bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1899: Induction of phase 2 antioxidant genes by the aqueous extract of Matricaria chamomilla (Chamomile) through Keap1-Nrf2 signaling pathway
Authors: Bhaskaran Natarajan , Shukla Sanjeev , Gupta Sanjay 
Published: February 2011

Abstract
Induction of phase 2 detoxifying enzymes in response to naturally occurring agents provides an effective means of protection against oxidative stress. Increasing lines of evidence show that the Keap1-Nrf2 complex is a key molecular target of phase 2 enzyme inducers. The transcription factor Nrf2 is a member of basic leucine-zipper NF-E2 family and interacts with the antioxidant response element (ARE) in the promoter region of phase 2 detoxifying enzymes. A cytoplasmic actin-binding protein, Keap1, is an inhibitor of Nrf2 and sequesters it in the cytoplasm. Various extracellular stimuli and inducers dissociate this complex, allowing Nrf2 to translocate into the nucleus, binding with ARE and induce the expression of various antioxidant genes. Recently natural compounds have been established as activators of phase 2 antioxidant enzymes through Nrf2 signaling pathway. We used aqueous chamomile extract obtained from dried flowers to investigate its effect on Nrf2 activation and induction of phase 2 enzymes in human prostate cancer PC-3 and LNCaP cells. Treatment of these cells with chamomile at 1-40μM concentration equivalent to aglycone apigenin caused significant dissociation of Keap1 from the Keap1-Nrf2 complex with significant decrease of Keap1 in the cytoplasm in dose- and time- dependent fashion. Similarly, a marked decrease in Nrf2 was observed in the cytoplasm after chamomile treatment. Chamomile treatment further led to increase in phase 2 enzymes including superoxide dismutase, NAD(P)H dehydrogenase [quinone] 1 and catalase in these cells which correlated with nuclear Nrf2 expression in dose- and time- dependent manner. Taken together, these molecular evidences provide an insight into the mechanism underlying the induction of phase 2 enzymes through Keap1- Nrf2 signaling pathway by chamomile, endorsing its antioxidant function.
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 1899.
Abstract 1902: A multilevel map of the immunological terrain in an orthotopic mouse model of lung cancer with emphasis on PGD2/DP1-dependent immunomodulation
Authors: Pyfferoen Lotte , Prijck Sofie De , Vanheerswynghels Manon , Deswarte Kim , Vergote Karl , Hammad Hamida , Lambrecht Bart N. , Vermaelen Karim Y. 
Published: February 2011

Abstract
The influence of the organ-specific micro-environment on the host immune response to tumors has been insufficiently adressed. We examined tumor-induced immunomodulation in an orthotopic mouse model of lung cancer. We focused on the PGD2-DP1 signalling axis given its contrasting roles in dendritic cell (DC)-dependent immunomodulation on one hand, and tumor angiogenesis on the other.
We found an enrichment of CD11b+ (inflammatory type) DCs within lung tumors. In sharp contrast to DCs in immediately adjacent peritumoral lung tissue, intratumoral DCs displayed a strong upregulation of the T-cell co-inhibitory molecules PD-L1 and ICOS-L on the cell surface. Remarkably, tumor-infiltrating CD4 and CD8 T-cells showed a robust upregulation of the activation marker CD69, while increased numbers of double-negative T-cells were seen within lung tumors as well. Regulatory T-cells were also clearly elevated within tumors as well as in draining lymph nodes (LN) of tumor-bearing hosts. Interestingly, DCs in lung-draining LNs appeared more immature in end-stage tumor bearing mice. Finally, systemic tumor-induced effects were manifest as a strong expansion of myeloid derived suppressor cells in the spleen.
DP1-deficiency did not significantly affect any of these immunological parameters. Moreover, in contrast to previous observations using heterotopically implanted lung tumor cells, DP1-deficiency had no impact on survival in our orthotopic lung cancer model.
In summary, we provide a multi-level detailed map of tumor-immune system interactions in an orthotopic mouse model of lung cancer. Our findings in DP1-deficient mice stress the importance of the local, organ-specific milieu in driving tumor development and shaping host immune responses.
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 1902.
Abstract 1904: Reversal of thymic involution and immunosuppression in tumor-bearing mice by IFN-γ
Authors: Carrio-Jardines Roberto , Iragavarapu-Charyulu Vijaya , Libreros Stephania , Garcia-Areas Ramon A. , Lopez Diana M. 
Published: February 2011

