bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 531: RNA interference-mediated downregulation of uPARAP decreases invasion and migration property in glioma cells through reorganization of the actin cytoskeleton
Authors: Takahashi Satoshi , Toda Masahiro , Sasaki Hikaru , Kawase Takeshi 
Published: February 2011

Abstract
OBJECTIVE: The aim of this study was to evaluate the role of membrane protein urokinase-type plasminogen activator receptor associated protein (uPARAP), which is one of the member of serine-protease cascade, urokinase plasminogen activator system, in the motile and invasive activities of glioma cells.
METHODS: In the present study, we first evaluate expression of uPARAP in various normal tissues as well as glioma patients’ samples and glioma cell lines using quantative PCR and Western blotting. To evaluate the function of uPARAP, we silence the uPARAP gene using two independent siRNAs designed for uPARAP, and evaluate its function on motile and invasive activities of glioma cells by Boyden chamber migration and invasion assays. We also evaluate the function of uPARAP on rearrangement of actin cytoskeleton by staining glioma cells with Alexa Fluor 488 conjugated Phalloidin.
RESULTS: uPARAP protein was expressed four out of four (100%) glioma samples regardless of its World Health Organization grade but did not express in normal brain control. Introduction of small interfering RNA targeted uPARAP into two different glioma cell lines; KNS42 and KNS81, resulted in down-reguration of uPARAP expression, and significantly suppressed glioma cells’ migration and invasion properties in vitro. Rearrangement of actin cytoskeleton was observed at Alexa Fluor 488 conjugated Phalloidin staining. In uPARAP knocked-down glioma cells, polymeric actin became organized in stress fibers and the lamellipodia disappeared.
CONCLUSION: On the basis of our findings, we conclude that RNA interference-mediated down-regulation of uPARAP decreases invasion and migration property in glioma cells. The inhibition of invasion and migration property was mediated via reorganization of the actin cytoskeleton. Downregulation of uPARAP may be a novel anti-invasion therapeutic strategy for malignant gliomas.
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 531.
Abstract 5311: Myeloid-derived suppressor cells and immune cell responsiveness in tumor-bearing mice
Authors: Mundy Bethany L. , Lesinski Gregory , Benninger Kristen , Khan Mahmood , Kuppusamy Periannan , Guenterberg Kristan , Kondadasula Sri Vidya , Chaudhury Abhik Ray , Kreiner Melanie , Young Gregory , Guttridge Denis C. , Carson William E. 
Published: February 2011

Abstract
Conditions that inhibit IFN-induced signal transduction and gene transcription can dampen the host immune system and its ability to recognize and eliminate tumors leading to impaired immunoediting. We hypothesized that in the setting of cancer, myeloid-derived suppressor cells (MDSC) could impair the responsiveness of immune effector cells to interferons. We used the murine adenocarcinoma cell line C26 which induces MDSC generation when implanted in C2DF1 mice. C26-bearing mice had significantly elevated levels of GR1+CD11b+ MDSC (p&lt;0.0001) and plasma IL-6 as compared to controls (p&lt;0.0001). The ability of IFNa or IFNy to stimulate phosphorylation of the STAT1 transcription factor (P-STAT1, a direct measure of IFN action) was measured by intracellular flow cytometry. Induction of P-STAT1 following a 15 minute stimulation of splenocytes with IFNa (102-104 U/mL) was significantly reduced in C26-bearing mice (Mean P-STAT1 = 18.8; Range = 4.0 - 33.4) as compared to control mice (Mean P-STAT1 = 37.9; Range = 27.0 - 50.0; p&lt;0.0001). A similar decrease in P-STAT1 in splenocytes of C26-bearing mice was observed following IFNy stimulation (1 ng/mL; 15 min; p=0.002). This decrease in IFN responsiveness was also observed in cells derived from inguinal lymph nodes following IFN-stimulation. The level of IFNa induced P-STAT1 was inversely correlated with the plasma IL-6 levels (Pearson correlation = −0.635; p=0.019). However, direct exogenous treatment of mice with IL-6 did not decrease splenic IFN response. In vitro co-culture experiments revealed that MDSC inhibited IFN-responsiveness of splenocytes from normal mice. Reduction of MDSC with either gemcitabine or anti-GR1 antibody treatment restored IFN responsiveness in splenocytes from C26-bearing mice as compared to tumor-bearing mice treated with vehicle or isotype control antibody. Spleens from C26-bearing animals displayed elevated levels of iNOS protein and nitric oxide (NO). The elevation in NO in C26-bearing mice was associated with increased levels of nitration on STAT1. In vitro treatment of splenocytes with a nitric oxide donor led to a decreased STAT1 IFN response. Taken together, these data suggest a novel link between MDSC and a decreased molecular response of the immune effectors responsible for promoting functional anti-tumor responses.
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 5311.
Abstract 5317: HLA-E and HLA-G tumor expression is of prognostic value for clinical outcome of early breast cancer patients, but exclusively in classical HLA class I tumor-negative patients
Authors: de Kruijf Esther M. , Sajet Anita , van Nes Johanna Gh , Natanov Russ , Putter Hein , Smit Vincent Thbm , Liefers Gerrit Jan , van den Elsen Peter J. , van de Velde Cornelis Jh , Kuppen Peter Jk 
Published: February 2011

