bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4147: Synergistic effect of combined EGFR and Src inhibitor in colon cancer cell migration
Authors: Wu Yi-Che , Wei Wan-Chen , Chao Wei-Ting 
Published: August 2015

Abstract
EGFR signaling plays the important role in cancer cell proliferation and cell migration. Cetuximab which is the antibody against EGFR was approved for colon cancer treatment. Recently, Src inhibitor, dasatinib has been demonstrated to improve drug sensitivity to cetuximab in KRAS mutant colorectal cancer cell growth. Src is a non-receptor tyrosine kinase which is necessary for full activation of EGFR and also functions in focal adhesion kinase activity in cell migration, therefore, the combination of cetuximab and dasatinib may has effect on colon cell migration. In this study, cetuximab and dasatinib were applied to SW480 colon cell which is KRAS mutant cell line. Cell viability and cell migration were analyzed, localization of Src and focal adhesion kinase (FAK) were observed by confocal microscopy. In the result, Combination of 5μM cetuximab and 40 nM dasatinib treatment resulted in synergistic effect on cell viability. However, when cetuximab combined with 25nM dasatinib was applied in trans-well migration assay, the synergistic inhibition on cell migration was observed. The immunofluorescence confocal microscopic image demonstrated cetuximab treatment induced phospho-Src accumulation on the cell membrane and colocalized with phospho-FAK. When the combination of 5μM cetuximab and 25 uM dasatinib were applied in the cell, the membrane accumulation of phospho-Src and Phospho-FAK were decreased. Taken together, cetuximab combined with dasatinib has synergistic efficacy in colon cancer cell proliferation, however, cetuximab combined with lower concentration of dasatinib (25nM) suppressed cell migration by inhibited FAK membrane localization through Src inactivation.
Citation Format: Yi-Che Wu, Wan-Chen Wei, Wei-Ting Chao. Synergistic effect of combined EGFR and Src inhibitor in colon cancer cell migration. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4147. doi:10.1158/1538-7445.AM2015-4147
Abstract 416: Carbon monoxide targets Notch1 and MAPK-ERK1/2 signaling pathways to block growth of lung carcinoma
Authors: Nemeth Zsuzsanna , Csizmadia Eva , Vikstrom Lisa , Li Mailin , Bisht Kavita , Feizi Alborz , Gallo David , Otterbein Leo , Fillinger Janos , Dome Balazs , B. Costa Daniel , Wegiel Barbara 
Published: August 2015

Abstract
We have recently shown that inhalation of low, non-toxic doses of carbon monoxide (CO) is a potential therapeutic adjuvant treatment for lung cancer and prostate cancer (Cancer Research, 2013, Wegiel B et al). We found that CO doses of 100 ppm daily or twice per week were the most effective in suppressing A549 xenograft tumors growth, Ki67 expression and increased cleaved caspase-3 staining. Additionally, we found that inhibition of xenografts and KRAS-driven lung tumor growth in response to CO was associated with increased expression of M1 macrophage markers (CD86, CD197, RANTES) and decreased M2 markers (MMR) and HO-1 blockage. We demonstrated a direct interaction between HO-1 and Notch1. Further, that CO promotes Notch 1 cleavage as well as phosphorylation of ERK1/2 in the stroma cells, which are the markers of M1 polarization. Moreover, we demonstrated a significant correlation between low HO-1 expression and high p-ERK ½ expression in primary human lung cancers (n = 30 patients). In summary, we describe a mechanism by which CO affects cancer growth through regulation of macrophage polarization via Notch1 and Erk1/2 pathways.
