bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3231: Chronic nicotine stimulates lung adenocarcinoma in vivo and in vitro via modulation of nicotinic acetylcholine receptor regulated excitatory and inhibitory neurotransmission characteristic of nicotine addiction
Authors: Al-Wadei Hussein A. , Al-Wadei Mohammed H. , Schuller Hildegard M. 
Published: February 2011

Abstract
Nicotine addiction is characterized by changes of nicotinic acetylcholine receptors (nAChRs) in the brain to increase the production of excitatory neurotransmitters noradrenaline/adrenaline while reducing inhibitory neurotransmitter γ-aminobutyric acid (GABA). We tested the hypothesis that nAChR-regulated neurotransmitters regulate lung adenocarcinoma (AC) and that nAChR changes in AC cells analogous to nicotine addiction in the brain contribute to the development and progression of this cancer.
Mice carrying xenografts of the human AC cell line NCI-H322 received no treatment or were given nicotine in the drinking water for 30 days with and without intraperitoneal injections of GABA. Xenograft sizes were measured. Noradrenaline and adrenaline in serum and cAMP in blood cells and tumor cells were measured by immunoassays. Protein expression of α7nAChR, α4β2nAChR, p-CREB, p-ERK1/2, glutamate decarboxylase 65 (GAD65) and GABA in xenografts were analyzed by Western blotting. Nicotine increased xenograft sizes and upregulated receptor protein of both nAChRs in xenografts while increasing noradrenaline, adrenaline and cAMP in the blood. Xenograft expression of GAD65 and GABA were suppressed by nicotine while p-CREB, p-ERK and cAMP were induced. GABA reversed all these effects of nicotine. In vitro exposure of AC cells for 7 days to nicotine upregulated and sensitized the α7nAChR, resulting in a significant increase in noradrenaline/adrenaline production in response to agonist and enhancement of its cAMP-dependent signaling responses. At the same time, the α4nAChR was desensitized by chronic nicotine causing a significant reduction in GABA production.
Nicotine-induced predominance of stimulatory noradrenaline and deficiency in inhibitory GABA in AC cells analogues to the nicotine addicted brain may therefore contribute to the development and progression of AC in smokers and GABA may be useful for the marker-guided prevention and adjuvant therapy of AC.
Supported by a grant from the National Lung Cancer Partnership and LUNGevity Foundation.
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 3231.
Abstract 3232: The proteome analysis of mice lung tumors
Authors: Yamano Shotaro , Kakehashi Anna , Tago Yoshiyuki , Tei Keikou , Wei Min , Wanibuchi Hideki 
Published: February 2011

Abstract
We have previously shown that lung squamous cell carcinoma (SCC) is induced by 20 weeks treatment with N-nitroso-tris-chloroethylurea (NTCU) The aim of the present study was to investigate the expression patterns of proteins in lung adenocarcinoma (AdCa) and SCC Seven mice were treated with single i p injection of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 2 mg/0 1 ml saline/mouse) on the first experimental day and sacrificed after 55 weeks (AdCa-induced model) Twenty six mice were treated topically with NTCU (0 01 M 75 μl/mouse) twice a week for eighteen weeks and sacrificed after 22 weeks (SCC-induced model) SCC and AdCa samples were collected from each group and proteome analysis was carried out by using QSTAR Elite LC-MS/MS 187 proteins were identified with 95% confidence or higher and quantified with ProteinPilot 2 0 Software Significant overexpression of 52 proteins (e g SP-C, TIM) were detected in lung AdCa compared to normal-appearing tissues and 46 proteins (e g cytokeratins 6A, 5, 19) were detected in SCC Expression patterns of proteins largely differed between AdCa and SCC Furthermore AdCa and SCC are suggested to be derived from type II pneumocytes and clara cell, respectively
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 3232.
Abstract 3234: AlgiMatrix™ 3-D cell culture system as an in vitro tumor model for H460 non-small cell lung cancer cell line
Authors: Desai Utkarsh S. , Chougule Mahavir B. , Sachdeva Mandip Singh 
Published: February 2011