Abstract
Background Non-classical human leukocyte antigens (HLA), HLA-E and HLA-G, are known to affect clinical outcome in various tumor types. We examined the clinical impact of HLA-E and HLA-G expression in early breast cancer patients, and related the results to tumor expression of classical HLA class I molecules, as together these cell surface molecules may determine natural killer (NK) cell responses.
Material and Methods Our study population (n=677) consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1995. Tissue micro array (TMA) sections of formalin-fixed paraffin-embedded tumors were immunohistochemically stained for HLA-E and HLA-G. For evaluation of HLA-E and HLA-G expression and the combined variable, HLA-EG, a binary score was used. Expression of classical HLA class I expression was previously determined.
Results HLA-E, HLA-G and HLA-EG were expressed in breast tumors in 50%, 60% and 23% of patients respectively. Remarkably, only in patients with loss of classical HLA class I tumor expression, expression of HLA-E (p=0.027), HLA-G (p=0.035) and HLA-EG (p=0.001) resulted in a worse relapse free period. An interaction was found between classical and non-classical HLA class I expression (p=0.002), suggestive for a biological connection.
Conclusions We have demonstrated that expression of HLA-E and HLA-G are important factors in the prediction of clinical outcome of breast cancer patients, but exclusively in patients with classical HLA class I negative tumors. HLA-E and HLA-G expression may specifically prevent NK-cell recognition by the host in this subset of tumors. These results provide further evidence that breast cancer is highly immunogenic, but also capable of evading tumor eradication by the host immune system in which both T cells and NK cells play a role.
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 5317.
Abstract 5319: The role of Notch and Delta-like 1 in antitumor immunity
Authors: Dikov Mikhail M. , Huang Yuhui , Yang Li , Lin Lupin , Carbone David P. 
Published: February 2011

Abstract
Defects in T cell function are evident in tumor bearing hosts. One potential mechanism for these hematopoietic defects is disruption of Notch signaling which is essential for T- versus B-lineage commitment, and it is clear that Delta-like 1 (DLL1) and Delta-like 4 (DLL4) are critical in this process 1-4. Here we show that tumor-associated defects in T cell development are characterized by attenuated levels of DLL1 and DLL4 in the bone marrow (BM) microenvironment, and elevated circulating vascular endothelial growth factor (VEGF) is one causative factor. We also show that elective therapeutic stimulation of Notch signaling in animals using multivalent form of DLL1 significantly reduces tumor growth, rescues T cell development and enhances T cell-mediated immune responses and that over-expression of DLL1 alone in BM precursors also inhibits tumor growth and improves anti-tumor immunity. Thus, stimulation of DLL1-Notch signaling represents a new strategy to overcome tumor immune dysfunction. As neutralizing DLL4 has been proposed as an approach to inhibit tumor growth by regulating tumor angiogenesis, our data suggest that combining stimulation or blockade of specific context-dependent Notch signaling may optimally inhibit tumor growth via multiple distinct mechanisms.
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 5319.
Abstract 5323: Distinct roles of IL-17A in inflammation-induced tumor development and tumor immunosurveillance
Authors: Kato Takuma , Hiroyoshi Nishikawa , Linan Wang , Jun Mitusi , Yuka Maeda , Hiorshi Shiku , Hiorshi Shiku 
Published: February 2011

