bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1269: Molecular changes underlying bortezomib sensitization of cancer cells to TRAIL-mediated apoptosis
Authors: Brooks Alan D. , Thompson Candace R. , Sayers Thomas J. 
Published: February 2011

Abstract
We have previously shown that the proteasome inhibitor bortezomib (Velcade/PS-341) specifically sensitized certain human renal carcinoma (RCC) lines to apoptosis induced by the TNF family-member TRAIL. A comparison of RCC sensitized by bortezomib with those that remained resistant revealed no major bortezomib-induced changes in the levels of many apoptosis proteins. Also, when bortezomib treatment induced specific changes in protein levels (mcl-1, Bik and survivin) these changes did not directly correlate with subsequent sensitization or resistance to TRAIL apoptosis. In addition changes in surface expression of TRAIL receptors (DR4, DR5, DcR1, DcR2) following bortezomib treatment also did not correlate well with sensitization or resistance. By contrast, enhanced procaspase 8 activation following bortezomib pretreatment and TRAIL exposure was only observed in the sensitized RCC. This increase in procaspase 8 activation in cell extracts of sensitized RCC was observed using both enzyme assays as well as western blotting for activated (cleaved) caspase 8. Use of the apoptosis-resistant MCF-7 cell line demonstrated that bortezomib pretreatment increased caspase-8 activation on exposure to TRAIL even in the absence of subsequent downstream caspase activation and apoptosis. This suggests that bortezomib increases caspase-8 activation upstream at the death-inducing signaling complex (DISC). Furthermore, immunoprecipitation of the DISC demonstrated higher levels of active caspase 8 in the DISC of sensitized but not resistant RCC. Interestingly ACHN (a bortezomib-sensitized RCC) was also sensitized to TRAIL apoptosis when adherence was prevented by coating cell culture dishes with poly-HEMA. In parallel this loss of adherence abolished the sensitizing effects of bortezomib treatment. Bortezomib and poly-HEMA treatment of RCC both result in reduced cellular proliferation, and may change cell adherence properties. Whether both of these treatments sensitize RCC to TRAIL using common or distinct molecular pathways is under further investigation.
Funded in part by DHSS #NO1-CO-12400
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 1269.
Abstract 1272: Targeting glioma stem cells through death receptor activation by AdsTRAIL
Authors: Puduvalli Vinay K. , Liu Yuanfang , Colman Howard , Lang Frederick , Xu Jihong 
Published: February 2011

Abstract
Emerging data suggests that human malignant gliomas may be sustained by the activity of a subpopulation of cells which have stem like characteristics; these glioma stem cells (GSC) exhibit resistance to conventional treatments and constitute novel targets for therapeutic strategies against these malignancies. The goal of this study was to examine whether GSC could be targeted using AdsTRAIL, an adenoviral vector expressing soluble TRAIL and to determine if AdsTRAIL effects could be potentiated by suppressing inhibitors of TRAIL-induced apoptosis. Analysis of expression of TRAIL activated death receptor pathway components showed that DR4, DR5, FADD and Caspase 8 were expressed in the majority of GSC although some cell lines expressed only one of the death receptors (DR4 or DR5). Several cell lines also showed high level of expression of survivin, an anti-apoptosis protein. Treatment of GSC, cultured as tumor spheres in stem cell medium, with AdsTRAIL resulted in dissociation of spheres into a single cell suspension and induction of apoptosis dose and time dependent manner, changes which were not seen in the AdEGFP control; no morphologic changes or induction of apoptosis was seen in GSC spheres treated with purified soluble TRAIL. To determine if induction of apoptosis by AdsTRAIL could be enhanced by suppressing inhibitors of TRAIL induced apoptosis, GSC were treated with AdXAF1, an adenoviral construct expressing XAF1, an endogenous inhibitor of XIAP, prior to exposure to AdsTRAIL. Viability was monitored by expression of the fluorescent marker EGFP in the treated cells. The combination of AdsTRAIL and AdXAF1 potently induced apoptosis to a greater degree than either agent alone. These results suggest that despite their resistance to conventional therapeutic agents such as chemotherapy and radiation, glioma stem cells could potentially be targeted by apoptosis inducing biological agents such as AdsTRAIL. Further characterization of the effects of AdsTRAIL against GSC is required to fully assess the potential of this agent against treatment resistant malignant gliomas.
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 1272.
Abstract 1278: Simultaneous downregulation of uPAR and cathepsin B inhibits angiogenesis and migration and induces caspase 8-mediated apoptosis in U87 stem cells and 4910 glioma xenograft stem cells
Authors: Gopinath Sreelatha , Malla Rama Rao , Gondi Christopher S. , Fassett Daniel , Klopfenstein Jeffrey D. , Dinh Dzung H. , Gujrati Meena , Rao Jasti S. 
Published: February 2011