Citation Format: Zsuzsanna Nemeth, Eva Csizmadia, Lisa Vikstrom, Mailin Li, Kavita Bisht, Alborz Feizi, David Gallo, Leo Otterbein, Janos Fillinger, Balazs Dome, Daniel B. Costa, Barbara Wegiel. Carbon monoxide targets Notch1 and MAPK-ERK1/2 signaling pathways to block growth of lung carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 416. doi:10.1158/1538-7445.AM2015-416
Abstract 4180: TGF-beta promotes angiogenesis in an RB-deficient, Kras-driven mouse model of pancreatic cancer
Authors: Gore Jesse , Craven Kelly E. , Wilson Julie L. , Korc Murray 
Published: August 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is projected to become the 2nd leading cause of cancer deaths by 2030. PDACs are associated with a high frequency of KRAS mutations (95%) and overexpression of many pro-angiogenic cytokines and growth factors. Using a genetically engineered mouse model (GEMM) that we established in which oncogenic Kras is combined with loss of RB (KRC), we have determined that PDACs arising in these mice (mPDACs) harbor many endothelial cells (ECs) and sinusoidal-like vessels that have blood flow, as determined by intravital confocal microscopy. Array analysis of pancreatic cancer cells (PCCs) derived from KRC tumors revealed gene expression profiles that correlate with active TGF-β signaling pathways, as determined by gene set enrichment analysis (GSEA), and include increased expression of multiple pro-angiogenic genes. In silico analysis indicated that many of these pro-angiogenic genes were TGF-β targets, and inhibition of the type I TGF-β receptor (TβRI) with SB505124 confirmed that TGF-βs drive pro-angiogenic gene expression in KRC PCCs. Moreover, TGF-β increased the levels of pro-angiogenic cytokines in conditioned media (CM) prepared from KRC PCCs, which when added to ECs, activated canonical TGF-β signaling pathways and stimulated EC proliferation and migration. Although SB505124 blocked TGF-β pathway activation in ECs, it failed to suppress CM-enhanced EC proliferation and migration. By contrast, SB505124 attenuated tumor angiogenesis, growth and metastasis in a syngeneic orthotopic mouse model using KRC PCCs. Taken together, these results suggest that TGF-β promotes angiogenesis in an indirect manner, by up-regulating pro-angiogenic factors in PCCs that act on ECs in a paracrine manner. Therefore, targeting TGF-β in PDAC could be a beneficial anti-angiogenic strategy.
Citation Format: Jesse Gore, Kelly E. Craven, Julie L. Wilson, Murray Korc. TGF-beta promotes angiogenesis in an RB-deficient, Kras-driven mouse model of pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4180. doi:10.1158/1538-7445.AM2015-4180
Abstract 4181: Chronic stress and beta adrenergic signaling promote angiogenesis and prostate cancer progression through suppressing the expression of Thrombospondin 1
Authors: Hulsurkar Mohit M. , Sang Meixiang , Song Haiping , Li Wenliang 
Published: August 2015

Abstract
Several recent studies have revealed that the activation of beta adrenergic signaling induced by chronic biobehavioral stress promotes the progression of ovarian, breast and prostate cancers. Conversely, the use of hypertension medicine, beta blockers (beta adrenergic antagonists), has been found to be associated with better prognosis in several human cancers. Although the beta adrenergic signaling has been shown to be activated by chronic stress and responsible for promoting cancers, the mechanisms through which beta adrenergic signaling promotes tumor angiogenesis and cancer progression are still unclear. We found that chronic stress and activation of beta adrenergic signaling suppressed the expression of Thrombospondin 1 (TSP1) in prostate cancer cells in vitro, as well as in mouse xenograft tumors in vivo, which in turn promoted tumor angiogenesis and cancer progression. TSP1 was the first endogenous angiogenesis inhibitor to be discovered and its down-regulation is associated with increased angiogenesis. We recently demonstrated that G-protein coupled receptor kinase 3 (GRK3, ADRBK2) promotes angiogenesis and prostate cancer progression through suppressing TSP1. Interestingly, GRK3 expression is up-regulated by chronic stress and activation of beta adrenergic signaling, suggesting that GRK3 acts as a mediator for chronic stress and beta adrenergic signaling in repressing TSP1 expression. Taken together, these results suggest that beta adrenergic signaling pathway stimulates angiogenesis through GRK3 mediated suppression of TSP1.