Abstract
While chronic inflammation is considered to be a critical component of tumorigenesis, the immune system can also prevent tumor development and/or growth. IL-17A and IL-17A secreting T cells, termed Th17 mediate inflammation via activation of a wide range of downstream inflammatory mediators that contribute to chronic inflammatory diseases. It also has been suggested that Th17 can be a constituent in tumor immunosurveillance since tumor-specific Th17 has been shown to eradicate established tumor. In the present study, we addressed the effects of inflammation/immunity driven by IL-17A on a primary tumor development model using a chemical carcinogen 3′-methylcholanthrene (MCA). We found that IL-17A deficient (IL-17A−/−) mice were protected from the primary tumor development by MCA. Paradoxically, the growth of primary tumors developed in IL-17A−/− mice was faster than that of tumors in WT (C57BL/6) mice. Although tumor cell lines derived from WT and IL-17A−/− mice grew equally in immunocompromised (T, B cell deficient C. B-17 scid) mice, those from IL-17−/− mice were easily rejected in C57BL/6 mice as compared to those from WT mice. Consistent with this, tumor growth of B16 melanoma, a non-immunogenic transplantable tumor cell line, was enhanced in IL-17A−/− mice. The apparently contrasting effects of IL-17A on tumor growth and development may reflect difference in cells producing IL-17A, namely cells mediate innate or acquired immunity. We transferred CD4+ T cells from WT mice into IL-17A−/−. While the transfer with CD4+ T cells from WT mice did not affect the primary tumor development in IL-17A−/− mice, the growth of primary tumors in IL-17A−/− mice transferred with WT CD4+ T cells was significantly suppressed. These results indicate that IL-17A promotes tumorigenesis possibly by enhancing inflammation and IL-17A produced by CD4+ T cells contributes to the immune surveillance to the emerging tumors as well. Overall, these results not only demonstrate that a single cytokine, IL-17A, plays contrasting role in tumor development and growth, but also indicate that immune inflammation-driven tumorigenesis and tumor immunosurveillance coexist in the same host.
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 5323.
Abstract 5326: CCL2 is critical for immunoresistance in association with cancer EMT
Authors: Kudo-Saito Chie , Kawakami Yutaka 
Published: February 2011

