bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4965: Metformin has an anticancer effect by repressing TWIST/N-cadherin signaling.
Authors: Rongbin Ge , Wang Zongwei , Olumi Aria F. 
Published: August 2014

Abstract
Introduction and Objective. Metformin, one of the most commonly used medications for treatment of type 2 diabetes, has emerged as a potential anticancer agent. The molecular mechanisms associated with the anti-cancer effect of metformin are poorly understood. We demonstrate, for the first time, that metformin inhibits prostate cancer proliferation through suppression of TWIST/N-cadherin signaling pathway.
Methods. RT–PCR, Western blot, immunofluorescence assays and confocal microscopy were applied to evaluate protein expression level. MTS assay and FACS analysis were applied to determine cellular proliferation. N-cadherin and TWIST-1 expression vectors were transfected into PC3 prostate cancer cells to establish stable cells with over-expression of N-cadherin and TWIST-1, respectively. Metformin-resistant prostate cancer cells were established by exposure to higher concentrations (10mM) of metformin over 4 weeks.
Results. Treatment with metformin (5mM) inhibited proliferation in three different types of cancer cells (PC3-prostate cancer cells; T24-bladder cancer cells and 786-O- kidney cancer cells). Metformin treatment suppressed expression of N-cadherin in all cell types. Similar findings were observed by confocal microscopy. In contrast to N-cadherin, expression of E-cadherin was not affected by metformin. Metformin-mediated repression of N-cadherin was dose and time- dependent in prostate cancer cells. PC3 prostate cancer cells with stable over-expression of N-cadherin became resistant to metformin-mediated inhibition. Stable PC3 prostate cancer cells, after selection for metformin, became resistant to metformin-mediated inhibition, and the metformin-resistant cancer cells had slightly higher baseline level of N-cadherin. In addition, in the metformin-resistant cells, N-cadherin levels were unchanged after treatment with metformin. The expression of AKT and AP-1, the downstream molecules of N-cadherin, closely correlated with expression of N-cadherin after treatment with metformin. Moreover, we also found that metformin inhibited expression of TWIST-1, a transcriptional activator of N-cadherin. Similar findings were observed by confocal microscopy. PC3 prostate cancer cells with stable over-expression of TWIST-1 became resistant to metformin-mediated inhibition.
Conclusions. We demonstrate that Metformin's anti-cancer therapeutic effect may be mediated through repression of the TWIST/N-cadherin signaling pathway.
Citation Format: Ge Rongbin, Zongwei Wang, Aria F. Olumi. Metformin has an anticancer effect by repressing TWIST/N-cadherin signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4965. doi:10.1158/1538-7445.AM2013-4965
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 4966: Influence of the microenvironment on drug sensitivity in breast cancer using a three-dimensional cell culture model.
Authors: Lovitt Carrie J. , Avery Vicky M. 
Published: August 2014

Abstract
Three-dimensional (3D) cell culture is an important research tool and an invaluable alternative to two-dimensional (2D) cell culture as it is more suitable to represent in vivo conditions. The tumor microenvironment influences cellular activity and using 3D cell culture allows these interactions to be studied in vitro. We have evaluated the efficacy of a novel 3D cell culture model for breast cancer and determined cellular responses caused by drug activity. We have recently developed and optimized a miniaturized 3D breast cancer culture model. Our model uses reconstituted basement membrane from Growth Factor Reduced Matrigel™ as a scaffold and is suitable for semi-automated early stage drug discovery. The newly developed 3D culture model has been extensively characterized for reproducibility and the activity of known anti-breast cancer therapies. Notably, anthracyclines and taxanes showed significantly altered drug sensitivity in 3D when compared to monolayer cell cultures of breast cancer cell lines. To determine the mechanisms underlying the altered sensitivity in 3D cell culture, we sought to identify the differences between untreated and drug treated spheroids, as well as the differences between 2D and 3D cell culture responses to anthracyclines and taxanes. We evaluated proliferation, penetration, cellular architecture and signaling of major cellular pathways in our 3D model. We will discuss the proliferation rate comparing 2D and 3D cell culture models and drug penetration (exemplified by doxorubicin) in 3D cell culture. The effect of anthracyclines and taxanes on the 3D cellular architecture, without the influence of extracellular matrix proteins in the microenvironment, will also be presented. In addition, we have characterized the signaling pathways in 2D and 3D cell culture commonly associated with enhanced drug resistance and other relevant proteins including those associated with apoptosis. Deconstructing the cellular processes in 3D breast cancer cell culture in response to breast cancer therapies has the potential to elucidate drug resistance mechanisms. The results obtained from this research illustrate the characteristics and mechanisms of both monolayer and 3D cell culture with respect to anthracycline and taxane drug activity. These results demonstrate the benefits of 3D cell culture in early stage novel compound evaluation for breast cancer.
Citation Format: Carrie J. Lovitt, Vicky M. Avery. Influence of the microenvironment on drug sensitivity in breast cancer using a three-dimensional cell culture model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4966. doi:10.1158/1538-7445.AM2013-4966
Abstract 4970: Folate metabolism defect induce invasion and Gefinitib resistance in lung cancer.
Authors: Ho Chun-Te , Liu Tsan-Zon , Chou Yu-Ting , Hsiao Shih-Hsin , Liu Jun-Jen 
Published: August 2014

