bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4174: Molecular changes in the EGFR pathway and RAS/RAF genes identify subtypes of metastatic and nonmetastatic colorectal cancer associated with different outcomes
Authors: Bahnassy Abeer A. , Salem Salem E. , Hussein Nehal , Yousif Hend F. , Marwa  , Al-Desouky Iman , Zekri Abdel-Rahman N. 
Published: August 2015

Abstract
Background: Categorization of colon cancers into distinct subtypes using a combination of pathway-based biomarkers and RAS/RAF mutations provides better insight into the variability in patient outcomes. We assessed the incidence, prognostic and predictive values of KRAS/BRAF mutations and some EGFR pathway genes in metastatic and non- metastatic CRC (mCRC and nmCRC) patients from Egypt.
Methods: 396 CRC patients (240 metastatic& 156 non metastatic) were assessed for KRAS/BRAF mutations by conventional PCR and immunohistochemistry (IHC). EGFR, PI3K, MEK and ERK expressions were assessed by quantitative real time PCR (qPCR) and IHC. Results were correlated to standard prognostic factors, response to treatment overall and disease free survival (OS&DFS).
Results: We detected KRAS mutations in 47.7% (27% in codon 12, 35.6% in codon 13 and 14.3% in 12/13), BRAF in 31.3% and EGFR in 54.6% of the cases. KRAS and EGFR were significantly higher in mCRC cases (p = 0.012& p = 0.045). Tumors were categorized into 4 genetically different groups: EGFR-/KRAS+, EGFR-/KRAS-, EGFR+/KRAS-, EGFR+/KRAS+ (30.3%,28.3%,24%, 17.4%). Significant correlations were found between EGFR, KRAS/BRAF mutations and PI3K-RNA in metastatic and non metastatic CRC (0.02&&lt;0.001). In mCRC, correlations were found between 1) RAS mutations and all markers except EGFR (0.028&&lt;0.001), 2) RAF and MEK/EGFR (0.045&&lt;0.005), 3) PI3K and all genes (&lt;0.001) except BRAF, 4) ERK and MEK (&lt;0.001). In nmCRC, correlations were reported between 1) PI3K and EGFR (p&lt;0.001), 2) RAS and MEK/ERK (p&lt;0.001), 3) MEK and ERK (p&lt;0.001), 4) EGFR and PI3K (p&lt;0.001). DFS significantly correlated with K13RAS mutations, PI3K and positive family history (p&lt;0.05). OS correlated with K13 RAS/BRAF mutation, PI3K and age (p&lt;0.05).
Conclusions: KRAS/BRAF mutations and aberrations in EGFR pathway contribute differently to the development and progression of metastatic and non metastatic CRC cases in Egypt. These markers could be used for monitoring patients during treatment with conventional chemotherapy regimens and can provide candidates for targeted therapy.
Citation Format: Abeer A. Bahnassy, Salem E. Salem, Nehal Hussein,Hend F. Yousif, Marwa, Iman Al-Desouky, Abdel-Rahman N. Zekri. Molecular changes in the EGFR pathway and RAS/RAF genes identify subtypes of metastatic and nonmetastatic colorectal cancer associated with different outcomes. [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 4174. doi:10.1158/1538-7445.AM2015-4174
Abstract 4177: Simultaneous activation of C-X-C chemokine receptor 4 and cannabinoid receptor 2 results in decreased angiogenesis
Authors: Scarlett Kisha A. , Sandifer Brittney , Coke Christopher J. , Hinton Cimona V. 
Published: August 2015

