bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1313: SPARC enhances radiosensitivity by inhibiting radiation-induced SOX-4 transcription factor in medulloblastoma
Authors: Chetty Chandramu , Bhoopathi Praveen , Gujrati Meena , Dinh Dzung H. , Rao Jasti S. , Lakka Sajani S. 
Published: February 2011

Abstract
Radiotherapy is frequently applied to control local tumors and works by directly killing tumor cells and inducing apoptosis of tumor vascular endothelial cells. Recently, it has been demonstrated that expression of secreted protein, acidic and rich in cysteine (SPARC), a member of the matricellular family of proteins that modulate cell-cell and cell-matrix interactions, correlates with radio-resistance in several tumor types. We therefore investigated the anti-tumor effects of combining exogenously expressing SPARC full length cDNA with irradiation (IR) on medulloblastoma in vitro and in vivo. We studied a combination response of SPARC overexpression and IR; specifically, we determined cell survival using clonogenic assay, conducted cell cycle analysis using flow cytometry, and assessed apoptosis using TUNEL staining in vitro in D283 and DAOY medulloblastoma cells. We demonstrated that SPARC overexpression prevented IR-induced p53 upregulation and p53 phosphorylation on serine 15. Irradiated tumor cells induced SOX-4-mediated DNA repair gene XRCC1, checkpoints-2, 1 and p53, which were abrogated with combined treatment of SPARC overexpression and IR as determined by western blotting. Further, DAOY orthotopic tumors treated with combined exogenously expressed SPARC and IR showed significantly greater growth inhibition than tumors treated with IR alone. These results suggest that SPARC overexpression in combination with radiotherapy can inhibit SOX-4-mediated DNA repair mechanisms induced by radiation and provide evidence of the anti-tumor efficacy of combining SPARC overexpression with ionizing radiation as a new therapeutic strategy for the effective treatment of medulloblastoma patients.
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 1313.
Abstract 1320: Molecular imaging of EMT reveals crosstalk of multiple pathways and provides novel sites for therapeutic intervention of EMT
Authors: Nyati Shyam , Bhojani Mahaveer Swaroop , Keshamouni Venkat , Schinske Katrina , Ross Brian D. , Rehemtulla Alnawaz 
Published: February 2011

Abstract
Ionizing radiation therapy have been also suggested to result in increased incidence of local or distant metastasis which is, at least in part, mediated by TGFß signaling. TGFß is a known potentiator of epithelial to mesenchymal transition (EMT), a complex process by which a tumor cell bolsters its metastatic potential by transmogrifying into a highly motile and invasive cell that is ready to take on the challenge of distant travel and resettlement in a new milieu. Therefore it is important, in order to increase efficacy of ionizing radiation, a combination therapy along with inhibitors of EMT pathway, be utilized in the treatment of cancers. To date there is no clinically relevant EMT inhibitor and therefore to assist in the process of identifying a small molecular weight inhibitor, we developed three distinct non-invasive and quantitative molecular imaging reporters for monitoring EMT. These were based on changes in expression profile of E-cadherin and N-cadherin and complementation of luciferase based TGFβR kinase (BTR) activity. In the lung cancer EMT model studies using TGFβ treated A549 cells we demonstrated a time and dose dependent increase in activity of luciferase reporter driven by N-cadherin promoter and a decrease in the activity of a luciferase reporter driven by E-cadherin promoter. These changes were validated by phenotypic alteration of A549 cells and by western blotting for signaling intermediates of EMT pathway. BTR (bioluminescent TGFβR reporter), was a gain of function sensor of SMAD2/3 phosphorylation wherein inhibition of TGFβR signaling leads to increased reporter activity. Such reporters are extremely useful in high throughput screening (HTS) as cytotoxic agents are eliminated early in the screening process. Treatment of A549 cells stably expressing BTR with SB431542 (TGFβR specific inhibitor) lead to a more than 20 fold increase in BTR activity. All three reporters were adapted for HTS assay and were used to screen a library of known kinase inhibitors. Analyses and validation of hits suggested that the loss of epithelial or gain of mesenchymal phenotypes are independent processes. Further it also highlighted complex cross talks between EMT and different pathways involving mTor, Src, p38 MAPK, Akt, JNK, PI3-K, PKA, PKC, GSK-3β, PDGFRK and EGFR. Efficacy of several lead compounds (Erlotinib, SP600125, SB203580, and SB431542) in combination with radiotherapy is being accessed to increase radiation sensitivity in epithelial cancers.
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 1320.
Abstract 1321: ERK1/2 show different activity profiles in vitro and in vivo subsequent to NOS inhibition
Authors: Robert Cardnell J G , Mikkelsen Ross B. 
Published: February 2011