Abstract
Malignant gliomas are characterized by invasive and infiltrative behavior. Gliomas are considered to be heterogeneous bulk tumors that comprise differentiated and undifferentiated cells with self-renewal and partial differentiation capabilities. These glioma-initiating cells (GIC) are responsible for the initiation and recurrence of gliomas even after various treatments. As such, novel therapies should target GIC. Cathepsin B and urokinase-type plasminogen activator receptor (uPAR) are overexpressed in gliomas, including GIC. We isolated GIC from U87 (U87S) and 4910 (4910S) by sorting the cells for both CD133 and STRO-1 by FACS analysis. The stem cell nature of these cells was confirmed by neurosphere formation assay and western blot analysis for CD133 and STRO-1 expression. GIC cells expressed 2 to 3-fold increased levels of CD133 and STRO-1 as compared to glioma cells (U87N and 4910N). By isolating and utilizing GIC, we demonstrate that downregulation of uPAR (pU) and cathepsin B (pC) individually and simultaneously (pCU) lead to remarkable inhibition of angiogenesis and migration and activated caspase 8-mediated apoptosis in GIC and U87N and 4910N cells. The treatment retarded the expression of pro-angiogenic molecules in both stem cells and glioma cells but responded differently in terms of expression of certain molecules, such as angiogenin and TIMP-1. Similarly, an apoptotic antibody array revealed that stem cells and glioma cells respond differently to pCU treatment, but both sets of cells exhibited increased expression of pro-apoptotic molecules. This induction of apoptosis was also confirmed by cleavage of caspase 8, caspase 3 and PARP as well as TUNEL assay. Similarly, spheroid migration and matrigel invasion assays, revealed that downregulation of uPAR and cathepsin B inhibited cell migration by 70-75% and 45-50% and invasion by 75-80% and 45-50% in GIC and normal glioma cells, respectively. Untreated glioma stem cells were more migratory (∼30%) and invasive (30-40%) as compared to normal glioma cells. In vivo studies showed few to no tumor cells in brain sections of mice implanted with either GIC or normal glioma cells treated with pCU as determined by H&E staining. These results indicate the potential of RNAi-mediated downregulation of uPAR and cathepsin B in developing new therapeutics for GIC in particular and gliomas in general.
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 1278.
Abstract 1285: The effects of the HK5-ferritin interaction and iron on tumor angiogenesis
Authors: Huhn Annissa J. , Parsonage Derek , Torti Suzy V. , Hollis Thomas 
Published: February 2011

