bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2790: Establishment and characterization of human skingraft model in immunodeficient mice.
Authors: Serin Guillaume , Morgand Loïc , Leblanc Marie , Bichat Francis 
Published: August 2014

Abstract
The humanization process of mice with various tissues named Chi-mice aimed to reproduce better the human situation and to be more predictive than conventional models. In order to evaluate new targeting therapies or adverse side effects involving skin components, pre-clinical studies need to be assayed with new molecules in adequate and validated mouse models bearing human skin.
The collection of skin samples was done under ethically approved master agreements and with the signed consent of each patient. The patient's clinical history, the serology results (HIV, HBV and HCV) and tissue banking were centralized in our internal approved biological resource center. To develop such models, we used skins of different origins including foreskin, breast and abdomen that were isolated by different methods (full recovery of about 1 cm depth sample or dermatomization of the 1-2 mm epidermal/dermal layer). These samples were xenografted on immune deficient NOD-SCID mice under different conditions including matrigel grafting. After one month implantation, skingrafts were collected and observed microscopically to confirm the preservation of human organization of skin by full histology. Also, the species nature of vessels was characterized by immunochemistry to evaluate the host penetration within human skingraft and both CD-31 positive mouse and human vessels were found in the skingraft. In the context of vascular leak syndrome (VLS) induction by IL2 treatment, we have used the wet/dry ratio of skingraft to measure the induced-edema and we have measured the blue evans uptake in those injured skingraft to appreciate the epidermal vasculature leaking. Anapathological comparisons were also performed to reveal the histological modifications observed during VLS.
These different characterizations performed during development of the skingraft model enabled us to obtain human skin xenografted on mice that retained the human characteristics of the primary material. The co-implantation of other human tissue (tumor) with skin in same mice which refined better the humanized model will be presented.
The use of fresh skin and various tissues in drug discovery and early preclinical development of new therapies aimed at corroborating results with clinical reality. Altogether, these processes from the clinical sample collection to the in vivo drug efficacy study through ex vivo assays should help the preclinical drug selection, development and clinical positioning as well as companion biomarker identification.
Citation Format: Guillaume Serin, Loïc Morgand, Marie Leblanc, Francis Bichat. Establishment and characterization of human skingraft model in immunodeficient mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2790. doi:10.1158/1538-7445.AM2013-2790
Abstract 2795: Establishment and molecular characterization of cell lines from Japanese patients with malignant pleural mesothelioma.
Authors: Tada Ryuhei , Yamamoto Hiromasa , Furukawa Masashi , Shien Kazuhiko , Hashida Shinsuke , Soh Junichi , Asano Hiroaki , Tsukuda Kazunori , Toyooka Shinichi , Miyoshi Shinichiro 
Published: August 2014

Abstract
Malignant pleural mesothelioma (MPM) is a poor prognostic malignancy that is distinctly resistant to the conventional therapies. Cell lines are useful materials for studying the biological characteristics of the tumors, thus the establishment of MPM cell lines is valuable for exploring the new therapeutic strategies of MPM. We established 4 MPM cell lines (YUMC8, YUMC44, YUMC63 and YUMC64) from Japanese patients, consisting of 2 epithelioid and 2 sarcomatoid types for histological subtype. We analyzed the status of methylation, mutation, copy number gains (CNGs), and protein expression in representative genes and the sensitivity to several drugs in these 4 cell lines. We detected the complete methylation of P16 in 3 cell lines, in which the protein expression of p16 was lost. Methylation of RASSF1A was observed in 3 of 4 cell lines. Copy number gains (CNGs) in EGFR, HER2 and MET were not detected in all the cell lines. Mutations in various genes including EGFR, KRAS, HER2, BRAF, and PIK3CA, which are frequently detected in non-small cell lung cancer, were not detected in all 4 cell lines. As for microRNA, miR-34b/c was completely methylated in 2 of 4 MPM established cell lines. About cell adhesion molecules, E-cadherin expression was detected in two epithelioid type MPM cell lines, whereas N-cadherin expression was detected in all four established cell lines by Western blot analysis. Vimentin was strongly expressed in two sarcomatoid type MPM cell lines. All established MPM cell lines showed no dramatic responses to the drugs tested including NVP-AUY922, 17-DMAG, Trichostatin A and Vorinostat. Although new molecular findings were not observed in the process of the current characterization of these new MPM cell lines, they seem to be useful for the future extensive analyses of biological behavior of MPM, so as to the development of new therapeutic strategies.
Citation Format: Ryuhei Tada, Hiromasa Yamamoto, Masashi Furukawa, Kazuhiko Shien, Shinsuke Hashida, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichi Toyooka, Shinichiro Miyoshi. Establishment and molecular characterization of cell lines from Japanese patients with malignant pleural mesothelioma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2795. doi:10.1158/1538-7445.AM2013-2795
Abstract 2799: Regulation of tumor cell attachment, spreading and migration by the GPR4 receptor and related G protein pathways.
Authors: Justus Calvin R. , Yang Li V. 
Published: August 2014