Citation Format: Mohit M. Hulsurkar, Meixiang Sang, Haiping Song, Wenliang Li. Chronic stress and beta adrenergic signaling promote angiogenesis and prostate cancer progression through suppressing the expression of Thrombospondin 1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4181. doi:10.1158/1538-7445.AM2015-4181
Abstract 4182: Gemcitabine triggers angiogenesis-promoting molecular signals in pancreatic cancer cells: Therapeutic implications
Authors: Khan Mohammad Aslam , Srivastava Sanjeev K. , Bhardwaj Arun , Singh Seema , Carter James E. , Singh Ajay P. 
Published: August 2015

Abstract
Pancreatic tumor microenvironment (TME) is characterized by poor tumor vasculature and extensive desmoplasia that together contribute to poor response to chemotherapy. It was recently shown that targeting of TME to inhibit desmoplastic reaction in a mouse model of pancreatic cancer resulted in increased microvessel density and intratumoral drug concentration, leading to improved therapeutic response. This approach; however, failed to generate a favorable response in a clinical trial. In that regard, we have previously demonstrated that gemcitabine-treatment of pancreatic cancer cells induces CXCR4 expression in a counter-defense mechanism and promotes pancreatic tumor cell invasiveness. The goal of present study was to examine the effect of chemotherapy on endothelial cell growth and migration. Pancreatic cancer cells were treated with gemcitabine or vehicle for 8 h and subsequently incubated in fresh low serum-containing media for next 48 h. Conditioned media was collected from vehicle- (V-CM) and gemcitabine-treated (Gem-CM) pancreatic cancer cells and used for the treatment of human umbilical vein endothelial cells (HUVEC). The data demonstrated stimulatory effects of Gem-CM on endothelial cell proliferation, migration, invasion and capillary-like structure (CLS) formation. Expression analysis of vehicle- and gemcitabine-treated pancreatic cancer cells and their conditioned-media revealed an upregulation of CXCL8/IL8, which is a known regulator of angiogenesis. Currently, we are investigating whether IL8 mediates the effect of Gem-CM on endothelial cells. Together, our findings suggest that gemcitabine triggers angiogenesis-promoting molecular signals in pancreatic cancer cells, which, in light of our previous observations, may hold important clinical and translational significance.
Citation Format: Mohammad Aslam Khan, Sanjeev K. Srivastava, Arun Bhardwaj, Seema Singh, James E. Carter, Ajay P. Singh. Gemcitabine triggers angiogenesis-promoting molecular signals in pancreatic cancer cells: Therapeutic implications. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4182. doi:10.1158/1538-7445.AM2015-4182
Abstract 4183: Differential expression of VEGF in breast cancer cells induced by gp130 cytokines
Authors: Hedeen Danielle S. , Tawara Ken , Nandakumar Madhuri , Fox Ryan , Chang David , Ide Alex , Oler Andrew , LaJoie Dollie , Jorcyk Cheryl L. 
Published: August 2015

Abstract
Glycoprotein 130 (gp130) is a glycosylated type 1 membrane protein and functions as a cytokine receptor modulating activity of the interleukin-6 (IL-6) family cytokines, which include IL-6, IL-11, IL-27, oncostatin M (OSM), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1), cardiotrophin-like cytokine (CLC), and neuropoietin (NP). This study was designed to determine differential expression of VEGF in breast cancer cells by IL-6 family cytokines, and to elucidate the molecular mechanisms and signaling pathways involved in cytokine-mediated VEGF induction. Triple negative breast cancer (TNBC) MDA-MB-231 and estrogen receptor positive/progesterone receptor positive/Her2 negative (ER+/PR+/Her2-) T47D cells were treated with three cytokines (25 ng/mL), OSM, IL-6, and LIF, and analyzed. Our results showed that all three cytokines increased levels of HIF1α by Western blot analysis. OSM lead to a greater production of VEGF compared to IL-6 and LIF, as measured by enzyme-linked immunosorbent assay (ELISA) and as seen by luciferase reporter assay. Of the three cytokines, OSM alone induced VEGF in TNBC MDA-MB-231 cells, and this effect was mediated by signal transducer activator of transcription 3 (STAT3) signaling. However, both OSM and IL-6 increased VEGF secretion levels in ER+/PR+/Her2- T47D breast cancer cells, and this signaling was mediated by both HIF1α and pSTAT3, utilizing ELISA and Western blot analysis. These results implicate OSM as the key gp130 cytokine inducing VEGF secretion, and also suggest that this induction is not always HIF1α dependent and is cell-line specific.