Abstract
The thymus is a central lymphoid organ critical for the development and maintenance of an effective peripheral T cell repertoire. Most important, it provides a specialized environment for the selection of rearranged clones that will function appropriately in the adaptive immune response. The tumor-induced immunosuppression observed during murine mammary tumorigenesis has been associated with a profound thymus involution accompanied with a severe depletion of the most abundant subset of thymocytes; CD4+CD8+ double positive (DP) immature cells. Thymic involution has been observed in several model systems; including graft-vs-host disease, aging, and tumor development, however, the mechanisms involved in this phenomenon remain to be elucidated. Previous results from our laboratory have reported that the severe thymic atrophy and impaired T cell development seen in mammary tumor bearers are associated with an arrest in at least two steps of T cell differentiation, changes in the levels of crucial cytokines expressed in the thymus microenvironment, and a progressive increase in apoptosis during the tumor development mainly due to downregulation of important molecules that control programmed cell death. Moreover, we have shown that mice bearing the murine parental D1-DMBA-3 mammary tumor and tumors derived from the parental tumor, the DA-3, develop many changes in their cytokine production. For example, in mice bearing these tumors there is a decrease in the IFN-γ in the peripheral circulation and production of this crucial cytokine is greatly diminished in the T cells. In the present study we have used our DA-3 mammary tumor model to investigate whether the levels of IFN-γ have an important role in anti-tumor activity, in the pathogenesis of thymic atrophy as well as the tumor-induced immunosuppression in these mice. Interestingly, our results show that the overexpression of IFN-γ in DA-3 tumor cells results in a marked delay of tumor growth and a blockage in the tumor-associated thymus atrophy. Importantly, peripheral T cells from IFN-γ-transfected DA-3 tumor-bearing mice, show markedly high levels of this cytokine. Moreover, when thymuses from tumor-bearing mice that received IFN-γ were analyzed, thymic populations were very similar to those observed in the thymuses of normal mice. Collectively, our data suggest that the replacement of the faulty levels of IFN-γ in tumor bearers results in a delayed tumor growth and thymic involution leading to a decrease of tumor-induced immune suppression caused by the mammary tumor development.
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 1904.
Abstract 1906: IL-6-mediated activation of STAT3 inhibits APC and T cell function in metastatic breast cancer
Authors: Anderson Karen S. , Sasada Tetsuro , Nelson Erik , Khazaie Khash , Feng Gang , Lin Simon , Frank David A. 
Published: February 2011

