on cell death was examined using clonogenic survival assays. Mouse hippocampal neurons, HT-22 were treated with 0.6 mM VPA for 7 days prior to irradiation. A significant increase in survival was seen in HT-22 cells treated with VPA compared to cells treated with radiation alone. In contrast, VPA treatment decreased the survival of irradiated cancer cells, D54 and GL-261 compared to radiation alone. To elucidate the mechanism of this selective increased survival in normal hippocampal cells we monitored for program cell death by Annexin V-FITC or DAPI staining. Irradiated HT-22 cells which were pretreated with VPA demonstrated 2 fold decrease in apoptosis than irradiated cells. Similar results were obtained using irradiated mice. Seven-days old C57BL6J pups were either irradiated with the single dose of 7 Gy or treated with VPA (200mg/Kg) followed by 7Gy irradiation. VPA pretreatment protected hippocampal neurons from radiation-induced apoptosis as demonstrated by counting the pyknotic nuclei in the subgranular zone of the hippocampal region. Western immunoblotting of HT-22 cells revealed that VPA not only inhibited HDAC, but also inhibited glycogen synthase kinase-3β (GSK-3β), an enzyme required for apoptosis. A heterotopic glioma model of GL-261 was used to evaluate the tumor growth delay following treatment with VPA (200 mM) and radiation (five fractions of 2Gy). VPA alone delayed the tumor growth; however VPA in combination with radiation significantly delayed tumor growth. In conclusion, VPA protected hippocampal neurons from radiation-induced damage in vitro and in vivo. This protection is specific to hippocampal neuronal cells and not to cancer cells. The molecular mechanism could involve enzymatic inhibition of both HDAC and GSK-3β. VPA could be used as a novel therapy for the prevention of neurocognitive deficits resulting from cranial irradiation.
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 1457. doi:1538-7445.AM2012-1457
Abstract 1470: Enhancing radiation therapy by simultaneous inhibition of thioredoxin- and glutathione-dependent metabolism
Authors: Rodman Samuel N. , Zhu Yueming , Ronnfeldt Tyler J. , Wilke Werner W. , Allen Bryan G. , Spitz Douglas R. , Fath Melissa A. 
Published: August 2012

Abstract
Cancer cells have been shown to be in a constant state of metabolic oxidative stress, concurrent with an elevated level of reactive oxygen species (ROS). In order to facilitate survival in the face of increased steady-sate levels of ROS, cancer cells rely on glutathione (GSH) and thioredoxin (Trx) dependent metabolism. We have recently demonstrated that the simultaneous inhibition of GSH using Buthionine sulphoximine [(BSO), a GHS synthesis inhibitor] and thioredoxin reductase using auronofin [(Au), a thioredoxin reductase inhibitor] effectively chemo-radio-sensitized lung cancer cells via a mechanism involving oxidative stress. In this work we extend this observation to demonstrate that Au 2 mg/kg and BSO 450 mg/kg, given prior to ionizing radiation (6 Gy x 2 doses) can significantly delay tumor growth rate for mice treated with radiation alone in H292 lung cancer xenografts. In addition, we demonstrate through clonogenic survival assays that the combination of Au (250-500 nM) and BSO (100 μM) radio-sensitizes two breast cancer cell lines in vitro, and more importantly the combination of Au and BSO given by intraperitoneal injection prior to radiation decreases the percent of breast cancer stem/progenitor cells in vivo. The rate limiting substrate for GSH synthesis is cysteine, whose level is controlled by the xc- cystine/glutamate antiporter. Sulfasazine (SSZ) has been shown to be a potent inhibitor of the xc- cystine/glutamate antiporter. We demonstrate that SSZ (0.1-0.5 mM) decreases total GSH (up to 90%) levels in a dose dependent manner in both Mia PaCa-2 and PANC-1 human pancreatic cell lines. The combination of Au (250 nM for 3 hours) with SSZ (0.2 mM for 24 hours) demonstrates an 80% and 30% decrease in clonogenic cell survival in MiaPaCa-2 and PANC-1 pancreatic cells that is inhibited by treatment with the thiol antioxidant, 15 mM N-acetylcysteine. These results indicate that inhibition of hydroperoxide metabolism using pharmacologically relevant agents to simultaneously disrupt GSH and Trx system, can sensitize multiple cancer cell lines to radiation. These results support the hypothesis that standard of care radiotherapy protocols could be enhanced using SSZ, Au, and/or BSO. Supported by The Iowa Center for Research by Undergraduates, R21CA139182, R01CA133114 and a Breast Cancer Research Group Seed Grand from the Holden Comprehensive Cancer Center.