Abstract
Tumor angiogenesis is a complex process modulated by numerous signaling molecules and pathways that influence cell migration, invasion, survival and tube formation. The expression of the G-protein-coupled receptor (GPCR) C-X-C Chemokine Receptor 4 (CXCR4) has been correlated with the increased angiogenic potential of cancer cells. The ligand-specific binding of CXCL12 to CXCR4 increases tumor angiogenesis by upregulating the expression of vascular endothelial growth factor (VEGF) at both mRNA and protein levels. Thus, modulating the CXCR4/CXCL12 signaling axis provides an attractive target for the inhibition of tumor angiogenesis and cancer progression. Recent studies have suggested that in addition to its palliative properties, cannabis may have anti-proliferative and anti-metastatic effects by acting through the GPCR, cannabinoid receptor 2 (CB2R). GPCR heterodimerization has emerged as a means by which new signaling entities can be created with respect to agonist binding. Preliminary co-immunoprecipitation data from our lab indicates that agonist-bound CXCR4 and agonist-bound CB2R interact at the cell membrane and that receptor interaction mitigates the effects of CXCL12-mediated CXCR4 signaling. Here we show that co-stimulation of prostate cancer cells with CXCR4 and CB2R-specific agonists results in decreased VEGF expression in vitro. Furthermore, treatment of human endothelial cells with conditioned medium collected from co-stimulated prostate cancer cells decreased endothelial cell migration in wound healing and invasion assays, and decreased endothelial cell tubulogenesis. Taken together, these results demonstrate that desensitization of CXCR4 signaling through association with CB2R is a novel anti-angiogenic strategy and reinforces the clinical relevance of cannabinoids in cancer treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Kisha A. Scarlett, Brittney Sandifer, Christopher J. Coke, Cimona V. Hinton. Simultaneous activation of C-X-C chemokine receptor 4 and cannabinoid receptor 2 results in decreased angiogenesis. [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 4177. doi:10.1158/1538-7445.AM2015-4177
Abstract 4178: L1CAM and integrin αvβ3 mediate direct cell contact between cancer stem cells and endothelial cells: Promotion of endothelial cell migration and survival
Authors: Burgett Monica E. , Lathia Justin D. , Roth Patrick , Nowacki Amy S. , Huang Ping , Vasanji Amit , Li Meizhang , Byzova Tatiana , Mikkelsen Tom , Bao Shideng , Rich Jeremy , Weller Michael , Gladson Candece L. 
Published: August 2015

Abstract
Sprouting angiogenesis requires endothelial cell (EC) migration. In glioblastoma (GBM), cancer stem cells (CSC) in the perivascular niche secrete factors that promote EC migration. Here, we identify a direct interaction between the CSCs and ECs that is mediated by RGD-peptide-dependent binding of L1CAM on CSCs with integrin αvβ3 on ECs. Using in vitro assays, we found that this interaction increased migration-associated signaling events in ECs, including activation of integrin
αvβ3, ERK, JNK and Akt, and VCAM-1 and E-selectin mRNA expression. Comparison of the effects of co-culturing CSCs with ECs versus the effects of conditioned media from CSCs co-cultured with ECs indicated that the effects of the direct interaction and soluble factors differed quantitatively and qualitatively. The direct interactions stimulated the migration of ECs and primed them to the migratory effects of soluble factors produced by the CSCs. The direct interaction also enhanced expression of pro-survival genes in CSCs and ECs. In GBM biopsies, Sox2-positive tumor cells were localized in close proximity to ECs and injection of β3-negative ECs or L1CAM-negative CSCs into brain slices in organotypic culture resulted in reduced interactions between ECs and CSCs.
RGD-peptide treatment of mice with established intracerebral GBM xenografts increased the mean distance of Sox2-positive tumor cells from ECs, decreased integrin αvβ3 activation and decreased vessel surface area. These data show that direct interactions between CSCs and ECs have potent effects on EC migration and angiogenesis in GBM and have implications for the design of angiogenesis-targeted therapies.
Citation Format: Monica E. Burgett, Justin D. Lathia, Patrick Roth, Amy S. Nowacki, Ping Huang, Amit Vasanji, Meizhang Li, Tatiana Byzova, Tom Mikkelsen, Shideng Bao, Jeremy Rich, Michael Weller, Candece L. Gladson. L1CAM and integrin αvβ3 mediate direct cell contact between cancer stem cells and endothelial cells: Promotion of endothelial cell migration and survival. [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 4178. doi:10.1158/1538-7445.AM2015-4178
Abstract 4187: Expression of ion channels in a cervical cancer mouse model
Authors: RAMIREZ ANA , VERA EUNICE , LAMBERT PAUL , GARIGLIO PATRICIO , CAMACHO JAVIER 
Published: August 2015