Abstract
Background: The transcription factor STAT3 is a negative regulator of myeloid inflammatory immune responses, leading to profound suppression of dendritic cell (DC) and T cell function, and anti-tumor immunity. Blockade of STAT3 signaling in tumor models results in activation of innate immune cells, DCs, and tumor infiltration of T cells. We hypothesized that tumor associated macrophages (TAMs) from breast cancer patients were dysfunctional, due to IL-6-mediated activation of STAT3.
Methods: To isolate sufficient numbers of CD14+ TAMs and CD3+ tumor infiltrating lymphocytes (TILs) for functional assays, 10 malignant effusions were obtained from breast cancer patients and peripheral blood was obtained from 8 healthy controls. Levels of up to 22 cytokines in the effusions and the blood were determined by Luminex cytokine assay. CD14+ TAMs and CD3+ TILs were magnetically sorted, and functional mixed lymphocyte reaction (MLR) assays were performed. Quantitation of STAT3 and tyrosine-phosphorylated STAT3 (pSTAT3) were determined by immunoblotting. RNA expression analysis of TILs and healthy donor CD3+ cells was performed using Affymetrix U133 microarrays.
Results: Malignant effusions from breast cancer patients have high levels of IL-6 (mean 3188 pg/ml; range 966-5235), compared with serum from healthy donors (mean 88 pg/ml; p&lt;0.0001). TAMs isolated from malignant effusions, but not peripheral blood, poorly stimulated healthy T cells in MLR, and showed increased expression of pSTAT3 and total STAT3 on immunoblot. A 30 minute exposure to a malignant effusion containing high levels of IL-6 markedly induced STAT3 activation in healthy donor CD14+ monocytes. Compared with CD3 cells from healthy donors (n=3), RNA microarray analysis of CD3+ TILs (n=3) showed downregulation in TCR signalling (Zap70, fyn, PI3K), NK/CTLs (CD160, KLRF1), and chemokines for T cell trafficking (CXCR4). Immunosuppressive factors (IL10, PDIA4, IL13R, STAT1, and VEGF) were upregulated (p&lt;0.05).
Conclusions: High levels of IL-6 in breast cancer malignant effusions are associated with both antigen presenting cell and T cell dysfunction. Inhibition of STAT3 is a potential target to enhance immune activation.
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 1906.
Abstract 1907: Mechanisms mediated by CXCL12 signaling through CXCR4 and CXCR7 in breast cancer
Authors: Mosley Lasharon D. , Singh Rajesh , Sharma Praveen K. , Triplett Ashley S. , Singh Shailesh , Lillard James W. 
Published: February 2011

Abstract
Interactions between chemokines and their receptors are involved in organ-specific homing and propagation of metastatic breast cancer (BrCa) cells. BrCa cells express higher levels of CXCR4 and CXCR7 mRNA and cell surface protein, than normal human mammary epithelial cells (HMECs). Recent studies show CXCR7 is highly expressed by activated endothelial cells (i.e., neovasculature), fetal liver cells, and many tumors, but not by non-transformed (or normal) human tissues. Unlike other chemokine receptors, activation of CXCR7 does not cause Ca2+ mobilization/flux or cell migration. However, CXCR7 activation by its ligands provides signals for growth, survival, and adhesion. CXCR4, CXCR7, and CXCL12 mRNAs and proteins are differentially expressed by BrCa cell lines (MCF-7 and MDA-MB-231) and breast tumor, than compared to HMEC or benign mammary tissue, respectively. Using selective G protein inhibitors, CXCR4/CXCR7-specific siRNAs as well as Amnis ImageStream, real time PCR, and active matrix metalloproteinase assays, we tested the hypothesis that CXCR7 and its interactions with CXCR4 and CXCL12 promote BrCa cell collagenase expression, alter NF-κB and ERK1/2 localization to the nucleus, and correlates with cell cycle. CXCL12-induced CXCR4 mRNA upregulation required Gβγ protein and/or JAK/STAT signal transduction; CXCL12 expression was negatively regulated by the presence of CXCR4. CXCL12-mediated CXCR7 mRNA expression in a pertussis toxin-sensitive manner. Lastly, CXCL12-dependent MMP-1 and MMP-13 mRNA expression was Gα protein-, Gβ protein-, and Gγ protein-dependent presumably through CXCR4, while elevated expression of CXCR7 suppressed these effects. Together, this study suggests that differential and cell cycle-dependent CXCR7 and CXCR4 expression plays a critical role in enhancing BrCa cell invasion and survival cell signals, which were CXCL12-dependent, but often G protein-independent.
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 1907.
Abstract 1914: Cross-talk between breast cancer cells and tumor-associated macrophages leads to tumor cell invasion, angiogenesis and metastasis
Authors: Luo Yun Ping , Liao Debbie , Chuang Tsung-Hsien , Xiang Rong , Reisfeld Ralph A. 
Published: February 2011