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 1470. doi:1538-7445.AM2012-1470
Abstract 1501: Direct interaction between human pancreatic cancer stem cells and stromal cells remodels extracellular matrix formation for cancer stem cell niche
Authors: Hori Yuichi , Shimizu Kazuya , Chiba Sachie 
Published: August 2012

Abstract
Human pancreatic ductal adenocarcinomas consist of highly heterogeneous tumor cells that form tumor microenvironment cooperatively with stromal cells. Pancreatic cancer stem cells are reported to play important roles in chemotherapy and radiotherapy resistance. However, little is known about the microenvironment of pancreatic cancer stem cells. To investigate the microenvironment of pancreatic cancer stem cells with stromal cells, we isolated and characterized a novel subpopulation of pancreatic cancer stem cells, tentatively named KMC cells, from seven disseminated pancreatic ductal adenocarcinoma patients. KMC cells required direct cell-cell contacts to stromal cells for their clonogenic growth. KMC cells had self-renewal capacity and in vivo tumorigenicity. In vitro experiments demonstrated that stromal cells induced extracellular matrix (ECM) formation with thin filament structures and KMC cells changed the thin filament structures to basic lamina-like thick and bundled filament structures where laminin proteins were enriched. Moreover, KMC cells induced mRNA expression of laminin-5α and collagen type-IV in stromal cells, major components of basic lamina, but reduced mRNA expression of collagen type-I, collagen type-III, and fibronectin-I in stromal cells, major components of ECM. Our findings demonstrated that pancreatic cancer stem cells have the potential to form their microenvironment with basic lamina-like structures cooperatively with stromal cells, suggesting that targeting KMC cells and KMC cell-induced basic lamina-like structures in cancer therapy may improve prognosis of disseminated pancreatic ductal adenocarcinoma patients.
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 1501. doi:1538-7445.AM2012-1501
Abstract 1503: Cancer testis antigen SPANXB2 and prostate cancer progression: Human prostate stroma promotes SPANXB2 expression
Authors: Li Hangwen , krou Ericka Diallo , Ressler Steven , Sreekumar Arun , Ayala Gustavo , Rowley David , Palapattu Ganesh 
Published: August 2012

Abstract
A critical problem in prostate cancer is our inability to reliably distinguish indolent from aggressive disease. Recent evidence has implicated a class of genes, termed Cancer Testis Antigens (CTA) that uniquely expressed on malignant tissue, in cancer progression. CTA SPANXB2 was reported to be associated with aggressive and metastasis of melanoma and other cancers. The role of SPANXB2 in prostate cancer is still uncertain. In preliminary studies, we observed that the CTA SPANXB2 is up-regulated in mRNA level in metastatic prostate cancer xenograft models (PC3 cells injected in mouse dorsal prostate with Matrigel). Compared with other injection sites, mouse dorsal prostate enriched prostate stroma. Therefore, we further tested whether prostate stroma is the key factor to influence SPANXB2 expression and enhance the metastasis potential of prostate cancer cells. We validated this through an in vitro epithelial-stroma interaction models: GFP labeled PC3 cells were placed on the top of human prostate stromal cells (HPS-19I); two days later PC3-GFP cells were isolated through flow cytometry with high purity (&gt; 99%). By real time PCR, the expression level of SPANXB2 in these purified PC3-GFP cells was found to be upregulated up to 10 folds. We also tested DU145 and LNCaP in this same model, and similar results were obtained. We further examined the migration and invasion