Abstract
Nitric oxide (NO) is a crucial mediator of several survival mechanisms in tumor cells. Previous studies demonstrated that ionizing radiation (IR) stimulates NO generation activating pro-survival mechanisms including receptor tyrosine kinase and NF-κB-dependent pathways. In vitro, the IR-induced activation of these pathways survival pathways is inhibited by the NO synthase inhibitor, NG-nitro-L-arginine (L-NNA). Furthermore, the addition of L-NNA to the drinking water of flank xenograft bearing animals slows tumor progression, kills tumor cells and with radiation enhances animal survival. To elucidate the mechanism(s) by which L-NNA acts in such tumors we conducted experiments to study intracelluar signaling pathway activation by L-NNA with and without radiation.
Animals bearing flank xenografts received 10 Gy whole body irradiation either with or without prior L-NNA treatment. Tumors were excised at times post IR up to 30 minutes and protein lysates prepared for analysis by western blot. Cell monolayers were also similarly treated prior to cell lysis and protein analysis.
The activation (phosphorylation) of ERK1 and ERK2 was assayed in cultured monolayers and in flank xenografts using the A431 and FaDu cell lines. In vitro, the addition of L-NNA to the culture medium had little effect upon the activation of either ERK. In vivo however, L-NNA treatment up-regulated the phosphorylation of both ERK isoforms without irradiation and following irradiation elicited a significant enhancement of ERK1 phosphorylation and an inhibition of ERK2.
The current consensus is that ERK1 and ERK2, due to the similarities of their protein sequence, are similarly regulated and in general activate the same substrates. However, recent evidence has emerged to indicate distinct roles for ERK1/2 in addition to their overlapping actions. Indeed, the targeting of ERK2 has been seen to abolish Ras-dependent cell proliferation, an effect not observed with ERK1 targeting. Distinct signaling roles, and the opposite effects we observe upon ERK1 and ERK2 phosphorylation in vivo following L-NNA treatment may explain our previously reported findings of enhanced tumor control. In addition, these findings my shed light upon why ERK inhibitors show only moderate efficacy in clinical trials.
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 1321.
Abstract 1326: Differential cytokine-related signaling pathways responded to ionizing radiation in two lung adenocarcinoma cell lines
Authors: Liu Yen-Chun , Lu Tzu-Pin , Hsiao Tzu-Hung , Lu Jo-Yang , Hsu Feng-Ming , Cheng Jason Chia-Hsien , Yang Pan-Chyr , Lai Liang-Chuan , Chuang Eric Y , Tsai Mong-Hsun 
Published: February 2011

Abstract
Lung cancer is the leading cause of cancer-related mortality in the world. Metastasis is the leading cause of death and an enormous therapeutic challenge for non-small cell lung cancer. Radiation therapy is a treatment of unresectable lung cancer and may palliate the symptoms, locally control tumor growth, and provide higher survival rate. Yet, the molecular mechanism of radio-sensitivity in lung cancer still remains unclear. Two lung adenocarcinoma cell lines (CL1-0 and CL1-5) with different metastatic potentials were irradiated with 10Gy γ-radiation. CL1-5 showed more radio-sensitive than CL1-0 since the surviving fractions in CL1-5 were ten times lower than CL1-0 by clonogenic assays. Gene expression profiles were also analyzed using microarray in order to better understand differential gene expression between these two cell lines after radiation. Total RNAs for whole genome gene expression analysis were extracted from these two cell lines at 0, 1, 4, 9 and 24 h after 10Gy irradiation. Gene Set Enrichment Analysis (GSEA) revealed the pathways of death, cytokine, cell adhesion, IL1R, NF-κB, and TNFR had differences between these two cell lines following 10Gy radiation exposure. Tumor necrosis factor (TNF) cytokine family and interleukin-1 (IL1) was up-regulated in CL1-5 after irradiation. The expression level of TNF-α validated by quantitative real time PCR was increased in CL1-5 and was not detected in CL1-0. Therefore, TNF-α released into the culture medium in CL1-5 after irradiation might be a death signal to activate the NF-κB pathway and cause more cell death. Moreover, the different responses of NF-κB-related pathways induced by radiation between the two cell lines might contribute the different survival. These cytokine modulations might provide promising targets for further investigation regarding radiation treatment in lung cancer.
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 1326.
Abstract 1331: BMP-6 induce IL-1β expression levels in macrophage cells
Authors: Jung Yeon Suk , Lee Geun Taek , Lee Jae-Ho , Kwon Seokjoo , Kim Isaac Yi 
Published: February 2011