Citation Format: Danielle S. Hedeen, Ken Tawara, Madhuri Nandakumar, Ryan Fox, David Chang, Alex Ide, Andrew Oler, Dollie LaJoie, Cheryl L. Jorcyk. Differential expression of VEGF in breast cancer cells induced by gp130 cytokines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4183. doi:10.1158/1538-7445.AM2015-4183
Abstract 4207: Secreted proteins from breast cancer cell lines as a source of cancer biomarkers
Authors: Birkeland Even , Mannelqvist Monica , Akslen Lars Andreas 
Published: August 2015

Abstract
Introduction:
Breast cancer is a heterogeneous disease whose molecular diversity is not well reflected in clinical and microscopic markers used for prognostic information and treatment decisions. Traditionally, most biomarkers are based on tissue samples. To increase efficiency, precise liquid biopsies are needed to detect breast cancer at an early stage including its molecular phenotype, to monitor disease progression, and to predict treatment response. Cell line secretomes are enriched with proteins already linked to tumorigenesis, many of which will be present in biological fluids.
Methods:
Here, we studied the secreted proteins in conditioned media (CM) from two basal-like (HS-578, MB-231) and two luminal-like breast cancer cell lines (MCF-7, BT-474), using liquid chromatography-tandem mass spectrometry. The resulting data were analyzed using SearchGUI, PeptideShaker, Progenesis software and DAVID.
Results:
In total, 954 proteins were identified, of which 93 significantly differentially abundant (P-value ≤ 0.05 Mann-Whitney U, two or more peptides quantified) in the CM between basal-like and luminal-like cell lines. 76 proteins were more abundant in the CM from basal-like cell lines, including several proteins related to angiogenesis and extra-cellular matrix remodeling.
Conclusion:
This study shows the potential for using the secretome of breast cancer cell lines combined with mass-spectrometry for biomarker discovery.
Citation Format: Even Birkeland, Monica Mannelqvist, Lars Andreas Akslen. Secreted proteins from breast cancer cell lines as a source of cancer biomarkers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4207. doi:10.1158/1538-7445.AM2015-4207
Abstract 4211: The proteomic characterization of HNSCC patient-derived xenografts
Authors: Li Hua , Wheeler Sarah E. , Park Yongseok , Ju Zhenlin , Egloff Ann Marie , Fichera Michele , Thomas Sufi , Mills Gordon B. , Grandis Jennifer R. 
Published: August 2015

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer in the US and a leading cancer worldwide. There has been little change in the prognosis for these patients despite extensive research and FDA approval of the targeted therapy cetuximab. Cetuximab has been effective in immortalized HNSCC cell lines but demonstrates only a modest benefit for a subset of patients. This gap between pre-clinical discovery and testing and final clinical efficacy can be narrowed improving the translational relevance of preclinical model systems. Patient derived xenografts (PDXs) have emerged as a promising approach in several cancers. We sought to define and compare the protein expression patterns between primary HNSCC and PDXs derived from 13 patient tumors and test predictive biomarkers to cetuximab therapy.
