bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5194: Induction of Fyn via the Ras/PI3K pathway is necessary and sufficient for enhanced migration and invasion
Authors: Yadav Vipin , Denning Mitchell F. 
Published: February 2011

Abstract
Over-expression and activation of Src family kinases, particularly Fyn, is relatively frequent in human cancers. Fyn promotes cancer progression, tumor survival and carcinoma invasion, making it a potential molecular target for cancer therapeutics; however the mechanism of Fyn over-expression in cancers is not clear. Since activation of Ras oncogenes in human cancers is a very common oncogenic event, we explored if an active Ras oncogene could induce Fyn expression. Interestingly, retroviral transduction of the immortalized human keratinocyte cell line HaCaT with oncogenic H-Ras dramatically upregulated Fyn mRNA, protein, and activity (&gt;100 fold mRNA induction, p&lt;0.001). Src levels and kinase activity were not affected by H-Ras transduction. Furthermore, activation of Akt, but not MAPK or EGFR, was necessary and sufficient for induction of Fyn by H-Ras. The enhanced migration and invasion induced by H-Ras could be significantly blocked (70% reduction, p&lt;0.0001) by Fyn specific siRNA knockdown or inhibition by PP2 (10 µM). In addition, expression of active Fyn in HaCaT cells was sufficient for increased migration or invasion of cells. These results implicate induction of Fyn in Ras-induced enhanced migration and invasion of cancer cells. Focal adhesion kinase (FAK) activation has been strongly linked with the Ras-mediated increased migratory phenotype of tumor cells. We found that Fyn was necessary and sufficient for Ras induced activation of FAK. In summary, we show that Fyn induction by oncogenic Ras/PI3K/Akt pathway can account for the elevated Src family kinase activity in cancers, and is a critical mediator of the Ras-stimulated invasive cell phenotype. These results have strong implications for the development of therapeutic strategies targeting Akt/Fyn pathway to block migration and invasion of tumor cells.
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 5194.
Abstract 5198: Different functions of the chemokine receptor CXCR3 in normal and malignant mammary epithelial cells
Authors: Li Yanchun , Ma Xinrong , Kundu Namita , Goloubeva Olga , Holt Dawn , Fulton Amy M. 
Published: February 2011

Abstract
Our previous studies detected chemokine receptor CXCR3 in malignant epithelium of early stage breast cancers by immunohistochemistry and the expression levels were positively correlated with significantly poorer survival. We also showed that CXCR3 contributes to metastatic potential in a murine model of metastatic breast cancer. Interestingly, although immortalized normal murine and human mammary epithelial cells (EpH4 and MCF-10A) also express CXCR3, they respond to CXCR3 ligands differently than malignant cells. Migration of tumor cells was enhanced by stimulation with CXCR3 ligands, but a negligible chemotactic response to these ligands was observed in normal cells. Signal transduction activation patterns also differ between malignant and normal cells. In tumor cells, ERK1/2 is robustly activated after CXCR3 ligand stimulation, whereas the same pathway is inhibited in normal cells. Likewise the p38 pathway is activated in tumor cells and decreased in normal cells. Thus, CXCR3 activation alters the behavior of both malignant and normal cells, but in different ways. One possible mechanism to explain different functions of CXCR3 between normal and malignant mammary epithelial cells is the expression of different CXCR3 isoforms. It has been shown that the “classical” CXCR3 receptor (CXCR3-A) mediates proliferation and migration of various cell lines, while CXCR3-B, a splice variant of CXCR3-A, has opposing functions. To determine the expression pattern of these two CXCR3 isoforms in a panel of human breast cancer cell lines, we conducted real-time quantitative PCR and showed that the CXCR3-B/CXCR3-A mRNA expression ratio is decreased (0.16-0.63) compared with normal epithelial cell line MCF-10A (2.16). CXCR3-B expression dominates in MCF-10A cells, while CXCR3-A expression dominates in tumor cells, with the most metastatic cell line (MDA-MB-231) exhibiting the lowest CXCR3-B/CXCR3-A ratio (0.16). Taken together, these data indicate that the level of CXCR3 receptor expression is not the only determinant of function; the relative amounts of CXCR3-A and CXCR3-B may also be important. Further studies will elucidate how the balance between CXCR3-A and CXCR3-B contributes to the behavior of cells and allow us to optimize therapeutic strategies targeting CXCR3.
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 5198.
Abstract 5202: MUC1 oncogene is required for EGF/Src-driven carcinoma cell metastasis
Authors: Lau Steven K. M. , Shields David J. , Murphy Eric A. , Cheresh David A. 
Published: February 2011