Abstract
Folate, act as an one-carbon units donator or acceptor, participate in numerous biochemical reactions. Because mammals can't synthesize folic acid de novo, obtain from diet or from microbial breakdown in the gut is essential. Pathological study revealed that tumor cell expressing high level of folate receptors (FR) comparing to normal tissue. Therefore, exploring the application of folate-related physiological properties as an anticancer strategy arose worldwide interesting. Previous studies in lung cancer revealed a positive correlation in folate receptors overexpression and efficacy of antifolate chemotherapy. Here we describe prolong Alimta treatment would prompt lung cancer cell's malignancy. Cultivation of lung cancer CL1-0, CL1-5, and A549 in low dose Alimta (15-30 ng/mL) for 2-3 weeks would dramatically cause cell morphology change . Compare to control cell with round and flat epithelial like morphology, low dose Alimta treated cells showed mesenchymal to amoeboid phenotype. Further examination of epithelial to mesenchymal transition (EMT) markers showed the expression level of N-cadherin, matrix metalloproteinase 1 (MMP-1) and matrix metalloproteinase 2 (MMP-2) increased. Associated with morphology and EMT marker changed, cell migration and invasion ability of those Alimta treated cells were 3 folds higher than control cells. Besides, evaluated drug sensitivity by sulforhodamine B (SRB) method showed that those alimta treated cells were more resistant to gefitinib. These prominent events provoked our interesting to investigate the mechanism involving in the oncogenic effect induced by low dose Alimta treatment. While examing EMT-related transcription factors, both Slug and SOX-9 expression increased significantly. These evidences indicated that the folate metabolism defect induced metastasis could through the SOX-9 and Slug mechanism.
Citation Format: Chun-Te Ho, Tsan-Zon Liu, Yu-Ting Chou, Shih-Hsin Hsiao, Jun-Jen Liu. Folate metabolism defect induce invasion and Gefinitib resistance in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4970. doi:10.1158/1538-7445.AM2013-4970
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 4976: Characterization of the neuroinflammatory response in a mouse model of brain metastatic inflammatory breast cancer.
Authors: Reed L. Tiffany , Palmieri Diane , Mason Ginny , Steeg Patricia 
Published: August 2014