We compared 13 PDXs propagated at the University of Pittsburgh and analyzed for the expression levels of 190 proteins by reverse-phase protein array (RPPA) to 212 HNSCC specimens and 4566 cancer specimens from TCGA also analyzed by RPPA. We found that 12/13 PDXs were more like HNSCC than any of 14 other cancer types analyzed. Unsupervised clustering of the primary HNSCC and the PDXs demonstrated that PDXs clustered together, indicating some differences in protein expression between HNSCC and PDXs. Further analysis demonstrated that a subset of the proteins were different between the mouse derived PDXs and the primary HNSCC while a second subset were similar between mouse derived PDXs and primary HNSCC. Proteins that were different between these two groups may be poor candidates for translational models, but proteins that were similar may prove useful. We tested the different responses to cetuximab using the PDXs. We found that a PDX with high EGFR/pEGFR expression was more sensitive to cetuximab treatment than a PDX with low EGFR/pEGFR expression.
These results suggest that improved model systems used for translational may predict clinical responses. RPPA measurement of protein expression in PDXs and primary cancers demonstrates that PDXs do represent HNSCC overall. Comparison of the PDXs specifically with primary HNSCC reveals that PDXs are not an appropriate model system for all targeted therapies/studies but provide an effective model for many studies of interest in the field.
Citation Format: Hua Li, Sarah E. Wheeler, Yongseok Park, Zhenlin Ju, Ann Marie Egloff, Michele Fichera, Sufi Thomas, Gordon B. Mills, Jennifer R. Grandis. The proteomic characterization of HNSCC patient-derived xenografts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4211. doi:10.1158/1538-7445.AM2015-4211
Abstract 4225: A novel pharmacological inhibitor CEP1430 for human pancreatic cancer stem cells
Authors: Jani Jitesh , Amiri Mandana , Sharma Cristian , Harris Joshua , Satish Shruthi , Sharma Michael , Rodriguez Robert , Navel Miriam , Amezcua Natalee , Sharma Shaleekha , Sharma Arun , Desai Dhimant , Amin Shantu , Narayan Satya , Punzalan Rubio , Sharma Jay P. 
Published: August 2015

Abstract
Pancreatic cancer is one of the most devastating human malignancies with an estimate yearly death of 280,000 and an overall median 5-year survival rate of less than 5%. The development of relevant preclinical models of the disease to evaluate novel therapeutic strategies can accelerate basic research findings into the much needed clinical application. We used our recently established three-dimensional (3D) in vitro culture assay system that resembles in-vivo tumor growth to screen small molecule libraries. We identified CEP1430, a sonic hedgehog (hh) pathway inhibitor as a potential drug lead molecule. We selected this molecule for further evaluation because the hh pathway is important for the maintenance of cancer stem cells. The CEP1430 treatment markedly inhibited in-vitro growth of human pancreatic CSC (IC50 value of ∼10 nM). In-vitro, CEP1430 induced apoptotic cell death of CSC and reduced pro-angiogenic but increased anti-angiogenic marker expression at the doses tested. In-vivo efficacy of CEP 1430 was evaluated in female SCID mice bearing human pancreatic CSC. The once daily administration (ip) of CEP1430 (doses:10, 15, and 20 mg/kg) for 30 days resulted in 80%, 89% and 90% tumor growth inhibition. The tumor growth inhibitory effect of CEP1430 in all treatment groups was statistically significant in comparison to vehicle treated control (P&lt;0.001). The administration of CEP1430 for a period of 30 days was well tolerated without significant changes in body weight or toxicity by histological examination of tissues and organs. We are using proteomic and miRNA platforms to monitor biomarkers of response, mode of action and selectivity of CEP1430. Further pre-clinical in-vivo studies are ongoing to project human dose and schedule as monotherapy and in combination with therapeutic vaccination to advance CEP1430 for clinical investigation.
Citation Format: Jitesh Jani, Mandana Amiri, Cristian Sharma, Joshua Harris, Shruthi Satish, Michael Sharma, Robert Rodriguez, Miriam Navel, Natalee Amezcua, Shaleekha Sharma, Arun Sharma, Dhimant Desai, Shantu Amin, Satya Narayan, Rubio Punzalan, Jay P. Sharma. A novel pharmacological inhibitor CEP1430 for human pancreatic cancer stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4225. doi:10.1158/1538-7445.AM2015-4225