Abstract
The tumor microenvironment has a characteristic low pH due to inadequate blood perfusion, hypoxia, altered cellular metabolism, and inflammation. The effects of acidic pH on cancer progression are complex. It has been shown that low pH increases the metastatic spread of cancer by assisting in the degradation of extracellular matrix. Other studies show that acidic microenvironments decrease metastatic potential in B16F10 melanoma cells upon activation of the GPR4 receptor and also inhibit Akt activity in breast cancer cells. In this study we have investigated the attachment, spreading, and migration of B16F10 cells that have been genetically modified to express the GPR4 receptor at a high level (named B16F10/GPR4 cells). The results showed that upon stimulation of GPR4 in B16F10/GPR4 cells with low pH, cell spreading, membrane ruffling, and migration were significantly decreased. The phosphorylation levels of paxillin Y118 and focal adhesion kinase (FAK) Y397 following one-hour cell attachment were also decreased, and the spatial localization of the phosphorylated paxillin and FAK was substantially altered. Further tests were performed to identify the G-protein signaling pathway responsible for this effect. By using a G13 dominant negative construct or inhibiting Rho activation with C3 transferase (CT04) in B16F10/GPR4 cells, the cell spreading and membrane ruffling abilities were almost completely restored back to the level of B16F10/vector control cells, whereas the inhibition of the Gs and Gq pathways had little effect. These results suggest that activation of the GPR4 receptor and subsequently the G13/Rho downstream pathway are responsible for decreased cell attachment, spreading and membrane ruffling, which may cause decreased metastatic potential of B16F10/GPR4 cells found previously.
Citation Format: Calvin R. Justus, Li V. Yang. Regulation of tumor cell attachment, spreading and migration by the GPR4 receptor and related G protein pathways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2799. doi:10.1158/1538-7445.AM2013-2799
Abstract 2802: Salmonella typhimurium A1-R inhibits brain metastasis in an orthotropic breast cancer nude-mouse model.
Authors: Zhang Yong , Zhang Nan , Hoffman Robert M. , Zhao Ming 
Published: August 2014

Abstract
We have previously developed tumor-targeting Salmonella typhimurium A1-R (A1-R), which has shown efficacy against multiple cancer types in nude mouse models. In this study, we demonstrated that S. typhimurium A1-R can inhibit and eradicate brain metastasis in an orthotopic metastatic BALB/c mouse model of breast cancer. To establish the model, 4T1 breast cancer cells expressing RFP (5.0 × 106/100 μL) in 100 μl serum-free solution were injected slowly into the right second mammary gland. Two weeks after cells implantation, the primary tumors were removed. Approximately 30% of post-surgery nude mice were found with brain metastasis using fluorescence imaging 4-5 weeks after injection of 4T1-RFP cells. When the mice were found with brain metastasis, S. typhimurium A1-R [5×107 CFU/100 μl] was injected into the tail vein once a week for 3 weeks. Inhibition of brain metastatic growth was observed noninvasively by the Maestro fluorescence imaging system (Perkin-Elmer Inc.) compared with untreated mice. Intravenous administration of S. typhimurium A1-R improved survival 70%. This study shows the important potential of bacterial therapy of brain metastasis.
Citation Format: Yong Zhang, Nan Zhang, Robert M. Hoffman, Ming Zhao. Salmonella typhimurium A1-R inhibits brain metastasis in an orthotropic breast cancer nude-mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2802. doi:10.1158/1538-7445.AM2013-2802
Abstract 2806: CD146, a suppressor of breast cancer, is a novel target of CD44-signaling.
Authors: Ouhtit Allal , Abdraboh Mohamed E. , Hollenbach Andrew D. , Gupta Ishita , Shanmuganathan Somya , Raj Madhwa HG 
Published: August 2014