ability of these cells and found that stromal exposed cells gained an enhanced ability to migrate and invade. Interestingly, we also observed that the stem cells marker, CD24 was highly up -regulated up to 6 folds in PC3 cells after co-culture with HPS-19I. In addition, we treated PC3 cells with TGF-β1 and TGF-β2, and noted that SPANXB2 and CD24 were significantly increased in PC3 cells after 24 hours treatment with TGF-β2. Our results reveal that i) the interaction between human prostate stromal cells and prostate cancer cells promote CTA-SPANXB2 and CD24 expression in prostate cancer cells, ii) these interactions further enhance the migration and invasion ability of prostate cancer cells and iii) TGF-β2 may regulate SPANXB expression relevant cells. These data provide rationale for studying SPANXB2 in stromal-epithelial interactions and may be potentially used to pinpoint druggable targets that drive metastasis and that distinguish indolent from aggressive prostate cancer. Keywords: Cancer testis antigen, SPANXB2, Prostate cancer, Metastasis, Stoma
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 1503. doi:1538-7445.AM2012-1503
Abstract 1504: Dual effect of MMP-9 and its fibronectin-like domain in tumor growth and invasion
Authors: Dayer Cynthia , Fusco Carlo , Le-Bitoux Marie-Aude , Stamenkovic Ivan 
Published: August 2012

Abstract
Tumors are often compared to wounds that do not heal, where the crosstalk between tumor cells and their surrounding stroma is crucial at all stages of development from the initial primary growth to metastasis. Similar to wound healing, fibroblasts in the tumor stroma differentiate into myofibroblasts, also referred to as “cancer-associated fibroblasts” (CAFs), primarily, but not exclusively, in response to transforming growth factor-β (TGF-β). Myofibroblasts in turn enhance tumor progression by remodeling the stroma. Among molecules implicated in stromal remodeling, matrix metalloproteinases (MMPs), and MMP-9 in particular, play a prominent role. However, the mechanisms that regulate MMP-9 activation and function remain poorly understood. Recent evidence indicates that tumor cell surface association of MMP-9 is an important event in its activation, and more generally in tumor growth and invasion. Based on these observations, we addressed the potential association of MMP-9 activity with cell-surface recruitment on human fibroblasts. We show for the first time that recruitment of MMP-9 to the MRC5 fibroblast cell surface occurs through the fibronectin-like (FN) domain, found only in MMP-9 and MMP-2. Functional assays suggest that the active form of MMP-9 triggers α-smooth muscle actin (αSMA) expression in resting fibroblasts that reflects myofibroblast differentiation, possibly through TGF-β activation. Preliminary xenograft experiments using HT1080 fibrosarcoma or MDA-MD231 breast adenocarcinoma cells stably expressing the FN domain of MMP-9 in NOD/SCID mice revealed decreased primary tumor growth suggesting that the FN domain alone can displace MMP-9 proteolytic activity from the cell surface. However, in the context of metastasis, expression of the FN domain by these same tumor cells dramatically increases their metastatic proclivity whereas expression of wt MMP-9 either promotes no change or actually reduces the number of metastases. These observations suggest a dual role of MMP-9 and its FN domain in primary tumor growth and metastasis, illustrating protective effects of MMPs in tumor progression and 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 1504. doi:1538-7445.AM2012-1504
Abstract 1505: Stroma-mediated DNA damage resistance of human breast cancer
Authors: Boelens Mirjam C. , Wu Tony J. , Yoon Taewon , Azzam Diana , Slingerland Joyce M. , Minn Andy J. 