Abstract
Inflammatory Breast Cancer (IBC) is a rare form of breast cancer, accounting for approximately 2% of all breast cancer cases worldwide. While rare, it is extremely progressive and has a high propensity for metastatic spread and decreased overall survival compared to non-IBC breast cancers. IBC has a five-year overall survival rate of 30%; the median age at diagnosis is 57 years of age. Approximately 15% of IBC patients develop brain metastasis, and most of the brain metastasizing IBC tumors are triple negative (ER-, PR- and HER2-) or Her-2 overexpressing. The goal of this study was to investigate the neuroinflammatory response of SUM190 cells, a Her-2 overexpressing IBC cell line, in a mouse model of brain metastasis. The SUM190 brain metastatic mouse model of IBC was developed following three-sequential rounds of injection of cells into the left cardiac ventricle, isolation of metastatic tumor cells from the brains of the mice, and growth in tissue culture to maintain brain metastatic potential of the cell line. In this model, brain metastases were widely disseminated throughout the neuroparenchyma. The lesions were round, and measured 0.5-1 mm in maximal diameter, with a central area of necrosis characterized by shrunken hypereosinophilic epithelial cells with karryorhectic or absent nuclei. There was no significant difference in vascular proliferation in the peritumoral microenvironment compared to the unaffected neuroparenchyma (p=0.57) following quantitative immunofluorescent analysis. However, there was a 4-fold increase in GFAP-positive astrocytes (p=&lt;0.0001) and CD11b-positive microglia (p=0.001) and a 3-fold increase in F4/80-positive macrophages (p=0.001) in the tumor microenvironment compared to the unaffected neuroparenchyma. CD3+ T cells were widely disseminated throughout the tumor microenvironment. The influx of inflammatory cells in brain metastases associated with IBC is greater than that of other brain-tropic breast cancer cell lines including MDA-MB-231-BR, and may explain the increased incidence of metastasis in IBC patients. This research was supported by the NIH Intramural Research Program and a grant from the Inflammatory Breast Cancer Research Foundation.
Citation Format: L. Tiffany Reed, Diane Palmieri, Ginny Mason, Patricia Steeg. Characterization of the neuroinflammatory response in a mouse model of brain metastatic inflammatory breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4976. doi:10.1158/1538-7445.AM2013-4976
Abstract 4978: Lung cancers regulate the immune suppressor PD-L1 by multiple mechanisms, altering its role in tumor survival.
Authors: Kadel Edward (Ward) E. , Walter Kimberly , Desai Rupal , Carbon Juliet , Boe Marigold , Shames David , Kowanetz Marcin 
Published: August 2014

Abstract
The immune system has multiple mechanisms by which it can eliminate cancer and yet, tumors are able to adapt resistance to host immune surveillance and continue to survive and grow. One critical resistance mechanism involves Programmed cell death 1 ligand 1 (PD-L1, CD274, B7-H1), the predominant ligand for PD-1, an inhibitory receptor expressed on T cells following activation. PD-L1 also binds to B7.1 (CD80), inhibiting its ability to provide an immune stimulatory signal. PD-L1 is expressed broadly on multiple peripheral blood mononuclear cell subtypes, placenta, and numerous cancers, including NSCLC. Tumor-specific T cells infiltrate tumors and recognize tumor cells, releasing Interferon-gamma (IFNγ), initiating signaling of the Janus kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway in the tumor cells. IFNγ induces and/or greatly enhances the expression of PD-L1 in the tumor, among other cell types, allowing the tumor to become resistant to the host T cell response. Blockade of PD-L1 binding to PD-1 and B7.1 can reinvigorate the host immune response against the tumor and overcome tumor adaptive resistance. The regulation of PD-L1 expression is complex and likely involves multiple types of pre- and post-translational events. We show that basal PD-L1 expression levels can vary greatly in cancer cells, as can PD-L1 induction by IFNγ. Here we describe the different categories of PD-L1 basal expression and IFNγ–dependent regulation across multiple lung cell lines and human tumor samples. Reverse Phase Protein Array and RNA microarray data show that the JAK/STAT canonical pathways are still intact among all of these distinct categories, so alternative mechanisms of expression regulation must be active in these cell lines and tumor samples. We provide evidence that a combination of mechanisms regulate both the basal and stimulated expression levels of PD-L1 across these distinct categories. This data regarding PD-L1 expression regulation provides valuable information to better understand the PD-1/PD-L1 pathway as a therapeutic target.
Citation Format: Edward (Ward) E. Kadel, Kimberly Walter, Rupal Desai, Juliet Carbon, Marigold Boe, David Shames, Marcin Kowanetz. Lung cancers regulate the immune suppressor PD-L1 by multiple mechanisms, altering its role in tumor survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4978. doi:10.1158/1538-7445.AM2013-4978
Abstract 4985: Expression of FasL on the tumor endothelium establishes a selective immune barrier in ovarian cancer.
Authors: Motz Greg , Coukos George 
Published: August 2014