Abstract
Purpose: Epitherial-to-mesenchymal transition (EMT) is a key step toward cancer metastasis, which is still a critical issue in cancer therapy. We previously reported that Snail-induced EMT accelerates cancer metastasis through multiple immunosuppressions using murine and human melanoma cells. However, the molecular mechanism is not completely understood. In this study, we confirmed the Snail-induced immunosuppressions using various human cancer cell lines, and further elucidated the mechanisms by identifying the specific mediators.
Results: We first established human pancreatic cancer cell line Panc-1 cells showing typical EMT features such as reduced adhesion and enhanced invasion after transduction with snail gene, which is a transcription factor governing EMT. When human PBMCs were cocultured with the Snail transfectants, CD11c+ cell differentiation was significantly inhibited, and immunosuppressive CD4+FOXP3+ Treg cells were increased as similarly observed using Snail+ melanoma, suggesting the general features of the Snail-induced immunosuppressive mechanisms. We next conducted GeneChip analysis to identify other possible mechanisms by comparing gene profiles between the Snail transfectant and the parental cells. CCL2 was significantly upregulated in various Snail+ tumor cells after transduction with snail or treatment with TGFβ, a potent EMT inducer. CCL2 not only enhanced tumor invasion but also caused immunosuppressions through induction of Lipocalin 2 (LCN2), which was reported to induce apoptosis in various cells. CCL2 also increased LCN2 receptor Megalin and immunosuppressive molecules IDO and PD-L1 in DCs; in turn, LCN2 increased CCR2 in DCs. Utilizing the cooperative mechanism induced by CCL2 and LCN2, Snail+ cancer cells severely hampered APC function through induction of apoptosis and PD-L1/IDO expressions followed by Treg generation and then CTL attenuation. CCL2 blockade utilizing the specific siRNA or antibody significantly inhibited both tumor invasion and those immunosuppressions in vitro. Intratumoral injection with these anti-CCL2 reagents significantly inhibited tumor growth and metastasis by enhancing anti-tumor response systemically in vivo.
Conclusion: These results demonstrate that CCL2 plays a vital role in the Snail-induced immunosuppressions. CCL2 blockade in tumor microenvironment may be an attractive strategy to overcome metastasis and immunoresistance of Snail+ cancers by restoring immunocompetence in cancer 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 5326.
Abstract 5331: Interleukin-6 as a therapeutic target in advanced ovarian cancer
Authors: Coward Jermaine , Kulbe Hagen , Leader David , Quigley Mary , Leinster David Andrew , Thompson Richard , Nemeth Jeffrey , Vermeulen Jessica , McNeish Iain , Balkwill Frances R. 
Published: February 2011

Abstract
The inflammatory cytokine IL-6 is a major component of an autocrine cytokine network in human ovarian cancer that influences angiogenesis, a stromal signature and leukocyte infiltration. We have used tissue culture experiments, animal models, and data from a Phase II clinical trial in women with advanced ovarian cancer to investigate the therapeutic potential and mechanisms of action of CNTO328, an antibody that neutralises IL-6. In tissue culture, CNTO328 had no effect on growth or survival of ovarian cancer cells that expressed IL-6 receptors and constitutively secreted the ligand. However, it inhibited constitutive production of IL-6 and other inflammatory cytokines and chemokines, including TNF-alpha, IL-8, IL-1beta and CCL2 by the malignant ovarian cells.
In intraperitoneal ovarian cancer xenograft models, CNTO328 reduced tumour growth and angiogenesis and decreased transcription of inflammatory cytokines in the tumour microenvironment.
Of eighteen patients with advanced, platinum-resistant ovarian cancer treated with CNTO328 in a single arm Phase II trial, there was one partial response, as defined by combined RECIST/CA125 criteria, seven patients experienced periods of disease stabilisation, and in four of these this lasted at least 6 months. Baseline plasma TNF-alpha, IL-8, VEGF, beta2 microglobulin and CRP were significantly lower in patients who had stable disease or partial response. After six weeks therapy, plasma levels of several cytokines were either stable or decreased in patients who had clinical benefit from the anti-IL-6 treatment and TNF-alpha and IL-8 were significantly lower in this group than in those who progressed. Plasma TNF-alpha, IL-8, VEGF and ascites TNF-alpha, IL-8, CCL2 and IL-1beta levels showed a strong decline in the patient with a partial response. We conclude that IL-6 antagonists may have a role to play in the treatment of ovarian cancer. Their actions involve inhibiting production of inflammatory cytokines, chemokines and angiogenic factors that have tumour-promoting actions in the ovarian cancer microenvironment.
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 5331.
Abstract 5334: Mechanism of cysteine-mcMMAF release from the stably linked antibody-drug conjugate SGN-75
Authors: Zhang Xinqun , Okeley Nicole M. , Setter Jocelyn , Law Che-Leung , Benjamin Dennis R. , Senter Peter D. , Alley Stephen C. 
Published: February 2011