Abstract
Cancer cell invasion and metastasis is the worst aspect of cancer, and disruption in the cell adhesion molecules (CAM) represents the initiating event in tumor cell invasion. While the hyaluronan receptor CD44 promotes breast cancer (BC) metastasis, CD146 is a melanoma CAM that appears to suppress BC (although it promotes other cancers). In addition, the molecular mechanism by which CD146 suppresses BC is still unclear. To shed light on this discrepancy, we initially used subtractive hybridization combined with northern blotting, and identified CD146 as a potential downstream target of CD44-signaling in the MDA-435 BC cell line. Here, we provide both structural and functional evidence indicating that CD146 is a downstream target for CD44, in a way that CD146 expression is regulated according to tumor microenvironment. Finally, this study demonstrates a new role for CD44 in regulating neovascularization and promoting cancer cell transmigration of blood vessels via CD146.
Citation Format: Allal Ouhtit, Mohamed E. Abdraboh, Andrew D. Hollenbach, Ishita Gupta, Somya Shanmuganathan, Madhwa HG Raj. CD146, a suppressor of breast cancer, is a novel target of CD44-signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2806. doi:10.1158/1538-7445.AM2013-2806
Abstract 2808: Morphine modulates the paracrine interaction between breast tumor cells and macrophages.
Authors: Afshar Imani Banafsheh , Baran JoAnne , Cabot Peter J. , Parat Marie-Odile 
Published: August 2014

Abstract
While opioids are highly effective perioperative analgesics, there have been concerns about their effects on the growth and spread of tumor cells when used in cancer surgery patients. Using a mouse syngeneic model of breast cancer, we studied the effect of morphine on breast tumor dissemination to lungs. Intraperitoneal injection of morphine (10mg/kg) to BALB/c mice (n=8) every 12h for 3 consecutive days, caused a reduction in the number of tumor foci in lungs as measured 18 days after intravenous tumor inoculation. Morphine treatment also caused a reduction in circulating extracellular matrix (ECM)-degrading matrix metalloproteinase-9 (MMP-9) measured by gelatin zymography. One of the major contributors to tumor cell invasiveness is the immune cells infiltrating the tumors, particularly macrophages. Therefore, we tested the effect of morphine on the production of gelatinases by murine breast cancer cells 4T1 and macrophages RAW264.7 alone or cultured together. The levels of MMP-9 as well as its endogenous inhibitor tissue inhibitor of metalloproteinase-1 (TIMP-1) were shown to be elevated in the conditioned media of the co-cultures. Interestingly, we found out that although morphine treatment did not have any significant effect on the level of gelatinases produced by individual cells, in the co-cultures it caused a significant decrease in MMP-9 while increasing TIMP-1.We observed the same effect when breast cancer cells were incubated with the conditioned media of morphine-treated macrophages, indicating that cell-cell interaction was not required. Our in vitro data thus suggest that the anti-tumor effect of morphine observed in our animal studies is at least in part mediated through modulating the paracrine communication between tumour cells and tumor associated macrophages in their microenvironment rather than an effect on tumor cells alone. Randomized prospective clinical studies are required to determine how opioids, as a part of the perioperative pain management, could affect breast tumor recurrence and metastasis in patients.
Citation Format: Banafsheh Afshar Imani, JoAnne Baran, Peter J. Cabot, Marie-Odile Parat. Morphine modulates the paracrine interaction between breast tumor cells and macrophages. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2808. doi:10.1158/1538-7445.AM2013-2808
Abstract 2809: Deficiency of Notch-1 signaling in liver increases neuroblastoma hepatic metastases.
Authors: Banerjee Debarshi , Garcia Alejandro , Andrews John , Sbiroli Emily , Kandel Jessica J. , Yamashiro Darrel J. 
Published: August 2014