Abstract
Interactions between neoplastic and stromal cells leads to crosstalk that contributes to tumor growth and progression. Since Fos-related antigen-1 (Fra-1) and Interleukin 6 (IL-6) are involved in tumor cell angiogenesis, invasion and metastasis, and are frequently deregulated in cancer cells, they represent attractive targets to regulate these effects. Here, we demonstrate that up-regulation of Fra-1 by tumor associated macrophages (TAMs) represents a malignant switch in breast carcinoma triggered by the deregulation of the IL-6/JAK/Stat3 signaling pathway which, in turn, increases the release of pro-angiogenesis factors MMP9, VEGF and TGF-β. Co-culture of 4T1 breast cancer cells with TAMs leads to up-regulation of Fra-1, IL-6 and Stat3 in TAMs. Furthermore, knockdown of Fra-1 in TAMs causes downregulation of IL-6, Stat3 and decreases the release of MMP9, VEGF and TGF-β. Together, these effects suppress the malignant characteristics of 4T1 breast tumor cells such as invasiveness, angiogenesis and metastasis. This study delineates novel mechanisms involved in the transcriptional deregulation of Fra-1 that lead to the activation of the IL-6/JAK/Stat3 signaling pathway in TAMs. Such events play a key role in promoting breast cancer cell invasion, growth and metastasis and our findings will determine if AP-1 family transcription factors such as Fra-1 are responsible for the overexpression of IL-6 in TAMs. Importantly, blocking of the IL-6/JAK/Stat3 signaling pathway will interrupt the crosstalk between TAMs and breast tumor cells in the tumor microenvironment (TME) and thereby change the biological function of TAMs, resulting in the suppression of breast cancer invasion and metastasis.
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 1914.
Abstract 1919: Phosphatidylserine on dying tumor cells suppresses dendritic cell activation and inhibits tumor immunity: reversal with PS-targeting antibody
Authors: Huang Xianming , Ye Dan , Thorpe Philip E. 
Published: February 2011

Abstract
We recently showed that PS on the surface of apoptotic cancer cells can suppress recognition of tumor antigens by the immune system. It appears from work in several laboratories that dendritic cells (DC) that ingest PS-expressing tumor cells fail to mature in response to external maturation signals. In the present study, we investigated whether masking PS on apoptotic tumor cells with anti-PS antibody (2aG4) can reverse the inhibitory effect of PS on DC. Mouse bone marrow derived DC were cocultured with irradiated (PS-expressing) 4T1 breast tumor cells in the presence or absence of 2aG4. We found that: (i) masking tumor cell PS with 2aG4 increases their phagocytosis by DCs; (ii) masking tumor cell PS with 2aG4 allows DCs to mature and express immunostimulatory molecules (CD40, CD80, CD86 and MHC II); (iii) masking PS with 2aG4 decreases the production of anti-inflammatory cytokines (TGFβ and IL-10) and increases the production of inflammatory cytokines (TNFα, CCL5, IL-1β and IL-6), indicating that PS-blockade polarizes DC towards the immunostimulatory type I phenotype; (iv) immunizing mice with 2aG4-treated irradiated 4T1 cells enhances the immunogenicity of the tumor cells, rendering them resistant to rechallenge with syngeneic viable 4T1 tumor cells. These results have important implications for our understanding of the immunosuppressive effects of PS in cancer and could lead to the development of a novel whole cell cancer vaccine strategy in which PS-blocking is used to enhance immunogenicity.
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 1919.
Abstract 1922: Do stress response genes play a role in maintaining MDSC survival and suppression
Authors: Beury Daniel W. , Fitzgerald Phillip , Srivastava Minu K. , Ostrand-Rosenberg Suzanne 
Published: February 2011