Abstract
Epidermal growth factor receptor (EGFR) and Src tyrosine kinase signaling promote epithelial to mesenchymal transition (EMT) and have been associated with increased metastatic capacity of tumor cells. We observed that EGFR/Src signaling leads to the activation of integrin αvβ5 on carcinoma cells, resulting in an increased invasive capacity without influencing primary tumor growth in vivo (Ricono, et al 2009). We explored potential downstream effectors of Src that may influence this metastatic cascade using an in silico screening approach. Leads were selected based on their ability to influence EGFR/Src/αvβ5-dependent invasion in vitro and metastasis in vivo in a chicken chorioallantoic membrane model. Here, we report the transmembrane glycoprotein mucin-1 (MUC1) as an essential mediator of the EGFR/Src/αvβ5 signaling axis leading to the metastasis of carcinoma cells in vivo. Disruption of MUC1 expression selectively abolished EGF/Src/αvβ5-dependent migration in vitro and metastasis in vivo without influencing primary tumor growth. Importantly, EGFR- and Src-dependent phosphorylation of the cytoplasmic tail of MUC1 (MUC1-CT) facilitated cleavage of MUC1-CT. Once cleaved, MUC1-CT was able to associate with β-catenin, enter the nucleus and modulate gene expression relevant to the metastatic properties of these cells. These findings support a critical role for MUC1 in the regulation of EGFR/Src/αvβ5-dependent metastasis of a wide range of carcinomas.
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 5202.
Abstract 5204: Nodal regulates invasive phenotypes in extravillous and choriocarcinoma trophoblast cells
Authors: Zhang Guihua , Postovit Lynne Marie 
Published: February 2011

Abstract
Nodal, an embryonic morphogen and a member of the transforming growth factor-beta (TGF-ß) superfamily, is highly expressed in embryonic development and some cancers such as breast cancer and melanoma. It has been noticed that altered Nodal expression leads to changes in cellular invasiveness both during embryogenesis and cancer metastasis. However, the roles of Nodal in trophoblast invasion and tumor progression remain unclear. The present study characterizes and examines the effects of Nodal on cell migration, invasion and proliferation by using a highly invasive first trimester trophoblast cell line, HTR-8/svneo, and three Chrioncarcinoma cell lines as in vitro models.
By knocking down Nodal expression with small hairpin RNA (shRNA) plasmid DNA and morpholino oligomers, stable and transient Nodal knockdown clones were created. RT-PCR and Western Blots were performed and analyzed to verify Nodal knockdown in comparison to the Non-transfected (control) cells. To further confirm successful Nodal knockdown, downstream Nodal signalling (phospho-Smad2) was tested and analyzed by Western Blot. Nodal knockdown cells were then subjected to: (1) growth curves to evaluate the effect of nodal level on cell growth capacity and viability; (2) transwell migration assays to assess the effect of Nodal on cell movement and mobility; (3) transwell invasion assays to investigate the effect of nodal on cell invasive potential. The data show that knockdown of Nodal results in a decrease in cell migration and invasion, but does not significantly alter proliferation in vitro. Furthermore, the addition of human recombinant Nodal results in a restoration of cell migration and invasion. In order to further confirm the involvement of Nodal in trophoblast invasion, and to correlate Nodal levels to trophoblast cell phenotype, we then quantified the amount of Nodal in three chrioncarcinoma cell lines (Jar, Jeg-3 and Bewo) with Western Blot, and checked their migratory and invasive potential by Transwell migration and invasion assays. The data show strong positive correlation between Nodal protein level and the cell migration and invasion capacity. Our data indicate that Nodal does play a significant role in trophoblast cell migration and invasion, the two major processes of tumor progression. By studying the first trimester invasive trophoblast cell line, a greater understanding about the role of Nodal shared by trophoblast invasion and tumor metastasis may be gained.
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 5204.
Abstract 5206: VEGF-A/VEGFR-2 signaling might be a promising target for the tumor invasion of pancreatic cancer
Authors: Doi Yosuke , Yashiro Masakazu , Yamada Nobuya , Amano Ryosuke , Kato Yukihiro , Kashiwagi Shinichiro , Noda Satoru , Fuyuhiro Yuhiko , Komoto Masahiro , Matsuoka Junko , Kubo Naoshi , Muguruma Kazuya , Tanaka Hiroaki , Inoue Toru , Sawada Tetsuji , Ohira Masaichi , Nakata Bunzo , Hirakawa Kosei 
Published: February 2011

