bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 207: Dual targeting of DLL4 and VEGF signaling by a novel bispecific antibody inhibits tumor growth and reduces cancer stem cell frequency
Authors: Yen Wan-Ching , Axelrod Fumiko , Bond Chris , Cain Jennifer , Chartier Cecile , Fischer Marcus , Ma Shirley , Meisner Rene , Raval Janak , Shah Jalpa , Gurney Austin , Lewicki John , Hoey Timothy 
Published: May 2015

Abstract
Both Notch/Delta-like ligand 4 (DLL4) and vascular endothelial growth factor (VEGF) pathways play a critical role in angiogenesis and tumor growth. Due to differential regulatory effects of VEGF and DLL4 on the vasculature, inhibition of DLL4 or VEGF inhibits tumor growth by distinct mechanisms: anti-DLL4 treatment induces an abnormal increase of poorly perfused blood vessels, which results in a nonproductive angiogenesis unable to support tumor growth, whereas the anti-VEGF therapy significantly decreases vasculature reducing the blood supply to tumors. We have recently developed a high binding affinity bispecific monoclonal antibody that targets both human DLL4 and human VEGF. In vitro, this antibody exhibited nanomolar affinity to hVEGF and hDLL4, and reduced HUVEC proliferation induced by VEGF. The bispecific antibody demonstrated significant in vivo anti-tumor efficacy in various solid tumors, delayed tumor recurrence following termination of chemotherapy, and decreased the frequency of tumor initiating cells. Analysis of tumor vasculature after treatment with anti-DLL4/VEGF revealed inhibition of vascular gene expression and endothelial cell proliferation, indicating that the anti-VEGF effect on the vasculature is dominant over the anti-DLL4 effect. Notably, at doses where both anti-DLL4 and anti-VEGF alone produced suboptimal anti-tumor effect, dual targeting resulted in additive tumor growth inhibition. These results indicate that our bispecific anti-DLL4/VEGF is broadly efficacious and may be useful for treatment of a variety of solid tumors.
Citation Format: Wan-Ching Yen, Fumiko Axelrod, Chris Bond, Jennifer Cain, Cecile Chartier, Marcus Fischer, Shirley Ma, Rene Meisner, Janak Raval, Jalpa Shah, Austin Gurney, John Lewicki, Timothy Hoey. Dual targeting of DLL4 and VEGF signaling by a novel bispecific antibody inhibits tumor growth and reduces cancer stem cell frequency. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 207. doi:10.1158/1538-7445.AM2014-207
Abstract 2075: Resistin promotes MMP-2 production and migration in human chondrosarcoma cells through AMPK/p38/mir 519d pathway
Authors: Huang Ho-Ning , Tang Chih-Hish , Huang Yuan-Li 
Published: May 2015

Abstract
Chondrosarcoma is a primary malignant bone cancer, with a potent capacity to invade locally and cause distant metastasis; it has a poor prognosis and shows a predilection for metastasis to the lungs. Resistin the most potent pro-inflammatory and plays a crucial role in migration and metastasis of human cancer cells. However, the effects of resistin on human chondrosarcoma cells are largely unknown. In this study, we found that treatment of human chondrosarcoma cells (JJ012) with resistin increased migration and expression of matrix metalloproteinase (MMP)-2. Resistin-mediated cell migration and MMP-2 expression were reduced by pretreatment with inhibitors of AMP-activated protein kinase (AMPK), and p38 mitogen-activated protein kinases (p38). Resistin treatment induced phosphorylation of AMPK and p38. In addition, resistin reduced miRNA 519d expression. Transfect ion of 519d mimic also reduced resistin mediated migration and MMP2 expression. Furthermore, we analyzed samples from chondrosarcoma patients by immunohistochemical staining. The expression of resistin and MMP2 in chondrosarcoma patients was significantly higher than in normal cartilage. Taken together, these results suggest that resistin increased MMP-2 expression and migration in human chondrosarcoma cells.
Citation Format: Ho-Ning Huang, Chih-Hish Tang, Yuan-Li Huang. Resistin promotes MMP-2 production and migration in human chondrosarcoma cells through AMPK/p38/mir 519d pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2075. doi:10.1158/1538-7445.AM2014-2075
Abstract 2076: βIII-tubulin is required for the tumorigenic phenotype and resistance to anoikis via the PTEN/AKT signaling axis in non-small cell lung cancer
Authors: McCarroll Joshua A. , Gan Pei Pei , Erlich Rafael B. , Liu Marjorie , Dwarte Tanya , Akerfeldt Mia C. , Chang Melissa , Shum Michael S. , Byrne Frances , Kavallaris Maria 
Published: May 2015