Abstract
The antibody-drug conjugate SGN-75 is composed of the humanized monoclonal antibody (mAb) h1F6 and the drug-linker mcMMAF conjugated through interchain disulfide cysteine residues. SGN-75 has been shown to be highly active against tumor cell lines both in vitro and in vivo. The mcMMAF drug-linker was designed to be protected from protease cleavage, and we have shown that cysteine-mcMMAF is the major released drug in vitro. We demonstrate that the cysteine residue in cysteine-mcMMAF comes from the mAb, implying antibody degradation as the mechanism for generation of cysteine-mcMMAF. Two isotope cysteine labeling approaches were utilized in which either total cysteine in tumor cells or the mAb cysteines of h1F6 were labeled with heavy isotope cysteine. Metabolic incorporation of heavy cysteine into CD70-expressing tumor cells or mAb-producing CHO cells using media depleted of cysteine and supplemented with heavy isotope cysteine gave complete labeling by heavy cysteine. Heavy cysteine-labeled cells were treated with unlabeled SGN-75, and unlabeled cells were treated with heavy-cysteine-labeled SGN-75. The results demonstrate that the mAb backbone of SGN-75 is the origin of the cysteine in cysteine-mcMMAF providing evidence that an active drug component can be released from a stably linked ADC through proteolytic degradation of the mAb inside of target cells.
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 5334.
Abstract 5338: Metastatic colorectal cancer cells from patients previously treated with chemotherapy are sensitive to T cell killing mediated by CEA/CD3-bispecific T cell-engaging BiTE antibody
Authors: Osada Takuya , Hsu David , Hammond Scott , Hobeika Amy , Devi Gayathri , Clay Timothy M. , Lyerly H. Kim , Morse Michael A. 
Published: February 2011

Abstract
Carcinoembryonic antigen (CEA; CD66e, CEACAM5) is a well-characterized tumor-associated antigen that is frequently and uniformly over-expressed in human carcinomas. A novel bispecific single-chain antibody of the bispecific T cell engager (BiTE) class named MEDI-565 (also known as MT111) was generated by genetic engineering. MEDI-565 binds CEA on cancer cells and CD3 present on T cells; such binding mediates T cell killing of cancer cells expressing CEA. However, MEDI-565 effectively mediates the killing of cancer cells only if it binds concurrently to CEA on a cancer cell and to CD3 on a T cell.
We hypothesized that metastatic human colorectal cancer (CRC) previously treated with conventional chemotherapy would be sensitive to T cell-mediated killing if T cells of a sufficient magnitude could be activated against the tumor. To test this hypothesis, we selected MEDI-565 to redirect a large number of polyclonal T cells against tumors expressing CEA instead of using a cancer vaccine approach that, in general, is anticipated to elicit few antigen-specific T cells in humans.
We analyzed proliferation and lysis of CEA-positive CRC specimens that had survived prior systemic chemotherapy and biologic therapy to determine if they could be killed by patient T cells engaged by MEDI-565 in vitro. The mechanism of redirected T cell killing was also investigated.
At low concentrations (0.1 to 1 ng/mL), MEDI-565 plus T cells caused reduced proliferation and enhanced apoptosis of CEA-positive human CRC specimens. High levels of soluble CEA (≤ 1,000 ng/mL) did not affect MEDI-565-induced T cell killing of cells expressing CEA, suggesting that endogenous circulating CEA may not impair the clinical activity of MEDI-565 in patients. Cancer cell lines expressing CEA remained sensitive to T cell mediated killing despite repeated exposure to T cells and MEDI-565. These results suggest that MEDI-565/T-cell treatment may not induce escape mechanisms in cancer cells, and, thus, might be suitable for long-term and repeated treatment. Granzyme B and perforin were implicated as potential mediators of MEDI-565-induced T cell killing. Furthermore, MEDI-565 activated T cells to secrete both Tc1 (Th1) and Tc2 (Th2) type cytokines.
This study demonstrates for the first time that metastatic CRC specimens derived from patients previously treated with conventional chemotherapy can be lysed by patient T cells. Clinical testing of cancer immunotherapies such as MEDI-565 that result in exposure of tumors to large numbers of T cells is warranted.
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 5338.