Abstract
There is an intimate relationship between angiogenesis and immune suppression in cancer, and anti-angiogenesis strategies can complement cancer immunotherapy. Previous research has implicated the tumor endothelium as a critical regulator of anti-tumor immunity, and our current work establishes a new role for the tumor endothelium as a critical barrier to T cell infiltration mediated through FasL. FasL is an important regulator of immunity and apoptosis, and we have found that, in contrast to the endothelium of normal tissues, the endothelium of multiple tumor types expressed FasL. FasL expression was restricted to tumor islets, and hypoxic tumor cell-conditioned media induced FasL on endothelial cells in vitro. Combination treatment with proangiogenic growth factors VEGF and PGE2 induced endothelial FasL expression in vitro, and COX1 and VEGF expression were associated with endothelial expression of FasL in ovarian cancer patients. Combinatorial blockade of VEGF and COX enzymes reduced endothelial FasL expression in mice, decreased tumor volume, and increased the CD8/FoxP3 ratio. In patients, low endothelial FasL expression was associated with a high CD8/Foxp3 ratio and increased survival. We found that endothelial FasL contributes to an unfavorable CD8/FoxP3 ratio through preferential killing of tumor-reactive CD8 T cells relative to Tregs. Increased intratumoral CD8/FoxP3 ratio was also observed in tumors grown on gld and lpr mice, but tumor growth was not robustly inhibited in these mice. Tumor control was dependent on the induction of an anti-tumor immune response, and CD8 depletion reversed the effects of VEGF and COX blockade. Additionally, combinatorial VEGF and COX blockade, tumors grown on gld mice, or the use of anti-FasL antibody all enhanced infiltration of adoptively transferred anti-tumor T cells and reduced apoptosis of transferred cells. Together, this work lends mechanistic insights into existing observations regarding T cells and tumor angiogenesis, and provides additional evidence for the paradigm that angiogenesis and immune suppression are intricately linked. Additionally, this work provides new strategies for cancer immunotherapy that may result in superior tumor control in patients.
Citation Format: Greg Motz, George Coukos. Expression of FasL on the tumor endothelium establishes a selective immune barrier in ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4985. doi:10.1158/1538-7445.AM2013-4985
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 4988: FOXP3, a critical mediator of regulatory T-cell function, is expressed in subsets of myeloid cells.
Authors: Gara Sudheer Kumar , Pang Yanli , Hollander Christine , Yang Li 
Published: August 2014

Abstract
Forkhead box P3 (FOXP3) is a well-known molecular marker for regulatory T cells (Tregs) and is considered as a master regulatory transcription factor for the development, maturation and function of Tregs. Mutations in FOXP3 lead to severe immune deficiencies and cancer in human and mice. Administration of Foxp3-expressing Tregs drastically reduced the disease severity in animal models of diabetes, asthma and multiple sclerosis giving rise to hope for therapeutic options. It is not clear whether cell types other than Treg express FOXP3. While investigating TGFβ-mediated signaling in the myeloid lineage, we discovered a subset of myeloid derived suppressor cells (Gr-1+CD11b+ cells or MDSCs) that express FOXP3. Indeed these cells were CD3 negative suggesting that they are not of T cell lineage. Upon further investigation, we observed that these FOXP3 expressing myeloid cells are present in different tissues of mouse. Moreover, we found that they are elevated under pathological conditions. We are currently identifying the molecular function and mechanisms of Foxp3 expression in the myeloid subsets. Our work will provide new insight into the FOXP3 research area beyond regulatory T cells, and might reveal its role in regulating the immunosuppressive activity of MDSCs.
Citation Format: Sudheer Kumar Gara, Yanli Pang, Christine Hollander, Li Yang. FOXP3, a critical mediator of regulatory T-cell function, is expressed in subsets of myeloid cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4988. doi:10.1158/1538-7445.AM2013-4988
Abstract 4994: Hypoxia-induced autophagy and TNF-alpha resistance in breast cancer cells leads to tumor evasion from NK-mediated immunosurveillance by downregulation of ICAM1.
Authors: Janji Bassam , Baginska Joanna , Medves Sandrine , Van Moer Kris , Chouaib Salem , Berchem Guy 
Published: August 2014