Abstract
Introduction. Because some ion channels have been suggested as early tumor markers and therapeutic targets, in the present study we examined the expression of ion channels in the cervical cancer transgenic mouse model K14E7 expressing the HPV16 E7 oncogene under the control of the human keratin 14 promoter.
Methods. We used the K14E7 transgenic mouse; some groups were treated with 17β-estradiol. Continuous release pellets delivering 0.05 mg of 17β-estradiol were implanted into 4-6 weeks old female mice during 90 days to obtain low grade cervical dysplasia or during 180 days to produce cervical cancer. The cervix was removed at the end of the treatment. Protein and mRNA expression of 4 ion channels (Cav3.1, Cav3.2, Kv10.1, KCa1.1) were analyzed by qRT-PCR and immunohistochemistry, respectively.
Results. We found increased expression of Cav3.1, Kv10.1 and KCa1.1 in mice with cervical dysplasia in comparison to control animals. This increase was even higher in animals with cervical cancer. In contrast, Cav3.2 expression decreased in animals with cervical dysplasia and increased in mice with cervical cancer. We also found overexpression of the KCa1.1 protein in the transformed zone of the cervical cancer group, but not in the control group.
Conclusions. The channel expression profile here studied might serve as a cervical cancer marker. This work was partially supported by Conacyt grant 141126 to JC.
Citation Format: ANA RAMIREZ, EUNICE VERA, PAUL LAMBERT, PATRICIO GARIGLIO, JAVIER CAMACHO. Expression of ion channels in a cervical cancer mouse model. [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 4187. doi:10.1158/1538-7445.AM2015-4187
Abstract 4189: Analgesic effect of quetiapine on the cancer induced bone pain animal model
Authors: Park Keon Uk , Heo Mi Hwa , Kim Jin Young , Hwang Ilseon , Ryoo Hun Mo 
Published: August 2015

Abstract
Background: Cancer induced bone pain is one of the most common pain in patients with advanced cancer. Because of treatment associated side effects, it has been reported that more than half of cancer patients have inadequate and undermanaged pain control. Therefore, new mechanism-based therapies need to be developed to reduce cancer pain. Quetiapine is a commonly used atypical antipsychotic drug that has superior therapeutic effects in patients with schizophrenia and other neurological disorders like depression. We reported that a study of anti-inflammatory effect of quetiapine on collagen induced arthritis mouse model. Now we focused on the potential analgesic effects of quetiapine on the cancer induced bone pain (CIBP) animal model and the mechanism of bone pain evaluated by various nociceptors expression.
Methods: Fifteen male C3H/HeN mice were randomly divided into five groups: Control, CIBP, CIBP + quetiapine treatment, CIBP + opioid treatment and CIBP + melatonin treatment. Treatments were started when mouse showed positive signs of bone tumor until the day 28, according to the protocol, daily for 12 days. Pain thresholds of CIBP mouse model were measured by aesthesiometer for each group. At the end of the treatment period, tissue of mouse tibia were removed and quantitative and qualitative evaluation of TRPV1, TRPV4, ASIC1, ASIC2, and ASIC3 expression were done.
Results: The data showed that mouse behavior about pain thresholds was marked improved in CIBP + quetiapine treatment group compared with CIBP group. The expression of TRPV1, TRPV4, ASIC1, ASIC2, and ASIC3 in CIBP + quetiapine treatment group was significantly lower than those in CIBP groups.
Conclusions: These results suggest analgesic effect of quetiapine on CIBP animal model and provide the possibility that TRPV and ASICs could be a potential target of cancer pain management.
Citation Format: Keon Uk Park, Mi Hwa Heo, Jin Young Kim, Ilseon Hwang, Hun Mo Ryoo. Analgesic effect of quetiapine on the cancer induced bone pain animal model. [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 4189. doi:10.1158/1538-7445.AM2015-4189
Abstract 4192: Identification of novel genetic drivers of vulvar carcinoma in a Sleeping Beauty model of spontaneous cancer
Authors: Guimaraes-Young Amy , Neff Traci , Meyerholz David K. , Dupuy Adam J. , Goodheart Michael J. 
Published: August 2015