Abstract
Introduction: Pancreatic cancer is one of the most lethal solid tumors. Vascular endothelial growth factor receptors (VEGFRs) are expressed not only by endothelial cells but also by some types of cancer cells, including pancreatic cancer cells. VEGFRs might play an important role for the development of cancer cells. The purpose of this study was to evaluate the efficacy of VEGF/VEGFR-2 targeted therapy in pancreatic carcinoma. We here demonstrated that VEGFR-2 signaling on pancreatic cancer cells might be a promising therapeutic target for the invasion of pancreatic cancer.
Materials & Methods: Three pancreatic carcinoma cell lines, MiaPaCa-2, OCUP-AT and Panc-1, were used. The effect of anti-VEGF antibody, bevacitumab, a tyrosine kinase inhibitor against VEGFRs, sunitinib, and VEGF-R2 siRNA on cancer invasion was examined by invasion assay. The expression level of VEGFR mRNA of cancer cells was examined by RT-PCR. The effect of VEGF, bevacitumab and sunitinib on MAPK and PI3K signaling pathway was examined.
Result: VEGF-A significantly increased the number of migration cells of MiaPaCa-2 and OCUP-AT, but not that of Panc-1. Bevacitumab and sunitinib significantly decreased the migration ability of MiaPaCa-2 and OCUP-AT cells. The expression levels of VEGF-R2 were high in MiaPaCa-2 and OCUP-AT cells, in compared with Panc-1 cells. Invasion and migration ability of MiaPaCa-2 cells significantly (p&lt;0.05) decreased by VEGFR-2 siRNA treatment. The level of VEGFR-2 autophosphorylation, p-ERK and p-Akt expression was increased by VEGF-A, and decreased by bevacitumab and sunitinib. Conclusion: The invasion of pancreatic cancer cells was closely associated with VEGF-A/VEGFR-2 signaling. VEGF-A/VEGFR-2 inhibition by bevacitumab or sunitinib appears therapeutically promising in pancreatic cancer with VEGFR-2 expression.
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 5206.
Abstract 5209: Abrogation of STAT3 activation by JSI-124 enhances dasatinib-induced cytotoxicity in malignant human glioma cell lines
Authors: Jane Esther P. , Premkumar Daniel R. , Agostino Naomi R. , Scialabba Joseph L. , Pollack Ian F. 
Published: February 2011