Abstract
Angiogenesis, or the development of new blood vessels from existing blood vessels, is a process essential to wound healing, reproduction, and tumor growth. Tumor angiogenesis is an important factor in the growth and spread of cancer. In order for tumors to grow beyond 2mm^3, vasculature is necessary to provide oxygen and nutrients and remove waste products. The imperfect blood vessels built within tumors also allow tumor cells to travel through the bloodstream and metastasize. Endogenous inhibitors of angiogenesis are known to form from plasma proteins. For example, angiostatin is derived from plasmin. A newly described angiogenesis inhibitor derived from high molecular weight kininogen (HK) is domain 5 of HK (HK5). HK5 has been shown to inhibit endothelial cell proliferation, migration and tube formation. HK5 binds to the endothelial cell surface receptors uPAR, cytokeratin-1, gC1qR and tropomyosin to disrupt angiogenic signaling. Our laboratory has shown that the iron storage protein ferritin binds to HK5, inhibiting its antiangiogenic effects and thereby allowing endothelial cells to migrate and proliferate. We have begun to investigate the physical interaction of ferritin with the HK5 protein with the long-term goal of developing inhibitors of the HK5-ferritin interaction. Human recombinant HK5 and ferritin H were purified and their interaction studied using fluorescence anisotropy. The two proteins were found to bind with a Kd of 1.36μM. The influence of metals on the interaction was also evaluated. We found that in the presence of iron the interaction between ferritin and HK5 was maximal, while in the presence of zinc, the interaction was minimal. EDTA pretreatment of the two proteins further improved binding. The results suggest that iron is essential to the optimal binding interaction of HK5 and ferritin. Future studies will be directed at the identification of specific amino acid residues involved in this interaction. (supported by NIH R01 DK071892)
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 1285.
Abstract 1289: The recombinant kringle domain of urokinase plasminogen activator (uPA) inhibits VEGF165-induced proliferation of HUVEC cells
Authors: Kim Byeong Mo , Joe Young Ae , Hong Sung Hee 
Published: February 2011

Abstract
Angiogenesis is associated with tumor growth, invasion and metastasis. Many growth factors and cytokines are engaged in angiogenesis. Among them, vascular endothelial growth factor (VEGF) is one of the most potent and specific angiogenic factors and stimulates endothelial cell proliferation, protease expression, migration and subsequent differentiation to form new vessels. It has been previously revealed that the recombinant kringle domain of urokinase plasminogen activators (uPA) (UK1) exerts antiangiogenic activity against VEGF-induced angiogenesis using in vitro or in vivo model. In this study, we explored molecular signaling mechanisms involved in this activity. The antiangiogenic mechanism of UK1 was investigated in vitro by measuring phosphorylation levels of VEGF signaling proteins. VEGF165 stimulates the phosphorylation of VEGF/VEGFR2 signal molecules, and pre-treatment with UK1 blocked not only VEGF-induced phosphorylation of VEGFR2 but also phosphorylations of downstream signaling proteins, such as Erk and Akt. In addition, VEGF induced secretion of MMP2 in HUVEC, which efficiently suppressed by UK1 pre-treatment. However, mRNA levels of MMP2 as well as of MMP9, Timp1 and Timp2 remained unaffected by UK1. Overall, our findings suggest that UK1 inhibits VEGF-induced proliferation and migration of HUVEC by suppressing VEGF/VEGFR2-mediated angiogenic signals and MMP2 activity.
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 1289.
Abstract 1295: Inhibition of platelet derived growth factor receptor tyrosine kinase reduces lymphangiogenesis of human gastrointestinal cancer
Authors: Kodama Michiyo , Kitadai Yasuhiko , Sumida Tomonori , Ohnishi Mayu , Ohara Eiji , Shinagawa Kei , Tanaka Miwako , Tanaka Shinji , Yasui Wataru , Chayama Kazuaki 
Published: February 2011

Abstract
Objective: Vascular endothelial growth factor (VEGF)-C/D induces lymphangiogenesis by activating VEGF receptor (VEGFR)-3, which is expressed on lymphatic endothelial cells. Platelet derived growth factor receptor (PDGF-R) has also been detected on lymphatic endothelial cells and PDGF-BB acts as a lymphangiogenic factor in murine fibrosarcoma. We have previously reported that PDGF-R is expressed by lymphatic endothelial cells in human gastric cancer and its expression levels in tumor tissue correlate with lymph node metastasis. In this study, we examined whether inhibition of PDGF-R tyrosine kinase signaling by imatinib affects lymphangiogenesis and lymph node metastasis of human gastrointestinal cancer cells growing in the orthotopic site of nude mice. Methods: TMK-1 human gastric cancer cells or KM12SM human colon cancer cells were injected into the orthotopic site of nude mice. Groups of mice (n=10) received saline (control), imatinib, the cancer chemotherapeutic irinotecan, or a combination of imatinib and irinotecan. The lymphatic vessels were then stained with antibodies against Lyve 1. Results: Lymphatic endothelial cells as well as activated fibroblasts in the tumor stroma express PDGF-R. Four weeks of treatment with imatinib and irinotecan significantly inhibited lymph node metastasis (relative to control or single-agent therapy). Imatinib alone or in combination with irinotecan significantly decreased number and area of lymphatic vessels in the tumor stroma. Conclusion: Administration of a PDGF-R tyrosine kinase inhibitor in combination with irinotecan inhibits the lymph node metastasis of orthotopically implanted gastrointestinal cancer cells in nude mice by blocking PDGF-R signaling in tumor-associated lymphatic endothelial cells.
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 1295.
Abstract 1298: Mechanisms of endothelial trophic support of genitourinary tumors
Authors: Liang June , Tilki Derya , Kobayashi Hideki , Rafii Shahin , Seandel Marco 
Published: February 2011