Abstract
BACKGROUND: Non-small cell lung cancer (NSCLC) has a dismal prognosis and remains the most common cause of cancer death worldwide. Expression of βIII-tubulin, encoded by the TUBB3 gene, is associated with clinical resistance and aggressive disease in NSCLC1. Herein, we interrogated the mechanistic role of βIII-tubulin in regulating the tumorigenic potential of NSCLC.
METHODS: Functional studies involved independent clones of NSCLC H460 cells stably expressing shRNA targeting βIII-tubulin, H460 controls stably expressing (non-functional) shRNA and βIII-tubulin rescue clones established in our laboratory2. Differential proteomics was conducted using fluorescence based 2D-DIGE and mass spectrometry. Gene and protein expression performed by qRT-PCR and western blotting respectively. To assess effects on tumor growth and incidence we used metastatic (tail vein) and subcutaneous models of NSCLC. Tumors monitored by CT or Xenogen imaging.
RESULTS: Functional and differential proteomics revealed that βIII-tubulin regulates expression of tumor growth- and metastases-associated proteins. In particular, the tumor suppressor maspin, associated with adhesion and metastasis, was differentially regulated by βIII-tubulin. Functionally, βIII-tubulin suppression led to altered cell morphology, increased cell adhesion and increased sensitivity to anoikis. Mechanistically, we identified PTEN and AKT kinase as a key signaling axis mediating anoikis and regulated by βIII-tubulin levels in NSCLC cells. Finally, βIII-tubulin suppression was shown to reduce NSCLC tumor growth and incidence in vivo. Collectively, these data identified βIII-tubulin as a regulator of tumor growth and metastasis through regulation of PTEN and AKT signaling. We conclude that suppressing βIII-tubulin may reduce tumor growth in NSCLC.
SIGNIFICANCE: This is the first study to show that silencing βIII-tubulin alters the expression of proteins involved in promoting tumorigenicity and increases sensitivity to anoikis, leading to reduced tumor incidence. Targeting βIII-tubulin could be a promising strategy for inhibiting tumor growth and metastasis in NSCLC.
1 Kavallaris, M. Nature Rev Cancer, 10:194-204, 2010
2 McCarroll et al. Cancer Res 70 :4995-5003, 2010
Citation Format: Joshua A. McCarroll, Pei Pei Gan, Rafael B. Erlich, Marjorie Liu, Tanya Dwarte, Mia C. Akerfeldt, Melissa Chang, Michael S. Shum, Frances Byrne, Maria Kavallaris. βIII-tubulin is required for the tumorigenic phenotype and resistance to anoikis via the PTEN/AKT signaling axis in non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2076. doi:10.1158/1538-7445.AM2014-2076
Abstract 2077: Snail modulates stemness properties in hypoxic Glioblastoma
Authors: srivastava Chitrangda , Irshad Khushboo , Sahu Arpit , Chattopadhyay Parthaprasad , Sarkar Chitra , Gupta Deepak kumar , Sinha Subrata , Chosdol Kunzang 
Published: May 2015

