bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2629: PIK3CA mutation promotes tumor cell invasion and migration independently from AKT and mTOR kinase in cancer cells.
Authors: Bhattachara Bhaskar , Stasik Enrico , Low Sarah , Sturz Andrea , Schatz Christoph , Soong Richie , Liu Ningshu 
Published: August 2014

Abstract
Although the role of phosphoinositide-3 kinase (PI3K) in promoting tumorigenesis, tumor cell survival, proliferation and metabolism has been extensively evaluated, the mechanisms of other oncogenic processes mediated by PI3K have not been fully addressed. We report here a novel molecular mechanism by which PI3K mediates tumor cell invasion and migration using isogenic cell lines and highly selective PI3K pathway inhibitors. First of all, using a set of MCF10A-derived isogenic cell lines with PIK3CAH1047R, PTEN-deletion, or AKTE17K mutations, we found that activating the PIK3CA mutation, but not PTEN-deletion or AKT mutation, promoted tumor cell migration in a wound healing assay. Treatment of the PIK3CAH1047R isogenic cell line with a highly selective PI3K inhibitor (BAY 80-6946) effectively blocked tumor cell migration. Interestingly, neither allosteric AKT inhibitor nor mTOR kinase inhibitors were able to inhibit PIK3CA-stimulated cell migration although both AKT and mTOR kinase inhibitors potently inhibited AKT phosphorylation in these cells. In contrast, AKT inhibition enhanced the migration of PIK3CA mutant isogenic cells. This result revealed a novel AKT- and mTOR-independent mechanism by which activating PI3K mutation stimulates tumor cell migration. This conclusion was further confirmed in a panel of gastric cancer cell line in both wound healing and migration assays. Additional mechanistic experiments are being performed to examine downstream signaling events and will be presented. Taken together, these data suggest a role of PI3K in contributing to tumour metastasis independent of the canonical PI3K-AKT-mTOR axis and further validation of using AKT inhibitor for the treatment of metastatic PIK3CA mutant tumors to be conducted.
Citation Format: Bhaskar Bhattachara, Enrico Stasik, Sarah Low, Andrea Sturz, Christoph Schatz, Richie Soong, Ningshu Liu. PIK3CA mutation promotes tumor cell invasion and migration independently from AKT and mTOR kinase in cancer cells. [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 2629. doi:10.1158/1538-7445.AM2013-2629
Abstract 2631: IL-6 promotes ICAM-1 expression and cell motility in human osteosarcoma.
Authors: Fong Yi-Chin , Tang Chih Hsin 
Published: August 2014

Abstract
Osteosarcoma is characterized by a high malignant and metastatic potential. Interleukin-6 (IL-6) is a multifunctional cytokine that is associated with the disease status and outcomes of cancers. However, the effect of IL-6 on migration activity in human osteosarcoma cells is mostly unknown. Here we found that IL-6 increased the migration and expression of intercellular adhesion molecule-1 (ICAM-1) in human osteosarcoma cells. Transfection of cells with ICAM-1 siRNA reduced IL-6-mediated cell migration. We also found that expression of IL-6 was significantly greater in human osteosarcoma tissues than in normal bone. The integrin-linked kinase (ILK)/Akt/AP-1 pathway was activated after IL-6 treatment, and IL-6- induced expression of ICAM-1 and migration activity was inhibited by the specific inhibitor and siRNA of ILK, Akt, and AP-1 cascades. In addition, over-expression of IL-6 shRNA inhibited the migratory ability and ICAM-1 expression in osteosarcoma cells. Taken together, these results indicate that IL-6 and IL-6 receptor interaction occurs through ILK and Akt, which in turn activates AP-1, resulting in the activations of ICAM-1 and contributing the migration of human osteosarcoma cells.
Citation Format: Yi-Chin Fong, Chih Hsin Tang. IL-6 promotes ICAM-1 expression and cell motility in human osteosarcoma. [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 2631. doi:10.1158/1538-7445.AM2013-2631
Abstract 2635: Galectin-1 modulates glioblastoma cell migration via interaction with FAK.
Authors: Velpula Kiran Kumar , Bhasin Arnima , Zhang Jane S. , Tsung Andrew J. , Veeravalli Krishna Kumar , Rao Jasti S. , Dasari Venkata Ramesh 
Published: August 2014