Abstract
Objective: In cancer research, three dimensional (3D) cell culture models are rapidly gaining importance as they create a pragmatic microenvironment and mimic an in vivo system, which helps to understand cell-cell interactions. AlgiMatrix sponge (Invitrogen Corporation, Carlsbad, CA, USA) is a non toxic and biodegradable material made from alginate, which seems to construct a cell culture model that resembles normal cell characteristics and morphology. The main objective of the current study was to appraise the AlgiMatrix 3D cell culture system as a 3D invitro tumor model and to ascertain the anticancer activity of docetaxel. Methods: Cell titration was done to optimize seeding density (0.05, 0.10, 0.15, 0.25, 0.50, 0.75, 1.0, 1.25, 1.50, 3 & 6 million H460 cells/well using 6-well plate) and to determine the optimal incubation time for the formation of spheroids. On day 4, 9 & 13, the number and average size of the spheroids were determined using inverted phase contrast microscopy and imaging software. Further, optimized cell density (0.15 million cells/well) was used to determine the IC50 & IC90 values of docetaxel. The alamarBlue® assay was performed to determine the number of viable cells in control & treatment wells. Results: Optimized seeding density and the optimal incubation time was found to be 0.15 & 0.25 million H460 cells/well and 14 days respectively. Average size and the total number of the spheroids for 0.15 and 0.25 million H460 seeded cells was determined as shown in the table. Time PointsAverage size of spheroids (µm)Total Number of spheroids 0.15 million0.25 million0.15 million0.25 million4th day177.88 ± 61.79220.69 ± 61.2748 ± 477 ± 89th day205.35 ± 78.03232.90 ± 82.8790 ± 8189 ± 1513th day232.27 ± 89.07263.94 ± 86.40153 ± 18228 ± 17
Total number of cells obtained by alamarBlue® assay on 14th day was 38.64 ± 4.94 & 42.92 ± 3.29 million cells/well for 0.15 & 0.25 million seeded cells respectively. The IC50 & IC90 concentration of the docetaxel was found to be 193.19 µM & 290.47 µM when ascertained with 0.15 million cells/well. Conclusion: These results strongly support that the AlgiMatrix 3D Cell Culture System may be used as an in-vitro tumor model and to evaluate cytotoxicity of anticancer drugs.
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 3234.
Abstract 3245: SRC-3: A prostate cancer oncogene with the same modus operandi in different niches
Authors: Tien Jean , Liu Zhaoliang , Liao Lan , Wang Fen , Xu Jianming 
Published: February 2011