Abstract
Introduction: Glioblastoma (GBM) is the most aggressive form of glioma characterized by hypoxic regions with surrounding areas of necrosis. Hypoxia is responsible for inducing cancer invasiveness via epithelial-mesenchymal transition (EMT), thereby promoting tumor aggressiveness and therapeutic resistance. HIF-1α is known to upregulate Snail in various cancers. Snail over expression correlates with cancer stem cell-like properties in cancers. The association of EMT and stemness properties plays a vital role in tumors progression and might helps in therapeutic targeting. We have, therefore, investigated the correlation of EMT and Stem cell markers in hypoxic GBM.
Method: mRNA expression of 5 EMT, 3 stemness and 5 hypoxia markers were analyzed in the 31 GBM samples and U373MG glioma cell line maintained under normoxia (20% O2) and severe hypoxia (0.2% O2) conditions for 24, 48 and 72 hrs. Correlation and cluster analysis were applied using SPSS 11.5, Cluster 3.0 software etc and R-software.
Result: In tumors, spearman correlation was found to be significant (p≤0.05) between EMT markers and Hypoxia markers. Of all EMT markers, Snail correlated significantly with the maximum hypoxia markers, including HIF-1α. In addition, Snail was significantly correlated with Stem cell markers SOX2 (p&lt;0.01) and Nestin (p&lt;0.05). Gene Cluster analysis in 31 GBM arranged in decreasing order of Snail expression showed significant upregulation of SOX2 and Nestin in the high Snail expressing tertile. This correlation of gene expression in tumors was validated by in-vitro expression analysis of the molecules in U373MG cells, where we assessed significant increase in the expression of hypoxia markers (HIF-1α, VEGF and CA9), EMT (Snail and LOX) and SC markers (SOX2 and OCT4) were significantly increased under severe hypoxic conditions.
Interpretation & conclusions: Our finding for the first time suggests the role of Snail in provoking stemness of cancer cells in hypoxic GBM, thereby promoting aggressiveness of GBM.
Note: This abstract was not presented at the meeting.
Citation Format: Chitrangda srivastava, Khushboo Irshad, Arpit Sahu, Parthaprasad Chattopadhyay, Chitra Sarkar, Deepak kumar Gupta, Subrata Sinha, Kunzang Chosdol. Snail modulates stemness properties in hypoxic Glioblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2077. doi:10.1158/1538-7445.AM2014-2077
Abstract 208: Metformin represses stem cell properties and induces apoptosis in human breast cancer cells and mouse mammary epithelial cells
Authors: Kang Eun Joo , Seo Jae Hong , Kim Jun Suk , Kim Ji Young 
Published: May 2015

Abstract
Cancer stem cells (CSCs) are small portions of cancer cells that have important self-renewal and proliferation characteristics, and therefore, they play a significant role in cancer development and metastasis. Recently, several studies have revealed CSCs of several solid tumors. The identification and targeting of CSCs are expected to advance treatment outcomes, but until now, only a few drugs that specifically target CSCs have been developed.
Metformin, an antidiabetic drug used for the treatment of type 2 diabetes mellitus, suppresses gluconeogenesis in the liver and increases insulin sensitivity and glucose uptake in peripheral tissues such as muscles. Moreover, the drug has shown an anti-cancer effect by inhibiting cellular proliferation and protein synthesis in several cancer cell lines. Additionally, many clinical and epidemiological studies have suggested that metformin might be associated with a decreased risk of cancer development and an increased response to chemotherapy.
In addition to its anticarcinogenic effect, studies about the anti-cancer stem cell effect of metformin have been recently reported. Several reports revealed that metformin could preferentially kill cancer stem cells, including breast cancer stem cells. However, the mechanism of anti-cancer stem cell activity is not well known.
Therefore, this study was planned to confirm the cytotoxicity of metformin, especially for breast cancer stem cells as well as breast cancer cells. To this end, several human breast cancer cell lines and normal mouse mammary epithelial cell lines were used. In this study, metformin showed cell growth inhibition in human breast cancer cells and mouse mammary epithelial cells by inducing cell cycle arrest and apoptosis. Moreover, metformin specifically killed breast cancer stem cells. Metformin showed reduced mammosphere formation in all cell lines. In addition, decreasing breast cancer stem cell population by metformin treatment was identified through FACS analysis. For the mechanism of anti-cancer stem cell activity, western blot assay was performed. We identified decreased levels of cyclin D and cycline E and increased levels of Bax in secondary mammaospheres according to metformin treatment. In conclusion, this present study show that metformin kills breast cancer stem cells as well as breast cancer cells, and these phenomena occur by the induction of cell cycle arrest and apoptosis.
Citation Format: Eun Joo Kang, Jae Hong Seo, Jun Suk Kim, Ji Young Kim. Metformin represses stem cell properties and induces apoptosis in human breast cancer cells and mouse mammary epithelial cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 208. doi:10.1158/1538-7445.AM2014-208
Abstract 2081: FoxM1 transactivates PTTG1 and promotes colorectal cancer cell migration and invasion
Authors: Guo Jinjun , Zheng Yun , Tong Yunguang , Koeffler H Philip 
Published: May 2015