Abstract
Myeloid- derived suppressor cells (MDSC) contribute to immune suppression in tumor bearing individuals. Their suppression and survival are increased by inflammation. MDSC production of toxic radicals is the primary mechanism of suppression but the toxic mediators do not affect the MDSC themselves. We are investigating stress response genes that may maintain MDSC survival and facilitate suppression. BALB/c mice were injected with BALB/c derived mammary carcinoma 4T1 or 4T1 constitutively expressing the pro-inflammatory cytokine IL-1β (4T1/IL-1β). Primary tumors were surgically removed after 25 days. At 35 days, spleens were harvested and assayed for the percentage of Gr1+ CD11b+ MDSC. Surgical removal of 4T1 results in a regression of the MDSC population, however MDSC do not regress in mice bearing 4T1/IL-1β tumors, confirming that inflammation increases MDSC survival. Western blots and confocal microscopy of MDSC induced by 4T1 and 4T1/IL-1β tumors localize Nrf2 in the nucleus, demonstrating that Nrf2 is activated in MDSC. In flow cytometry assays, MDSC induced by 4T1/IL-1β have higher expression of one chain of the cystine transporter, xCT, compared to 4T1 induced MDSC. 4T1/IL-1β induced MDSC also expressed more reactive oxygen species (ROS) compared to 4T1 MDSC. The increased expression of ROS and xCT in 4T1/IL-1β induced MDSC represent mechanisms for the increased suppression of CD4+ and CD8+ T cells compared to 4T1 induced MDSC. Catalase, a protein transcriptionally regulated by Nrf2, when added to a T cell activation assay eliminates MDSC suppressive activity. Addition of catalase to T cells co-cultured with MDSC and peptide causes a synergistic effect, activating T cells to a greater level than peptide alone. Collectively these data suggest that stress genes may play a role in maintaining MDSC survival and suppressive 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 1922.
Abstract 1923: Regulatory T-cell subsets suppress high avidity CD8 T-cell activation and trafficking
Authors: Weiss Vivian L. , Lee Timothy H. , Armstrong Todd D. , Jaffee Elizabeth M. 
Published: February 2011

Abstract
Cancer vaccines are one treatment modality that can prevent the development of some cancers. The advantage of cancer vaccines is their ability to target cancer proteins specifically, thereby resulting in minimal toxicities to normal tissue. Unfortunately, immune tolerance mechanisms provide a formidable barrier to effective treatment of cancer when vaccines are used as a single agent. One way to overcome these barriers is to develop vaccination strategies that combine vaccines with tolerance-reducing agents that allow the recruitment and activation of the most potent tumor-specific T cells. In fact, accumulating data suggest that the availability and activation of a diverse high avidity T cell repertoire is a key factor in the effectiveness of cancer vaccines. To further understand the role of high avidity T cells in the treatment of cancer, we developed TCR transgenic mice that are high avidity and specific for the immunodominant CD8+ T cell epitope, RNEU420–429, that derives from the HER-2/neu breast cancer antigen. By adoptively transferring these high avidity T cells into the tolerant environment of the neu-N mouse, we have studied their proliferation, trafficking, and tumor-clearing capacity. High avidity T cell responses were evaluated following vaccination using a neu-expressing, GM-CSF-secreting, whole cell vaccine. Vaccine was given either alone or in combination with two T regulatory cell (Treg) depleting agents: Cyclophosphamide (Cy) and the anti-CD25 antibody, PC61. Our data demonstrate that the Cy specifically targets a subset of Tregs and the depletion of this subset allows for more effective tumor clearance by high avidity T cells. While most tolerance reduction strategies focus on the depletion of CD4+CD25+ T regulatory cells, our studies reveal the existence of a population of CD25low effector Tregs that can effectively traffic to the tumor microenvironment and mediate tolerance. Through targeted removal of this CD25low effector Treg population, high avidity T cells undergo increased activation, T cell trafficking, and tumor clearance. Thus, we demonstrate that vaccination in combination with targeted, effector Treg depletion can activate higher avidity T cell populations to eradicate pre-existing tumor burdens. Through an in-depth understanding of the tolerance mechanisms that mediate high avidity T cells suppression, it will be possible to design more effective vaccination strategies to activate the small but potent high avidity T cell populations present 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 1923.