Abstract
Prostate cancer is the most 2ND leading cause of cancer death among men in United States. In metastatic prostate cancer patients, androgen ablation leads to symptomatic improvement and a decrease in serum prostate-specific antigen (PSA), but in almost patients the disease will eventually become refractory to hormone ablation. Previously, it has been published that IL-1β from macrophage regulates AR dependent signal transduction. In the prostate cancer, Bone morphogenetic protein-6 (BMP-6) levels are elevated than normal prostate. BMPs are members of TGF-β super family that regulates bone formation, hematopoiesis and development. BMP-6 is a pleiotropic growth factor with frequently increased levels of expression in the context of loss of its cognate receptors in prostate cancer cells. In this study, we demonstrated that BMP-6 secretion in CaP affects on macrophage cell line, RAW 264.7. Results showed that BMP-6 increased IL-1β levels in the macrophage and the induction is concentration and time dependent. In association with these observations, it is demonstrated that IL-1β expression by BMP-6 is mediated through ALK3, BMPRII and Smad1/4. Taken together, ERK inhibitor and JNK inhibitor may block IL-1β induction by BMP-6 completely in RAW264.7, macrophage cell line.
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 1331.
Abstract 1337: Soluble IL-6Rα regulates endothelial survival and vascular integrity and promotes ovarian cancer progression
Authors: Wei Lin-Hung 
Published: February 2011

Abstract
The immunoregulatory cytokine interleukin 6 (IL-6) has been recognized as an important modulator of ovarian cancer progression. However, whether IL-6 plays a direct role in the process remains controversial. On target cells, IL-6 binds to the IL-6 receptor (IL-6Rα) and signals via complex formation with the ubiquitously expressed gp130 receptor. Soluble IL-6 receptor protein (sIL-6Rα) binds IL-6 and can activate target cells that are deficient in or lack IL-6Rα, such as endothelial cells. This process is named trans signaling and serves as the major proinflammatory paradigm of IL-6 signaling under various pathologic conditions, including cancers. In the present report, we showed that sIL-6Rα is significantly elevated in malignant ascites from ovarian cancer patients and is associated with poor prognosis in advanced ovarian cancer patients. We identified that IL-6 trans signaling on endothelial cells prevents chemotherapy-induced apoptosis, induces endothelial hyperpermeability, and increases transendothelial migration of ovarian cancer cells. Selectively blocking the MAPK pathway with the ERK inhibitor PD98059 substantially reduced the IL-6/sIL-6Rα complex-mediated endothelial hyperpermeability. The activation of ERK by the IL-6/sIL-6Rα complex modulated endothelial integrity by initiating the activation of Src kinase activities and Y685 phosphorylation of VE-cadherin. Collectively, these data indicate that sIL-6Rα in malignant ascites of ovarian cancer may drive IL-6 signaling on endothelial cells, which, importantly, is involved in ovarian cancer progression. Specifically, blockage of sIL-6α-mediated signaling may present a promising therapeutic strategy for the management of ovarian cancer.
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 1337.
Abstract 134: DHA induces apoptosis via lipid rafts modulation and downregulation of EGFR and Akt inactivation
Authors: Kim Yong-Nyun , Lee Eun Jeong , Park Byung-Kiu 
Published: February 2011

Abstract
Lipid rafts are plasma membrane micro-domains that are known to be a depot of various signaling molecules, including EGF receptor. Intact lipid rafts are critical for Akt activation, which is important for cell survival. Therefore, lipid rafts have been involved in regulations of cellular functions such as cell survival and adhesion. (n-3) PUFAs, such as and eicosapentaenoic acid (EPA), are known to influence lipid rafts and have anti-cancer effects. In this study, we hypothesized that DHA induces apoptosis via alteration of lipid rafts-associated survival signaling and we investigated PUFA's anti-cancer effects and a possible mechanism involved in this process using human breast cancer cell line, MDA-MB-231. We found that DHA inhibited the growth of MDA-MB-231 cells up to 50-60% in the presence of DHA in a dose- and time-dependent manner, which was due to apoptosis. Interestingly, DHA treatment down-regulated multiple proteins that are associated with lipid rafts, including EGFR, AKT, Src in their protein levels, and thus inactivated those proteins. DHA stimulated rafts internalization from cell surface to the cytoplasm. DHA attenuated EGF-induced EGFR activation, probably due to EGFR down-regulation. Akt was inactivated with DHA treatment and the over-expression of active-Akt or wt-Akt was able to attenuate cell death by DHA. Cholesterol, a major component of rafts, reversed DHA-induced effects, including lipid raft internalization, Akt inactivation, and apoptosis. All these data indicate that DHA's anti-cancer effect is mediated by rafts internalization and subsequently Akt inactivation. Our study suggests that DHA is a putative modulator of lipid rafts and thus could be developed as an anticancer drug by targeting lipid rafts.
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 134.
Abstract 1342: Roles for CD40 ligation in tumor-macrophage interaction and tumor metastasis
Authors: Richardson Katharine S. , George Courtney , Suttles Jill , Stout Robert ,   Department of Microbiology and Immunology and James Graham Brown Cancer Center
Published: February 2011