Abstract
Purpose: The Notch signaling pathway has been extensively studied for its role in tumor angiogenesis but its function in tumor metastasis is largely elusive. In the present study we investigated the role of a notch receptor, Notch-1, in the regulation of neuroblastoma liver metastatic process.
Methods: To investigate the function of Notch-1 in neuroblastoma liver metastasis we first generated immunodeficient (rag2gammaC deletion) Notch-1 heterozygous (+/-) mice. We crossed a Notch1 heterozygous (+/-) mouse with a rag2/gamma-c double knockout (-/-) mouse. The mouse with Notch1(+/-)rag2(+/-)gammaC(+/-) genotype was then backcrossed with a rag2gammaC double knockout (-/-) mouse to generate rag2(-/-)gammaC(-/-)Notch1(+/-) mouse or rag2(-/-)gammaC(-/-)Notch1(+/+)control mouse . These mice (n=5) were intracardically injected with 105 neuroblastoma NGP (MYCN amplified) cells expressing Firefly luciferase. The mice were subjected to IVIS- bioluminescence imaging, once in a week, to monitor the metastatic spread. All mice were sacrificed at week 8. At the time of sacrifice, mice were injected with Luciferin, sacrificed and liver was then dissected out, imaged and bioluminescence flux was measured (ex vivo imaging). The liver tissues were also sectioned (5um, paraffin) and H&E stained at multiple levels to further confirm the presence of metastases.
Result: Intracardically injected NGP cells formed increased liver metastases in rag2(-/-)gammaC(-/-)Notch1(+/-) mice compared to littermate control rag2(-/-)gammaC(-/-)Notch1(+/+) mice. 4 out of 5 (80%) mice in Notch-het group and only 1 out of 5 (20%) mice in control group developed hepatic metastases. Notch-het livers showed multiple metastatic lesions with diameter ranged from 1-5 mm. Ex vivo bioluminescence imaging showed total flux (photon/sec) of Notch1 (+/-) livers were significantly higher (p&lt;0.01) compared to Notch1 (+/+) control livers. Immunohistochemical staining against blood vessel markers such as Collagen IV, endomucin (endothelial cells) and aSMA (pericyte) showed extensive network of angiogenesis in Notch1 (+/-) liver metastases.
Conclusion: Deficiency of Notch1 signaling in liver microenvironment presented an increase in metastases in Notch-het mice in NGP intracardiac injection metastatic model. Therefore our study indicates that Notch1 acts as tumor suppressor in neuroblastoma liver metastasis.
Citation Format: Debarshi Banerjee, Alejandro Garcia, John Andrews, Emily Sbiroli, Jessica J. Kandel, Darrel J. Yamashiro. Deficiency of Notch-1 signaling in liver increases neuroblastoma hepatic metastases. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2809. doi:10.1158/1538-7445.AM2013-2809
Abstract 2814: Sonic hedgehog in gastric cancer metastasis; MAP Kinase/NFκB-dependent signaling pathway.
Authors: Kang Myoung Hee , Kim Bo Ram , Park Joo Sung , Jeon Jung Guk , An Hyun Sook , Jang You Jin , Kim Sun Il , Kim Jun Suk , Oh Sang Cheul 
Published: August 2014