Abstract
Prostatic adenocarcinoma will affect one in six American men and represents the second leading cause of cancer death in this population. Tumors that are locally invasive/ metastatic at diagnosis cause the majority of prostate cancer deaths. SRC3 is a p160 family coactivator overexpressed in invasive prostate cancers. A recent study in our laboratory demonstrated it is also highly expressed in tumors of the TRAMP mouse, a cancer model in which an androgen-responsive probasin promoter drives expression of the SV40 viral oncogene in several prostate cell types. Global deletion of SRC3 in TRAMP mice arrested primary prostate tumors at the well-differentiated stage and eliminated metastasis.
Transformation of prostatic luminal epithelial cells (LECs) into invasive cancers is a key feature of the TRAMP phenotype. Therefore, we hypothesized selective deletion of SRC3 in these cells would inhibit primary tumor growth and metastasis. To test the hypothesis, we crossed floxed SRC3/TRAMP mice with mice harboring a Cre recombinase gene driven by the LEC-specific probasin promoter. Efficacy of SRC3 knockout in SRC3c−/−/TRAMP mice was confirmed via immunohistochemistry and Western blotting.
We compared prostate tumor size, composition and metastases in SRC3c−/−/TRAMP vs. WT/TRAMP mice at 12 (n=3/5), 18 (n=7/7), 24 (n=9/9) and 30 (n=6/6) weeks of age. We observed no statistically significant differences in prostate or GU tract weight at any time point, though a trend toward decreased tumor size in the knockout was evident at 30 weeks. Tumor composition differed between SRC3c−/−/TRAMP and WT/TRAMP mice at 24 and 30 weeks. While synaptophysin(+) (neuroendocrine) cells were virtually absent in dedifferentiated regions of WT/TRAMP prostate, large synaptophysin(+) cell clusters were visible in the majority of sections taken from prostates of in SRC3c−/−/TRAMP mice. Neuroendocrine cell clusters were positive for SRC3 and negative for AR. Interestingly, 24 and 30 week-old SRC3c−/−/TRAMP mice also had tumors of the liver, lung and kidney: common sites of neuroendocrine metastasis in the TRAMP model.
Given that SRC3c−/−/TRAMP mice have primary tumors of equivalent size to WT/TRAMP but skewed toward neuroendocrine composition, SRC3 deletion in luminal epithelial cells appears to inhibit cancer growth in a cell autonomous fashion thus enabling neuroendocrine proliferation and metastasis. Since global SRC3−/−/TRAMP mice have no neuroendocrine tumors, our findings indicate SRC3 may also act as an oncogene in neuroendocrine cancer.
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 3245.
Abstract 3246: Important differences between exosome biosignatures from prostate cancer patient plasma samples and prostate cancer cell lines
Authors: Tinder Teresa , Pawlowski Traci , Spetzler David , Conrad Amber , Ellis Phil , Kennedy Patrick , Tyrell Annemarie , Jariwala Unnati , Kuslich Christine 
Published: February 2011

Abstract
Exosomes are endosome-derived vesicles secreted by many cell types, including tumor cells. The vesicles are formed intracellularly by invagination followed by fusion with the multivesicular body (MVB). The MVB ultimately merges with the plasma membrane, leading to exocytosis of the exosomes, which consequently have a similar membrane protein composition as their cell of origin; this provides the exosomes with unique biosignatures. Furthermore, these circulating exosomes participate in cellular communication by transporting mRNAs, microRNAs and proteins to target cells where they can elicit biological responses. This study compared the biosignatures identified from prostate cancer (PCa) cell line-derived exosomes to those found in exosomes isolated from the plasma of PCa patient samples. To develop an exosome-specific protein and RNA signature for PCa, we studied RNA and surface membrane protein profiles by flow cytometry (FACS) of exosomes derived from four prostate cancer cell lines, VCaP, 22Rv1, LNCaP and DU145. The exosome biosignatures identified from the cell lines were then measured in plasma exosomes isolated from PCa patients. We found that there was variability between the four cell line exosome-specific mRNA expression levels and exosome surface protein content. The mRNA exosome biosignatures identified in the four cell lines were not found in the exosomes from plasma samples of patients with PCa. Using a combination of antibodies for B7H3, PSMA and CD63 by FACS, we identified a protein signature from all prostate cancer cell line exosome populations that defined a specific subpopulation of exosomes containing all 3 proteins on their surface. Interestingly, this same exosome subpopulation was not found in exosomes derived from patients with PCa. Additionally, exosome-specific mRNA expression of two mRNA transcripts often found to be overexpressed in PCa, STEAP1 and SPINK1, were consistently identified in exosomes derived from prostate cancer cell lines VCaP and 22Rv1, but were only found in the plasma derived exosomes from one out of eight patients with PCa. Our results show that prostate cancer cell lines are not appropriate models for the development of exosome-specific disease profiles in prostate cancer; this will be investigated in additional cell lines. We find that patient samples are essential to identify disease-specific exosome biosignatures. These findings support the development of a versatile diagnostic platform based on exosome-specific biosignatures found in the plasma of patient samples for prostate and other cancers.
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 3246.
Abstract 3250: Bioluminescence imaging of prostate cancer progression and response to therapy in PTEN-deficient mice
Authors: Svensson Robert U. , Henry Michael D. 
Published: February 2011