Abstract
Src family kinases (SFK) collectively regulate a variety of cellular functions in many cancer types including proliferation, invasion, motility, survival, differentiation, and angiogenesis. Src greatly enhances EGFR-mediated transformation, raising the possibility that Src and/or its related family members may be effectors of EGFR signaling in cancer, including in glioblastoma. Although Dasatinib (BMS-354825), an ATP-competitive, small molecule tyrosine kinase inhibitor, suppresses the activity of SFKs at nanomolar concentrations, IC50 values ranged from 7 to 30 µM for inhibition of proliferation, well above the clinically achievable range. Because Src kinases were initially implicated in STAT activation, we hypothesized that the combination of Src inhibitor dasatinib and JAK2/STAT3 inhibitor JSI-124 would promote glioma cytotoxicity by decreasing both the activation status of c-Src and STAT3, as well as downregulating the levels of other relevant signaling effectors. We, therefore, examined the effects of dasatinib and JSI-124, alone or in combination, on signal transduction, migration and apoptosis in a series of malignant human glioma cell lines. JSI-124 significantly enhanced the efficacy of dasatinib in vitro. Combination of dasatinib and JSI-124 displayed a significant inhibition of cell migration in all cell lines. The effects on cell migration correlated with the inhibition of Src and downstream mediators of adhesion (e.g. focal adhesion kinase). Cells exposed to dasatinib and JSI-124 induced morphological changes that were consistent with an upstream role for Src in regulating focal adhesion complexes. Taken together, targeting Src and STAT pathway may contribute to the treatment of cancers that demonstrate increased levels of EGFR, Src and STATs, including malignant human glioma
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 5209.
Abstract 5214: Role of mitogen-activated protein kinase (ERK) signaling in cyclooxygenase 2-mediated colon cancer cell migration
Authors: Hessel Kara , Bean Ronald R. , Jakobi Rolf , Chang Yu-Wen E. 
Published: February 2011

Abstract
Colon cancer is the second most common cause of cancer-related deaths. Many patients present with colon cancer in advanced stages of metastasis, where the outcome is poor and mortality is high. Invasion is an essential capability acquired by cancer cells to metastasize to distant organs. Currently there are no effective strategies to prevent invasion because the underlying mechanisms are poorly understood. During early development of colon cancer, cyclooxygenase 2 (COX-2) is constitutively induced. We have shown that COX-2 promotes invasion by disrupting cell adhesion and increasing motility in HCA-7 colon cancer cells that constitutively express endogenous COX-2. To further determine the mechanisms by which COX-2 stimulates motility and to confirm this cellular behavior in other colon epithelial cells, we established HCT-15 colon cancer cells that stably express recombinant COX-2 (HCT-15-COX-2). Scratch wound gap assays were used to monitor cell motility and proliferation in HCA-7 and HCT-15-COX-2 cells. HT-29 colon cancer cells that do not express COX-2 and parental HCT-15 cells were used as controls. HCA-7 and HCT-15-COX-2 cells closed the gap significantly faster than HT-29 and HCT-15 cells. Inhibition of COX-2 in HCA-7 and HCT-15-COX-2 cells by the COX-2 selective inhibitor NS-398 decreased the gap closing. Interestingly, the enhanced gap closing ability of HCA-7 and HCT-15-COX-2 cells correlated with activation of ERKs, mitogen-activated protein kinases that are known to mediate COX-2 signaling to stimulate colon cancer cell growth. Activation of ERK depended on COX-2 activity. Inhibition of ERK signaling in HCA-7 and HCT-15-COX-2 cells reduced gap closing as effectively as NS-398. Furthermore, inhibition of ERK signaling prevented migration of both HCA-7 and HCT-15-COX-2 cells in modified Boyden chamber assays. Interestingly, reduced migration by inhibition of ERK signaling correlated with increased protein levels of adherens junction protein alpha-catenin. Our data reveal for the first time a role for ERK to promote cell migration in response to COX-2 signaling in addition to its stimulation of cancer cell growth. Since cardiovascular toxicity caused by long-term use of COX-2 inhibitors raises several concerns, targeting ERK can be an alternative approach for preventing colon cancer growth and invasion.
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 5214.
Abstract 522: Comparison of ovarian cancer spheroids and three-dimensional cell movement with the spheroids formed by normal ovarian surface epithelial and fallopian tube epithelial cells using an in vitro culture system
Authors: Choi Pui-Wah , Megan Hanna , Fong Wing-Ping , Ng Shu-Wing 
Published: February 2011