Abstract
The major obstacle for defining efficient immunotherapeutic approaches for the treatment of solid tumor is the capability of tumor cells to evade host immune response under hypoxic microenvironment. We have investigated how breast cancer cells manage to evade effective immunosurveillance. Since the host's immune evasion of many breast cancer cells is correlated with the acquisition of resistance to TNF-α, we used TNF-sensitive (MCF-7) and TNF-resistant (1001) breast cancer cells. We showed that the acquisition of TNF resistance in 1001 cells is correlated with the induction of hypoxia inducible factor (HIF)-1α and a constitutive activation of autophagy. When cultured under hypoxia, TNF-sensitive tumor cells activate autophagy and resist to the cytotoxic effect of TNF-α. This data strongly argue for a role of hypoxia in the development of TNF-resistant tumor cell population. Furthermore, we showed that TNF-resistant cells evade natural killer (NK) cells-mediated lysis by a mechanism involving a decrease in the conjugate formation between TNF-resistant and NK cells. The decrease in the ability of NK cells to recognize TNF-resistant tumor cells is related to a dramatic down-regulation of Intercellular Cell Adhesion Molecule (ICAM-1) at the surface of tumor cells. The mechanism responsible for the decrease of ICAM-1 expression in TNF-resistant cells and its functional link with autophagy is currently under investigation. Together, this study discloses the major role of hypoxic microenvironment in the activation of the autophagic process in tumor cells which ultimately leads to tumor evasion from immunosurveillance.
Citation Format: Bassam Janji, Joanna Baginska, Sandrine Medves, Kris Van Moer, Salem Chouaib, Guy Berchem. Hypoxia-induced autophagy and TNF-alpha resistance in breast cancer cells leads to tumor evasion from NK-mediated immunosurveillance by downregulation of ICAM1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4994. doi:10.1158/1538-7445.AM2013-4994
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 4995: Tumor-dervied gammadelta regulatory T cells suppress innate and adaptive immunity through the induction of immunosenescence.
Authors: Ye Jian , Ma Chunling , Hsueh Eddy C. , Zhang Yanping , Varvares Mark A. , Hoft Daniel F. , Peng Guangyong 
Published: August 2014

Abstract
Fundamentally understanding the suppressive mechanisms utilized by different subsets of tumor-infiltrating regulatory T (Treg) cells is critical for the development of effective strategies for anti-tumor immunotherapy. Gammadelta Treg cells have recently been identified in human diseases including in cancer patients. However, the suppressive mechanisms and functional regulations of this new subset of unconventional Treg cells are largely unknown. In the current studies, we explored the suppressive mechanism(s) utilized by human breast tumor-derived gammadelta Treg cells on innate and adaptive immunity. We found that gammadelta Treg cells induced immunosenescence in targeted naïve and effector T cells, as well as dendritic cells (DCs). Furthermore, senescent T cells and DCs induced by gammadelta Treg cells had altered phenotypes and developed potent suppressive activities, further amplifying the immunosuppression mediated by gammadelta Treg cells. In addition, we demonstrated that manipulation of TLR8 signaling in gammadelta Treg cells can block gammadelta Treg-induced conversion of T cells and DCs into senescent cells in vitro and in vivo. Our studies identify the novel suppressive mechanism mediated by human tumor-derived gammadelta Treg cells on innate and adaptive immunity, which should be critical for development of strong and innovative approaches to reverse the tumor suppressive microenvironment and improve effects of immunotherapy. This work was supported by the grant from the American Cancer Society (RSG-10-160-01-LIB).
Key words: gammadelta T cells; Regulatory T cells; Dendritic cells; Senescence; Immune suppression
Citation Format: Jian Ye, Chunling Ma, Eddy C. Hsueh, Yanping Zhang, Mark A. Varvares, Daniel F. Hoft, Guangyong Peng. Tumor-dervied gammadelta regulatory T cells suppress innate and adaptive immunity through the induction of immunosenescence. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4995. doi:10.1158/1538-7445.AM2013-4995