Abstract
Background: Classically, principal roles of the vascular endothelium have been considered to be support of oxygenation, nutrient delivery, waste product removal, and cellular trafficking. But the endothelium may also release paracrine signals to neighboring cells. Targeting such interactions could lower the threshold for sensitivity to conventional therapies, if pro-survival signals are blocked. We hypothesize that a subset of tumor cells are protected by endothelial-derived NF-kappa B (NF-KB)-mediated trophic signals that enhance tumor growth. Due to the confounding effects of circulating signals, it has been difficult to address these hypotheses using animal models. In contrast, in vitro models are limited by the requirement of primary endothelial cells (PECs) for serum and/or growth factors (GFs), complicating efforts to identify novel secreted factors. We employed a strategy to maintain PECs without serum by expressing the non-transforming adenoviral E4ORF1 gene. Under these conditions, E4ORF1-expressing (E4) PECs retain features of native tumor endothelium, including responsiveness to endothelial GFs and the ability to form functional vessels in vivo. Using solid tumor cell lines, including testicular germ cell tumor (GCT) and prostate cancer (PC) lines, we tested the ability of E4 PECs to support solid tumor progression. Methods: Constitutive expression of E4ORF1 in primary human umbilical vein endothelial cells (HUVECs) was achieved using lentivirus. Co-culture assays in serum-free media were used to test the effect of E4 PECs on cancer cell survival, proliferation and clonagenicity. Xenografts were performed by delivering cancer cells subcutaneously in the presence or absence of E4 PECs. Results: We first identified minimal media in which significant cancer cell proliferation was not observed in the absence of feeders. Under these conditions, we observed massive expansion of cell numbers for certain lines (e.g., 27×1) in the presence of E4 PECs (62.6+/-3.1 fold [mean+/-s.d.] for 27×1) vs. feeder-free control (2.2+/-0.1 fold) over 4 days. Changes in expression of stem cell-related genes in tumor cells during exposure to E4 PECs were examined to determine the frequency of stem-like cells in the culture. Results of co-inoculation studies using tumor cells in NOD-SCID mice will be discussed. Interventions to address the role of endothelial inside-out NF-KB signaling are on-going. Conclusions: Under stressful microenvironmental conditions, some but not all solid tumor cell lines require endothelial-derived growth and survival signals. Targeting these signals may lead to alternate strategies for eliminating residual tumor present after optimal therapy.
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 1298.
Abstract 1302: Role of the low-affinity leukotriene B4 receptor BLT2 in VEGF-induced angiogenesis
Authors: Hong Joe Y. , Kim Geun-Young , Kim Jae-Hong 
Published: February 2011