Abstract
Prostate specific deletion of PTEN function in mice has been reported to recapitulate histological progression of human prostate cancers. Here we describe an improvement on this previously characterized model of prostate cancer by incorporation of a luciferase reporter allele. Specifically, the cancer initiating event is coupled to activation of firefly luciferase from the endogenous ROSA26 promoter in the same prostate epithelial cells. Additionally, we have extensively backcrossed our model onto the albino C57BL/6J background which enhances BLI sensitivity. Consistent with previous studies, we show that progression of prostate cancer from 3-12 weeks is rapid and is correlated with an increase in bioluminescence. However, longitudinal BLI from 12-40 weeks reveals a plateau in bioluminescence signal that is correlated with a halt in cellular proliferation as evidenced by Ki67 staining at necropsy. This may be related to activation of a cellular senescence pathway as reported previously in PTEN deficient mice. We further demonstrate the utility of this model to evaluate the effects of diet induced obesity on disease progression and to monitor response to therapy. Our model may offer advantages in sensitivity and specificity of cancer detection compared to other similar approaches.
This work is supported by NIH grant R21 CA137490
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 3250.
Abstract 3251: Zebrafish: Is it a viable model for prostate cancer
Authors: Jagadeeswaran Pudur , Hutson Angela , Radhakrishnan Uvaraj , Kim Seongcheol 
Published: February 2011

Abstract
Since its introduction as a vertebrate model organism for developmental studies, the Zebrafish model has continued to improve in its useful applications for studying human disease and more recently cancer. However, because there has been no evidence for the presence of prostate glands in fish, this model has not been exploited to study cancer of the prostate gland. In this abstract, we present evidence that fish carry prostate-like cells and, therefore, we postulate that zebrafish could be used as a model for prostate cancer research.
We hypothesized that even though a well-defined prostate gland is not present in fish, there may be a few cells similar to thyroid gland. As a first approach, we developed an experimental design for detection of Prostate Specific Antigen (PSA) gene and protein expression, as well as PSA gene mapping. PSA is a serine protease that binds in seminal plasma to protein C inhibitor, which is involved in the clotting cascade in humans. When we analyzed the zebrafish genome, we found a PSA gene that is syntenic to human PSA and at the protein level zebrafish PSA is 70% homologous to human PSA. We also found PSA mRNA by RT-PCR analysis of the total testes RNA. In situ hybridization of the 4 day old zebrafish larva revealed expression of PSA in gonad. Treatment of zebrafish larvae with the anti-androgen, hydroxyl-flutamide, showed a PSA response profile similar to that in mammalian models in which there is a reduction in PSA mRNA at low doses and an increase at high doses with a return to baseline levels. Based on these findings we contend zebrafish have cells which are functionally equivalent to the prostate gland. We further believe that this information supports the notion of using zebrafish as a model to generate prostate cancer -like symptoms and propose for future studies expression of SV40 large T antigen under the PSA promoter to be used to demonstrate proof of principle. Such a model would be useful to explore not only early detection of prostate cancer but also to provide the opportunity for large scale studies of chemical suppression of cancer progression.
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 3251.
Abstract 3256: Investigating the intrinsic signaling differences in MET- and ERBB2-driven breast cancers
Authors: Graveel Carrie R. , DeGroot Jack D. , Dykema Karl , Sigler Robert E. , Furge Kyle A. , Vande Woude George F. 
Published: February 2011