Abstract
Up-regulation of Sonic hedgehog and their receptors by tumor is an important hallmark in cancer progression, as it contributes through autocrine and paracrine mechanisms to tumor development, invasion, and metastasis, but the role and cellular mechanism in the invasive phenotype of gastric cancer cells is not known. Herein, we determined the roles of Mitogen-activated protein kinase (MAPK) signaling, nuclear factor (NF)-κB, and matrix metalloproteinase (MMP) expression in Shh-mediated metastatic function in gastric cancer. We found that stimulation of Shh in gastric cancer cells enhanced the phosphorylation of JNK and p38. Accompanying activation of JNK and p38 kinase, Shh also enhanced phosphorylation/degradation of IκBα and the nuclear translocation/activation of NF-κB.
Interestingly, blockade of JNK and p38 signaling using SP600125 and SB202190, respectively, significantly inhibited Shh-induced motility and invasiveness in association with the activation of NF-κB. In addition, phosphorylation of JNK, p38 and of IκBα, IκBα degradation, and the nuclear translocation of NF-κB was enhanced by treatment with N-shh, but not cyclopamin or shh neutralization antibodies. Furthermore, Shh-induced MMP-9 expression and enzymatic activity was also significantly blocked by treatment with MAPK, JNK, or NF-κB inhibitors. Immunohistochemistry staining of 178 gastric tumor biopsies indicated that expression of shh and MMP-9 had a significant positive correlation with lymph node metastasis and a poor prognosis. These results indicate that the Shh signaling pathway enhances tumor metastasis in gastric cancer by sequential activation of the JNK or MAPK pathway followed by the induction of NF-κB and MMP-9 activity, indicating that shh has the potential to be a therapeutic molecular target to decrease metastasis. Overall, our studies suggest that Shh promote motility and invasion of gastric cancer cells by activating MAPK/ NF-κB signaling and that targeting for these signaling may provide therapeutic opportunities in preventing metastasis mediated by Shh.
Citation Format: Myoung Hee Kang, Bo Ram Kim, Joo Sung Park, Jung Guk Jeon, Hyun Sook An, You Jin Jang, Sun Il Kim, Jun Suk Kim, Sang Cheul Oh. Sonic hedgehog in gastric cancer metastasis; MAP Kinase/NFκB-dependent signaling pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2814. doi:10.1158/1538-7445.AM2013-2814
Abstract 2817: The contribution of bone marrow cells to carcinogenesis in the chronic inflammatory lung conditions.
Authors: Takikawa Sachiko , Powell Charles 
Published: August 2014

Abstract
The role of inflammation in lung carcinogenesis is suggested by the independent association between chronic obstructive lung disease, a systemic inflammatory process, and lung cancer risk. To investigate that chronic inflammation in the lung potentiates tobacco smoke-induced lung carcinogenesis, we utilized two murine models of chronic lung inflammation: a model of sustained intranasal exposure to lipopolysaccharide (LPS) and a transgenic model of inducible interleukin-1β overexpression in the lung. In preliminary experiments, nicotine-derived nitrosamine (NNK) tobacco carcinogen induced tumor multiplicity is significantly increased in stress markers in the lung tumors with chronic inflammation.
To determine the role of bone marrow-derived stem cells (BMDCs) in mediating the oxidative stress response in this model of chronic lung inflammation, we performed lineage tracing experiments. BMDCs are capable of self-renewal and recruited to the end organs where they differentiate into various terminal cells. In inflammation-associated gastric cancer, BMDCs contribute to the tumor microenvironment both by direct proliferation of epithelial cells and by differentiation into α-SMA positive cancer-associated fibroblasts. We hypothesize that BMDCs are recruited to inflammatory sites and contribute to the process of lung carcinogenesis through differentiation. We performed bone marrow transplantation from male GFP tagged donors to female chronic lung inflammation models. We investigated the localization and quantification of BMDCs contributions to subsequent lung tumors by immunohistochemistry of GFP and FISH for the Y chromosome. Additionally, we examined the differentiation of BMDCs in the tumor and associated microenvironment.
This study has the potential to identify novel pathways of lung carcinogenesis in cigarette carcinogen-induced lung cancers arising in the setting of chronic inflammation.
Citation Format: Sachiko Takikawa, Charles Powell. The contribution of bone marrow cells to carcinogenesis in the chronic inflammatory lung conditions. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2817. doi:10.1158/1538-7445.AM2013-2817