Abstract
Previous studies have shown that both Forkhead Box M1 (FoxM1) and pituitary tumor transforming gene 1 (PTTG1) were associated with cancer development and metastases. This study aims to investigate the relation between FoxM1 and PTTG1 and its role in colorectal cancer cell behavior.
The microarray data of colorectal cancer were analyzed to determine the association of FoxM1 and PTTG1 expression. Luciferase reporter assay, ChIP and EMSA were used to identify the regulatory mechanisms between FoxM1 and PTTG1. PTTG1 mRNA and protein levels were examined using real-time PCR and western blot after knocking down or over expressing FoxM1. The roles of FoxM1 and PTTG in tumor metastasis were investigated by cell migration and invasion assays.
Gene expression microarray data indicated that FoxM1 and PTTG1 are concordantly up-regulated in colorectal cancer tissues. Over-expression of FoxM1 up-regulated PTTG1 expression and knock-down of FoxM1 did the opposite, indicating that PTTG1 was regulated by FoxM1. Luciferase reporter assay indicated that -391 to +50 bps of PTTG1 promoter are important for FoxM1 to enhance PTTG1 promoter activity. Sequence analysis identified two potential FoxM1 binding sites. EMSA indicated that FoxM1 directly binds to PTTG1 promoter at the -350 to -343 binding motif. This binding was confirmed by chromatin immunoprecipitation in HCT116 and SW620 cells. Boyden chamber assay indicated that FoxM1 and PTTG1 concordantly regulate migration and invasion of HCT116 and SW620 colorectal cancer cells.
In summary, our results elucidate that FoxM1 up-regulates PTTG1 transcription through binding to PTTG1 promoter. PTTG1 likely mediates effects of FoxM1 on colorectal cancer cell migration and invasion.
Citation Format: Jinjun Guo, Yun Zheng, Yunguang Tong, H Philip Koeffler. FoxM1 transactivates PTTG1 and promotes colorectal cancer cell migration and invasion. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2081. doi:10.1158/1538-7445.AM2014-2081
Abstract 2082: PHD3 regulates EMT and therapy response in lung cancer
Authors: Gonzalez Jose Higinio Dopeso 
Published: May 2015

Abstract
The hypoxic microenvironment is a characteristic feature of solid tumors. Hypoxia initiates a number of adaptive responses that collectively promote a more aggressive tumor phenotype. One important process that is activated by hypoxia is epithelial-mesenchymal transition (EMT), a cellular program that induces cell detachment and increases the invasive capacity of the cells. The prolyl hydroxylase domain proteins PHD1, 2 and 3 play a central role in adaption to hypoxia and act as oxygen sensors that regulate the hypoxia-inducible factors (HIFs) response. Here, we identify PHD3 as a crucial regulator of central tumor hallmarks in lung cancer. We show that PHD3 is regulated during EMT and that modulation of PHD3 levels in lung carcinoma cells controls EMT, the tumorigenicity and metastatic capacity of lung cancer cells in various animal tumor models. Mechanistically we show that these functions of PHD3 are mediated through a signaling cascade leading to increased SMAD activity. Moreover, we show that these effects are mechanistically linked to the acquisition of therapeutic resistance in lung cancer and may therefore serve to predict therapy response. These findings highlight PHD3 as an important regulator of lung cancer progression, which controls several cancer hallmarks including growth, invasion, metastasis and therapy resistance.
Citation Format: Jose Higinio Dopeso Gonzalez. PHD3 regulates EMT and therapy response in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2082. doi:10.1158/1538-7445.AM2014-2082
Abstract 2090: Novel role of STAT-3 in anoikis resistance and metastasis in melanoma cells in vitro and in vivo
Authors: Fofaria Neel Manoj , Srivastava Sanjay K. 
Published: May 2015