Abstract
Understanding the signaling pathways that drive aggressive breast cancers is critical to the development of effective therapeutics. Over 20% of breast cancers overexpress ERBB2 and are associated with an aggressive tumor phenotype and poor outcome. Patients with ERBB2-positive tumors are often treated with the humanized monoclonal antibody trastuzumab, yet the majority of patients develop resistance. Recent studies show that the receptor tyrosine kinase MET is expressed in ERBB2 positive tumors and contributes to trastuzumab resistance in ERBB2-expressing cell lines. Other studies have shown that MET correlates with poor clinical outcome independent of ERBB2. We are utilizing mouse models to examine the intrinsic signaling differences between MET and ERBB2-mediated breast cancers.
We have developed a novel mouse model of mutationally activated MET (Metmut) that develops a high incidence of diverse mammary tumors with basal characteristics. Using this mouse model and human breast cancer tissue, we have examined the role of MET in aggressive breast cancers. By gene expression and tissue microarray analysis, we observe that high MET expression in human breast cancers significantly correlates with estrogen receptor negative/ERBB2 negative tumors and with basal breast cancers (Graveel et al., 2009). We performed gene expression analysis on mammary tumors from Metmut mice and activated ErbB2 (Neu-Ndl2-5) mice. Unsupervised hierarchical analysis revealed that solid Metmut tumors clustered separately from Metmut tumors with a mixed pathology and that solid Metmut tumors have expression patterns very similar to ERBB2 tumors. The similarity of solid Metmut tumors to ErbB2 tumors suggests that MET signaling may be influential in ERBB2-driven tumors. To investigate this hypothesis further, we performed a parametric gene set enrichment analysis (PGSEA) and observed that the Ras activation signature was significantly associated with the Metmut mixed tumors. Currently, we are also investigating expression patterns of MET and ERBB2 in human breast cancers by coimmunostaining. Collectively, our studies indicate that MET may play a critical role in the development of the most aggressive breast cancers and may be a rational therapeutic target for trastuzumab-resistant ERBB2 breast cancers.
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 3256.
Abstract 3257: NEDD9 is required for initiation of HER2/Neu-dependent mammary tumor development
Authors: Little Joy L. , Izumchenko Eugene , Singh Mahendra K. , Seo Sachiko , Kurokawa Mineo , Egleston Brian L. , Klein-Szanto Andres , Golemis Erica A. 
Published: February 2011

Abstract
Neural precursor cell-Expressed Developmentally Downregulated gene 9 (NEDD9; HEF1, CAS-L) is a scaffolding protein regulating mitosis, survival, and migration. Within the last 3 years, overexpression of NEDD9 has been implicated in the progression and metastasis of several cancers. Using a Nedd9 knockout strain, we have evaluated the in vivo requirement for NEDD9 in mammary tumorigenesis. Loss of Nedd9 increased the latency of tumor formation in the aggressive MMTV-Polyoma Virus middle T antigen (PyV(m)T) model of mammary tumorigenesis (Izumchenko et al. Cancer Res, 2009). We and others have shown that NEDD9 interacts with and positively regulates activity of key oncogenic signaling proteins such as Aurora-A kinase (AURKA) and Src in cell culture. Tumors harvested from MMTV-PyV(m)T;Nedd9−/− mice had greatly reduced activation of AURKA, SRC, and also FAK and AKT, with the lowest levels of activation correlating with the greatest delays in tumor onset.
To explore the role of NEDD9 in a second highly physiological model of mammary tumorigenesis, Nedd9−/− mice were crossed to MMTV-neu (HER2; ErbB2) transgenic mice, and compared with MMTV-neu;Nedd9+/+ counterparts. Strikingly, after over 18 months, 89% of MMTV-neu;Nedd9+/+ mice developed tumors, in contrast to only 29% of MMTV-neu;Nedd9−/− mice. Between genotypes, there is no statistical difference between tumor growth rates or metastasis. Cell lines derived from tumors of both MMTV-neu;Nedd9+/+ and MMTV-neu;Nedd9−/− animals were then used for xenograft tumor growth and experimental metastasis assays. MMTV-neu;Nedd9−/− tumor-derived cell lines grew similarly to MMTV-neu;Nedd9+/+ counterparts as xenografts in the mammary fat pads of SCID mice, but metastasized to the lungs of SCID mice less readily following tail vein injection. These and other data indicate a novel role for NEDD9 in mammary tumor initiation distinct from the role controlling metastasis and progression of tumors in cooperation with the oncogenes FAK and SRC. Further, the work suggests that HER2-driven mammary tumorigenesis is dependent on NEDD9 at initial stages, but NEDD9 is not required for tumor maintenance, progression, or metastasis from primary organ sites.
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 3257.