Abstract
Macrophages are now known to play multiple roles in the progression and metastasis of many solid tumors. Although tumor-derived cytokines play a role in stimulating cytokine production by the macrophages, the extent of tumor-macrophage cross-talk remains to be explored. We have previously demonstrated that CD154:CD40 interactions are a dominant mechanism of contact-dependent communication between a variety of cell types. We therefore initiated a study of the role of CD154:CD40 interactions in tumor-macrophage interactions. Flow cytometric analysis reveals CD154 expression on 3LLC carcinoma cells. In corroboration of previous studies, co-culture of supernatants of tumor cell cultured with normal macrophages stimulated moderate cytokine production and this was equally effective with both CD40+/+ and CD40-/- macrophages. Co-culture of paraformaldehyde-fixed tumor cells with normal macrophages stimulated cytokine production by the macrophages, indicating that a cell contact dependent mechanism was also involved in the stimulation of macrophages by the tumor cells. Implantation of 3LLC tumors subcutaneously in CD40+/+ and CD40-/- mice resulted in similar growth of the primary tumor mass. However, no lung metastases were detectable in the CD40-/- mice. Bone marrow chimeric mice were generated by reconstituting irradiated CD40+/+ mice with either CD40+/+ or CD40-/- bone marrow. Nine weeks later, the splenic and peripheral blood leukocytes were &gt;94% donor derived. Both recipients of CD40+/+ and CD40-/- bone marrow displayed similar growth of the primary tumor and similar frequency of lung metastases, indicating that CD40 expression by bone marrow derived macrophages was not critical for tumor metastasis. The study demonstrates that ligation of CD40 on hematopoietic and non-hematopoietic cells may play critical roles in tumor progression and metastasis. This research was supported by grants from the Kentucky Lung Cancer Foundation (J.S.) and the Susan G. Komen Race for the Cure (R.S.) and by an NRSA T32 Postdoctoral Training Grant (K.R.) and a Ruth Kirschstein T31 Predoctoral Fellowship (C.G.).
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 1342.
Abstract 1348: Expression of Bone Morphogenetic Protein-6 closely related to Interleukin-10 in renal cell carcinoma and BMP-6 induced IL-10 in vitro
Authors: Lee Jae-Ho , Lee Geun Taek , Kwon Seok Joo , Kim Wun-Jae , Kim Isaac Yi 
Published: February 2011

Abstract
Primary kidney cancers are the third most common genitourinary tumor in USA in 2008. The majority of kidney tumors (80-85%) are classified as RCC. Since RCCs are generally resistant to chemotherapy and hormonal therapy, only a few therapeutic options are available, such as immunotherapy and molecular targeted therapy when surgical treatment is not available.
Bone morphogenetic proteins (BMPs) are the largest group of proteins in the TGF-β family. BMPs are known to have critical role in the various kinds of developmental processes and frequently over-expressed in the various cancers including prostate, bladder and kidney. Recently, BMP-6 has been reported to play a role in the immune system, inhibit T cell proliferation and activate the macrophages.
Interleukin-10 (IL-10) is a type II cytokine and has anti-inflammatory function in the immune system. It is reported that IL-10 or IL-10 receptor expression is related to the metastasis of RCC.
In this study, we found that BMP-6 expression level is tightly co-related to anti-inflammatory cytokine IL-10 expression (P &lt; 0.001) in 74 human RCC tissue samples. In vitro assay, BMP-6 induced IL-10 in dose and time dependent manners in the mouse peritoneal macrophage and RAW 264.7 cell line. This induction was inhibited by cycloheximide, not by Actinomycin D. IL-10 induction was mediated by the canonical Smad dependent BMP-6 signal pathway. In the IL-10 promoter luciferase activity assay, BMP-RII, ALK-2/3, Smad 5 and Smad 4 were responsible for the BMP-6 induced IL-10 expression. Smad 5 bound to the −800 to −600 region of IL-10 promoter in the ChIP assay. Also Smad-independent STAT3 pathway is required for the IL-10 induction. STAT3 also bound to the −800 to −600 region in ChIP assay and interacted with Smad 5.
In conclusion, BMP-6 expression related with IL-10 in RCC and the direct induction of IL-10 by BMP-6 was observed in macrophages. Thus, BMP-6 seemed to induce IL-10 in RCC and modulated tumor immune environment.
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 1348.