Abstract
Anoikis is an anchorage-independent cell death. Resistance to anoikis is one of the key features of metastatic cells. The role of STAT-3 in anoikis resistance in various melanoma cells was analyzed in the current study. Significant proportion of SK-MEL-28, SK-MEL-2, MeWo, SK-MEL-5 and B16-F0 cells resisted anoikis when grown under anchorage-independent conditions. Cells that resisted anoikis were observed to a have higher rate of migration and invasion as compared to the cells grown under anchorage dependent conditions. The anoikis resistant cells also exhibited significantly higher expression and phosphorylation of STAT-3 at Tyr 705 than the cells that were attached to the basement membrane. Treatment of these cells with IL-6, a cytokine which phosphorylates STAT-3, prevented the induction of anoikis. STAT-3 inhibitors AG490 and PL induced anoikis in a concentration-dependent manner in anoikis resistant cells, whereas IL-6 blocked anoikis. Over-expression of STAT-3 by transfection in SK-MEL-28 and SK-MEL-2 cells significantly increased the anoikis resistance, confirming the role of STAT-3 in anoikis resistance. On the other hand, silencing STAT-3 in SK-MEL-28, SK-MEL-2, SK-MEL-5 and MeWo cells decreased the potential of cancer cells to resist anoikis. Furthermore, STAT-3 (-/-) melanoma cells were more sensitive to anoikis, as compared to cells overexpressing STAT-3 (+/+) cells. STAT-3 (-/-) SK-MEL-28 cells and the SK-MEL-28 cells that were treated with PL completely failed to develop tumors when injected subcutaneously in immune-compromised mice. Moreover, these cells also failed to metastasize when injected intravenously. On the other hand, anoikis resistant wild type cells not only formed aggressive tumors subcutaneously but also highly metastasized when injected intravenously. The metastasis was confirmed by H & E staining. In summary, our results establish STAT-3 as a critical player that renders anoikis resistance to pancreatic cancer cells and enhance their metastasis potential. [Supported in part by R01 grant CA129038 (to S.K.S) awarded by the National Cancer Institute].
Citation Format: Neel Manoj Fofaria, Sanjay K. Srivastava. Novel role of STAT-3 in anoikis resistance and metastasis in melanoma cells in vitro and in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2090. doi:10.1158/1538-7445.AM2014-2090
Abstract 21: Stromal fibroblasts in breast carcinomas promote angiogenisis through Adrenomedullin (AM) secretion
Authors: Benyahia Zohra 
Published: May 2015

Abstract
Tumor stroma is an active part influencing the biological properties of malignancies via molecular cross-talk. Tumor- or cancer-associated fibroblasts (TAFs or CAFs) play a significant role in this interaction. These cells frequently express smooth muscle actin and can be classified as myofibroblasts. CAFs often constitute the majority of the stromal cells within a breast carcinoma. Adrenomedullin (AM), a multifunctional peptide, is highly expressed in several tumors and plays an important role in angiogenesis and tumor growth through its receptors calcitonin receptor-like receptor/receptor activity modifying protein-2 and -3 (CLR/RAMP2 and CLR/RAMP3). In this study, RT-QPCR showed the expression of AM and AM receptors mRNAs in CAFs and breast carcinoma cell lines (MCF7 and MDA 231). Immunostaining demonstrates the presence of immunoreactive AM in all the CAFs analyzed (n=15). AM activates MAP kinase pathway by inducing a phosphorylation of ERK1/2 and p38 in both cell types suggesting a cross-talk between tumor cells and CAFs ensured by AM. In vivo, CAFs in Matrigel plugs induce angiogenesis by promoting recruitment of endothelial cells, pericytes, myeloid precursor cells and by promoting channel formation. AM and AM receptors neutralizing antibodies blocked neovascularisation of Matrigel plugs suggesting strongly that angiogenesis induced by CAFs into carcinoma are mediated in part by AM. Our findings indicate that CAFs within breast carcinomas may contribute to tumor promotion in part through the secretion of AM.
Note: This abstract was not presented at the meeting.
Citation Format: Zohra Benyahia. Stromal fibroblasts in breast carcinomas promote angiogenisis through Adrenomedullin (AM) secretion. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 21. doi:10.1158/1538-7445.AM2014-21