Published: August 2012

Abstract
Chemotherapy and radiation are often employed to decrease breast cancer deaths. However, patients with metastatic disease invariably manifest resistance to chemotherapy and/or radiation, ultimately causing breast cancer deaths due to ineffective treatment. We have defined a gene expression signature, the interferon-related DNA damage resistance signature (IRDS), that is highly associated with radiation and chemotherapy resistance of breast cancer in both cell lines and patients. Interestingly, IRDS-mediated resistance in experimental models appears to be much greater in vivo than in vitro, suggesting a potential contribution of the tumor microenvironment. To address the question of whether the tumor microenvironment plays a role in IRDS-mediated radioresistance, we investigated the influence of heterotypic interactions between breast cancer and stromal cells on IRDS expression. We found that breast cancer cell lines primarily of the basal subtype increase IRDS expression after tumor-stroma interaction, resulting in enhanced resistance to radiation and chemotherapy. This increase in IRDS and DNA damage resistance depends on STAT1, a member and transcriptional regulator of the IRDS. Tumor-stroma interaction also leads to induction of a population of breast cancer cells with properties of breast cancer stem-like cells (BCSC). Evaluation of a tumor-stroma extracellular interactome revealed that a stroma-directed NOTCH signaling pathway can cooperate with STAT1 signaling to regulate common target genes. STAT1 and NOTCH signaling direct the expansion and/or survival of BCSC, an inherently DNA damage resistant population. Using available primary breast cancer data sets, a similar activation of NOTCH signaling is observed, as well as transcriptomic activation of the NOTCH pathway in breast cancer. Importantly, a marker for NOTCH signaling cooperates with the IRDS to identify breast cancer patients likely to fail adjuvant chemotherapy. The ability of gamma secretase inhibitors to inhibit both stroma-mediated expansion of BCSC and DNA damage resistance highlights the therapeutic potential of this class of targeted agents for breast cancers that express the IRDS. In conclusion, our data suggests that stroma can regulate DNA damage resistant BCSC populations in a subset of basal breast cancers through STAT1 and NOTCH signaling.
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 1505. doi:1538-7445.AM2012-1505
Abstract 1508: TNF-receptor 2 plays a critical role in liver metastasis by regulating sinusoidal endothelial VCAM-1 expression, LY6G+ leukocyte recruitment and transendothelial migration
Authors: Ham Boram , Auguste Patrick , Evrard Maximilien , Wang Ni , Lu Yifan , Brodt Pnina 
Published: August 2012

Abstract
The hepatic microenvironment can play an important role in promoting liver metastasis. We and others have shown that when metastatic carcinoma cells enter the liver, a rapid inflammatory response mediated by TNF-α is triggered, enabling tumor transendothelial migration and metastasis. TNF-α binds to the cell surface through two receptors; the p55/p60 TNFR1 and the p75/p80 TNFR2. To elucidate the roles of these receptors in the inflammatory cascade and in liver colonization by tumor cells, we used mice with tnfr1, tnfr2 and combined tnfr1/tnfr2 gene deficiencies and investigated parameters of the host response and the outcome of metastasis in these mice using the highly metastatic mouse colon carcinoma MC-38 and lung carcinoma H-59 cells. We found that experimental liver metastasis following intrasplenic/portal inoculation of the tumor cells was markedly reduced in TNFR2−/− and even further in TNFR1−/−/TNFR2−/- female mice as compared to wild-type controls but no reduction was observed in TNFR1−/− mice. To identify the underlying mechanism(s), we investigated changes in the liver microenvironment following tumor inoculation using a combination of immunohistochemistry, confocal microscopy, qRT-PCR, and cytokine/chemokines profiling. We found that while in wild-type and TNFR1−/- mice, VCAM-1 expression on the sinusoidal endothelium was significantly upregulated within 16 hr post tumor injection, it was unchanged in TNFR2−/− and double negative female mice. In addition, qRT-PCR analysis revealed that the production of the neutrophil chemokine CXCL1, while upregulated in control mice, was suppressed in TNFR2−/− mice. These changes were associated with a parallel decrease in Ly6G+ neutrophil recruitment into extravascular, pro-metastatic niches 16-48 hr post tumor inoculation. Interestingly, these reductions were not observed in male TNFR2−/− mice and correspondingly, their metastatic burden was not reduced relative to control mice. Taken together, the results suggest that TNFR2 plays a critical and gender-specific role in Ly6G+ cell recruitment into the tumor-microenvironment by regulating sinusoidal endothelial VCAM-1 expression and chemokine production. In turn, the recruitment of these cells into extravascular pro-metastatic niches appears to promote liver metastasis. Supported by grant MOP-80201 from the Canadian Institute for Health Research. (to PB) and by a McGill Integrated Cancer Research Training Program fellowship (to BH).
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 1508. doi:1538-7445.AM2012-1508