Abstract
Introduction:
The purpose of this study was to develop a Sleeping Beauty (SB)-induced mouse model of metastatic vulvar carcinoma with which we could identify novel tumor-driving mutations.
Experimental Procedures:
An existing transgenic mouse model known to induce development of benign vaginal papillomas, (PrCre/+;KrasG12D), was bred to mice containing the components of the SB system to render (PrCre/+;KrasG12D;SB) mice. The SB system consists of a transposable element (transposon) and an activating enzyme (transposase) that induces excision of the transposon from one site to another in the host cell genome. Insertional mutations that enhance cell survival and proliferation are selected for, resulting in the development of cancer. We utilize the SB system to identify candidate driver mutations since the transposon is not only the mutagen but also serves as a sequence tag for localization of mutations. Mice were aged and monitored for phenotypic signs of disease. Upon necropsy, gynecologic and other grossly abnormal organs were harvested. Genomic DNA was extracted from each sample, prepared for genetic analysis, and sequenced using the Illumina platform. Candidate genes were identified using an unbiased Monte-Carlo approach in conjunction with a gene-centric Chi-Squared analysis. Paraffin-embedded human tumor samples were obtained from the University of Iowa Hospitals and Clinics for immunohistochemical labeling of protein expression for selected genes.
Results:
Vulvar carcinoma developed in 29 of 29 PrCre/+;KrasG12D;SB female mice with metastases by seven months of age confirmed in 13 animals. Organs within the abdominal cavity including the uterus and ovaries contained metastatic lesions in some mice. In one mouse, a distant metastasis within the subcutaneous tissue of the thoracic back was observed. Illumina sequencing of primary lesions from all mice revealed 77 candidate tumor drivers.
Conclusions:
To our knowledge, the PrCre/+;KrasG12D;SB mouse is the first reported metastatic model of vulvar carcinoma. Protein expression of candidate genes identified by our SB screen are being assessed in human tissue samples. Patient clinical data will be incorporated into analyses to determine whether candidate genes are correlated to patient outcomes. This work will permit insights into the pathophysiology and future treatment of vulvar cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Amy Guimaraes-Young, Traci Neff, David K. Meyerholz, Adam J. Dupuy, Michael J. Goodheart. Identification of novel genetic drivers of vulvar carcinoma in a Sleeping Beauty model of spontaneous 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 4192. doi:10.1158/1538-7445.AM2015-4192
Abstract 4195: GNASR201H and KrasG12D cooperate to promote murine pancreatic tumorigenesis recapitulating human intraductal papillary mucinous neoplasm
Authors: Furukawa Toru , Tanji Etsuko , Ohmuraya Masaki , Taki Katsunobu , Araki Kimi 
Published: August 2015

Abstract
Intraductal papillary mucinous neoplasm (IPMN) is the most common pancreatic cystic neoplasm, which is a precursor of the invasive ductal adenocarcinoma. IPMNs recurrently harbor activating somatic mutations in GNAS and KRAS, mostly GNASR201H and KRASG12D. GNAS encodes the stimulatory G-protein α subunit (Gsα) that mediates a stimulatory signal to adenylyl cyclase to produce cyclic AMP (cAMP), a second messenger activating cAMP dependent protein kinase (PKA). The GNASR201H mutation is known to result in constitutive activation of Gsα and its downstream signaling molecules, which induces expression of various genes including mucin genes. To study a role of GNAS in pancreatic tumourigenesis in vivo, we generated transgenic mice lines of which transgene is consisted of Lox-STOP-Lox (LSL)- GNASR201H under the control of the CAG promoter (Tg(CAG-LSL-GNAS)). The transgene contains genetic elements that inhibit transcription and translation of GNASR201H flanked by functional LoxP sites. These mice lines were crossed to pancreatic transcription factor 1 a (Ptf1a)-cre mice, and generated Tg(CAG-LSL-GNAS);Ptf1a-cre mice. This mouse line showed elevated cAMP levels and a compensatory upregulation of PKA in the pancreas. GNASR201H alone was not sufficient to induce tumourigenesis by 2 months of age, but small dilated tubular complex formation, loss of acinar cells, and fibrosis, which could be a very early phenotype of IPMN. To know a cooperative effect of GNASR201H and KRASG12D in pancreatic tumorigenesis, we crossed Tg(CAG-LSL-GNAS);Ptf1a-cre mice with LSL-KrasG12D mice. Tg(CAG-LSL-GNAS);LSL-KrasG12D;Ptf1a-cre mice developed multiple cysts consisting of marked dilated ducts lined with papillary dysplastic epithelia in the pancreas within 5 weeks, which recapitulated human IPMNs. Our data strongly suggest that mutated GNAS cooperating with mutated KRAS may sufficiently cause to develop IPMN.
Citation Format: Toru Furukawa, Etsuko Tanji, Masaki Ohmuraya, Katsunobu Taki, Kimi Araki. GNASR201H and KrasG12D cooperate to promote murine pancreatic tumorigenesis recapitulating human intraductal papillary mucinous neoplasm. [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 4195. doi:10.1158/1538-7445.AM2015-4195
Abstract 4196: Neuregulin signaling in development and transformation of the luminal breast epithelium
Authors: Vaught David B. , Hicks Donna , Sanchez Violeta , Cook Rebecca 
Published: August 2015