Abstract
Ovarian cancer is the most lethal cause of death among gynecological cancers. Recent studies have suggested that the cells of origin of ovarian cancer might be the ovarian surface epithelial (OSE) cells and epithelial cells derived from other Mullerian ducts such as distal fallopian tube. It is believed that these cells exist as cortical inclusion cysts in the ovary, to which the extracellular matrix (ECM) proteins, proteases, secreted growth factors and chemokines from the stromal microenvironment can provide oncogenic signals in a paracrine fashion. In order to investigate the molecular mechanisms and signaling events governing these processes, we grew ovarian cancer cell lines, normal OSE and fallopian tube epithelial (FTE) primary cells as three-dimensional (3D) cultures in Matrigel, which was enriched with basement membrane proteins. Most of the cells formed spheroid structures resembling ovarian inclusion cysts, with sizes ranging from 50 to 100 μm. One cancer cell line formed spindle-like structure. The multicellular structures were stained for membrane markers and examined using confocal laser scanning microscopy. Most of the cancer spheroids were consisted of tightly packed polarized epithelial cells, as revealed by lateral β-catenin and E-cadherin staining, and GM130 staining at the apical surface outlining a central lumen. In contrast, normal OSE spheroids and FTE spheroids showed less organized structure with random β-catenin and GM130 staining. To evaluate the growth and progression of the cancer cells in response to stimuli from a stromal microenvironment, the spheroids were transferred to a collagen matrix. Interestingly, the majority of the cancer cells migrated out of the spheroids in a collective movement similar to the lymphatic metastasis observed in breast cancer. The morphology of the collectively moving cells was distinctively different from that expected from an epithelial-mesenchymal transition model. Ongoing gene expression profiling and characterization of the cells growing in the 3D spheroids will reveal the molecular mechanisms underlying the morphogenic changes and may provide insights into the growth and progression of clinical ovarian cancer from inclusion cysts.
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 522.
Abstract 5221: Angiogenesis Imaging of Orthotopic Bladder Tumors using a Smart MRI Contrast Agent Containing VEGF121/rGel
Authors: Yang Jaemoon , Cho Eun-Jin , Mohamedali Khalid A. , Farhangfar Carol J. , Hittelman Walter N. , Suh Jin-Suck , Rosenblum Michael G. , Huh Yong-Min 
Published: February 2011

Abstract
Comprehension of the angiogenic vessels from solid tumors and metastatic lesions is a crucial step for the treatment of cancer. In particular, recognition of VEGFR-2 (KDR) as primary proangiogenic factors and their distribution analysis is very important for establishment of the treatment strategy. In this research, we thus formulated the smart imaging probes based on VEGF121/rGel conjugated MnFe2O4 for imaging of tumor neovasculature using an orthotopic bladder tumor xenograft model. VEGF121/rGel was conjugated to MnFe2O4 nanoparticles (MNPs). Their colloidal size was around 45 nm and a high relaxivity coefficient was 423 mM−1s−1. As in vitro test, the targeting efficiency and detection capability of the VEGF121/rGel-MNPs were investigated in both KDR deficient (253JB-V) and KDR-overexpressing (PAE/KDR) cell lines using MRI, respectively. The targeting and internalization of VEGF121/rGel-MNPs into cells was confirmed by electron microscopy. Their phosphorylation ability and cytotoxicity were compared to unconjugated VEGF121/rGel. They demonstrated astonishing targeting capability against KDR-overexpressing PAE/KDR cells, as confirmed by dose-dependent MR images and VEGF121 inhibition tests. The phosphorylation activity of KDR and cytotoxicity of VEGF121/rGel-MNPs were evaluated. The orthotopic tumor mouse model was established by implanting low KDR-expressing 253JB-V cells into the bladder dome. After tail-vein injection of VEGF121/rGel-MNPs, the MR signal enhancement of intratumoral vessels by VEGF121/rGel-MNPs was observed and inhibition test using VEGF121 was also conducted. VEGF121/rGel-MNPs successfully targeted the tumor and provided accurate anatomical details through: i) acquisition of clear neoangiogenic vascular distributions and ii) obvious enhancement of the MR signal in T2*-weighted images. Immunostaining and blocking studies demonstrated the specific targeting ability of VEGF121/rGel-MNPs towards intratumoral angiogenesis. Furthermore, ex vivo MR imaging of tumor tissue, and a CD-31 and rGel fluorescence immunostaining study revealed the targeting ability to VEGFR-2 on the angiogenetic vessels. Consequently, synthesized VEGF121/rGel-MNPs as valuable MR imaging contrast agents can be specifically delivered to tumors and bind to KDR-expressing angiogenic tumor vessels.
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 5221.