Abstract
The leukotriene B(4) (LTB(4)) receptor BLT2 is expressed in endothelium, but no clear physiological function for it has yet been identified, especially in vascular angiogenesis. The purpose of this study is to characterize the potential function of BLT2 in vascular endothelial growth factor (VEGF)-induced angiogenesis. VEGF significantly upregulates BLT2 expression in human umbilical vein endothelial cells (HUVECs), and BLT2 knockdown by siRNA or inhibition of BLT2 by a specific BLT2 antagonist LY255283 attenuates VEGF-induced angiogenesis, which was determined by its effect on the formation of tube-like structures and on transmigration. The role of BLT2 in VEGF-induced angiogenesis was more evident in vivo, where BLT2 inhibition by LY255283 almost completely blocked VEGF-induced vessel formation in Matrigel-plug assays. In addition, we found that VEGF upregulates synthesis of the BLT2 ligand, 12(S)-hydroxyeicosatetraenoic acid (HETE). siRNA knockdown of 12-lipoxygenase (12-LO) expression attenuates VEGF-induced angiogenesis in HUVECs, and the addition of 12(S)-HETE to the 12-LO knockdown-HUVECs restores VEGF-induced angiogenesis. The activation of BLT2 itself by either 12(S)-HETE or LTB(4) evoked significant angiogenic phenotypes, both in vitro and in vivo. Our findings indicate that BLT2 plays an essential role in mediating VEGF-induced angiogenesis.
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 1302.
Abstract 1309: Inhibition of the ATR/CHEK1 pathway overcomes reduced sensitivity to ionizing radiation associated with distal 11q loss
Authors: Sankunny Madhav , Gollin Susanne M. 
Published: February 2011

Abstract
Genetic changes play a significant role in carcinogenesis. A commonly observed genetic alteration is amplification of chromosomal band 11q13. This has been reported at relatively high frequency in breast, ovarian, head and neck (HNSCC), and lung carcinomas. Previous studies in our lab have shown that the breakage-fusion-bridge (BFB) cycle mechanism responsible for this amplification results in distal 11q loss with concomitant loss of critical DNA damage response (DDR) genes, like ATM, MRE11A, and H2AFX. We showed in HNSCC that distal 11q loss leads to a defective DDR and decreased sensitivity to DNA damaging agents like ionizing radiation (IR). Further, HNSCC, Non-Small Cell Lung Carcinoma (NSCLC), and ovarian carcinoma cell lines with partial copy number loss of distal 11q show reduced sensitivity to IR and overexpression of the ATR/CHEK1 pathway. siRNA knockdown of CHEK1 in carcinoma cell lines with distal 11q loss resulted in 60-70% decreased cell survival in response to a single dose of IR. Cell lines without distal 11q loss did not show differential sensitivity to IR. These findings have led us to investigate whether these cell lines show decreased sensitivity to other DNA damaging agents such as various chemotherapeutic drugs.
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 1309.
Abstract 1312: Functional significance for an hnRNP A18 signature RNA motif in the 3'UTR of Ataxia Telangiectasia and RAD3 related (ATR) transcript
Authors: Yang Qingyuan , Yang Ruiqing , Zhan Ming , Nalabothula Narasimharao , Carrier France 
Published: February 2011

Abstract
The predominantly nuclear hnRNP A18 translocates to the cytosol in response to cellular stress and increases translation by specifically binding to the 3'untranslated region (UTR) of several mRNA transcripts and the eukaryotic Initiation Factor 4G. Here, we identified a 51 nucleotides motif that is present 11.49 times more often in the 3'UTR of hnRNP A18 mRNA targets than in the unigene data base. This motif was identified by computational analysis of primary sequences and secondary structures of hnRNP A18 mRNA targets against the unaligned sequences. Band shift analyses indicate that the motif is sufficient to confer binding to hnRNP A18. A search of the entire unigene data base indicates that the hnRNP A18 motif is also present in the 3'UTR of the Ataxia Telangiectasia and Rad3 related (ATR) mRNA. Validation of the predicted hnRNP A18 motif is provided by hnRNP A18 binding to ATR 3'UTR and amplification of endogenous ATR transcript on polysomal fractions immunoprecipitated with hnRNP A18 antibodies. Moreover, over expression of hnRNP A18 results in increased ATR protein levels and increased phosphorylation of Chk1, a preferred ATR substrate, in response to UV radiation. To our knowledge, this constitutes the first demonstration of a post-transcriptional regulatory mechanism for ATR activity. hnRNP A18 could thus become a new target to trigger ATR activity as back up stress-response mechanisms to functionally compensate for absent or defective genotoxic stress responders.
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 1312.