Abstract
ErbB3 and ErbB4 are members of the ErbB family of receptor tyrosine kinases (RTK) that can be activated by neuregulins (NRGs) and as a result are often referred to as the neuregulin receptors. The neuregulin receptors are required for growth and survival of the ductal and alveolar luminal epithelium. We have recently shown that ErbB3 is required for survival and growth of the ductal luminal epithelium and to maintain the balance of differentiated epithelial cell types in the mammary gland, which is consistent with the fact the ErbB3 expression is highest in the ductal luminal epithelium and in luminal progenitor populations of the mouse and human mammary glands. ErbB4, is also required for growth in the luminal mammary epithelium, but not within the ductal luminal population, rather in the alveolar luminal population. In addition to neuregulin receptor signaling in development, ErbB3 and ErbB4 expression has been found to be at the highest levels in luminal breast cancers compared to other molecular breast cancer subtypes. Furthermore, human luminal breast cancer cell lines also express higher levels of ErbB3 and ErbB4 than cell lines derived from other molecular breast cancer subtypes. Since both ErbB3 and ErbB4 are capable of binding to neuregulin ligands and heterodimerizing with other ErbB family members, there is evidence that ErbB4 may compensate for loss of ErbB3, and vice versa. Thus, our goal is to understand how combined loss of ErbB3 and ErbB4 impact the normal luminal cell populations and the transformed cell populations of the breast epithelium. We hypothesize that loss of ErbB3 and ErbB4 will decrease cellular growth and survival during development and in our mouse models of breast cancer. Early studies demonstrate conditional loss of ErbB3fl/fl and ErbB4fl/fl independently and in combination decrease pup weights compared to control mice and demonstrate reduced epithelium/alveolar cell expansion in whole mount and histology analysis. In addition, early analysis of ErbB3fl/fl, ErbB4fl/fl ErbB3fl/fl/ErbB4fl/fl crossed to the p110 inducible mouse model of breast cancer are trending to a delay in tumor onset. Molecular analysis demonstrates a reduction in Pi3K/Akt signaling and Jak/Stat signaling in ErbB3fl/fl and ErbB4fl/fl respectively, with ongoing studies currently underway to analyze signaling in ErbB3fl/fl/ErbB4fl/fl mice in development.
Citation Format: David B. Vaught, Donna Hicks, Violeta Sanchez, Rebecca Cook. Neuregulin signaling in development and transformation of the luminal breast epithelium. [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 4196. doi:10.1158/1538-7445.AM2015-4196
Abstract 4199: Developing therapies for rare tumors: Using mouse models of malignant peripheral nerve sheath tumors to complement rare human samples in drug screens
Authors: Reilly Karlyne M. , Tuskan Robert G. , Widemann Brigitte C. 
Published: August 2015

Abstract
Rare cancers are defined by the US Orphan Drug Act as affecting &lt;200,000 patients in the US. For patients with these cancers, there may be an urgent need for new therapies; however, these rare cancers present challenges to drug development. Because of the small number of patients, the cancers are not well characterized, the molecular mechanisms may not be well-understood, and there may not be adequate model systems available for research and drug development.
The Rare Tumors Initiative in the Intramural Research Program at the National Cancer Institute is focusing on overcoming hurdles in rare tumor research by developing new approaches to treat malignant peripheral nerve sheath tumors (MPNST). MPNSTs occur in younger adults with an incidence of 1 in 100,000, with a higher incidence in patients with Neurofibromatosis type 1. Due to a limited number of high quality human MPNST tumor lines, drug testing has been challenging both in vitro and in vivo. A genetically engineered mouse model carrying mutations in Nf1 and Trp53 develops MPNST spontaneously starting around 3 months of age. We have generated tumor lines from over 30 independent mouse MPNSTs, from different sexes and genetic backgrounds that we are using to test drugs in combination with available human MPNST lines. We find good concordance between the mouse and human MPNST lines in response to drugs. Furthermore, although the MPNST lines show good dose response and high maximum response to many targeted compounds, the concentrations of drug required to achieve inhibition is often high, suggesting that one of the difficulties in developing MPNST therapy is the inherent resistance of MPNST cells to drug inhibition.
We will present results of ongoing drug screens in panels of mouse and human MPNST cell lines, using drugs that are in different phases of clinical trials or approved for other diseases.
Citation Format: Karlyne M. Reilly, Robert G. Tuskan, Brigitte C. Widemann. Developing therapies for rare tumors: Using mouse models of malignant peripheral nerve sheath tumors to complement rare human samples in drug screens. [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 4199. doi:10.1158/1538-7445.AM2015-4199