Abstract
Malignant glioblastomas (GBM) are the most common brain tumors and exhibit excessive growth, cell cycle regulation, neovascularization, angiogenesis, migration, immune escape and resistance to apoptosis. Galectin-1 (Gal-1) is a 14.5-kDa β-galactoside-binding protein, which displays intracellular (i.e., protein-protein interactions) and extracellular (i.e., protein-oligosaccharide interactions) functions with marked pro-angiogenic and pro-migratory effects in gliomas. Although glioma is considered one of the deadliest cancers with median survival ranging from nine to twelve months, therapeutic treatments that target Gal-1 may prove effective since Gal-1 is one of the genes that cause aggressive behaviors of human GBM such as migration and invasion. Gal-1 controls glioma cell migration and invasion by modifying the actin cytoskeleton and expression of small GTPases. In the present study, immunohistochemical, Real Time PCR and Western blot experiments performed with clinical samples demonstrated that Gal-1 is highly expressed in human GBM tissue as compared to healthy brain tissue. Matrigel invasion assays confirmed that treatment of glioma cell lines U251 and 5310 with human umbilical cord blood stem cells (hUCBSC) almost completely blocked invasion of GBM cells. We also observed that treatment of GBM cells with hUCBSC decreased the expression of both Gal-1 and FAK. Additionally, silencing either the Gal-1 or FAK gene using shRNA decreased migration and invasion of glioblastoma cells. Furthermore, using immunocytochemistry and Western blot analyses, we observed that Gal-1 and FAK interact with each other in glioblastoma. Taken together, our results suggest that Gal-1 and FAK might have a direct protein-protein interaction for their function in the tumorigenesis of glioblastoma.
Citation Format: Kiran Kumar Velpula, Arnima Bhasin, Jane S. Zhang, Andrew J. Tsung, Krishna Kumar Veeravalli, Jasti S. Rao, Venkata Ramesh Dasari. Galectin-1 modulates glioblastoma cell migration via interaction with FAK. [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 2635. doi:10.1158/1538-7445.AM2013-2635
Abstract 2640: HEF1 is an important regulator of mesenchymal and amoeboid invasion in breast cancer.
Authors: Jones Brandon , Pugacheva Elena 
Published: August 2014

Abstract
In previous studies, the focal adhesion-associated scaffolding protein HEF1, also known as NEDD9, has been implicated as a possible dynamic switch between the mesenchymal and amoeboid migration methods of melanoma cancer cells. Management of this switch provides a possible mechanism of control that could potentially open up new strategies for treatments of metastatic cancers. We have sought to investigate whether HEF1’s involvement in cell migration could also be applied to breast cancer. To monitor the switch between the two methods of migration, we decided to monitor activation of the Rac1 and RhoA proteins of the Rho subfamily of GTPases, which are renowned for their roles in actin cytoskeletal dynamics and have been linked to cancer cell invasion. High levels of active Rac1 result in an elongated cell morphology accompanied by mesenchymal cell movement, whereas high active RhoA levels result in a rounded cell morphology accompanied by amoeboid cell movement. Using a series of GST-tag pulldown experiments, we pulled and quantified amounts of active Rac1 and RhoA from an MDA-MB-231LN human breast cancer cell line grown in both 2D and 3D conditions under a HEF1 shRNA knockdown. Our HEF1-reduced cell line shows a decrease in active Rac1 and an increase in active RhoA compared to a control cell line with normal HEF1 levels. With this data, we aim to further substantiate HEF1 as a relevant key player in the balance between mesenchymal and amoeboid dominance in cancer cells.
Citation Format: Brandon Jones, Elena Pugacheva. HEF1 is an important regulator of mesenchymal and amoeboid invasion in breast cancer. [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 2640. doi:10.1158/1538-7445.AM2013-2640
Abstract 2652: Multiplex detection of stem cell pluripotency markers in reference cancer cell lines.
Authors: Wiese Frederick W. , Stankiewicz Nikolai , Reiners Ralf , Warmke Tim , Maheshwari Reeti 
Published: August 2014

Abstract
Several proteins, including Oct-3/4, Sox2, KLF4 and Nanog, play a critical role in the maintenance of pluripotency in stem cells. Overexpression of one or a combination of these factors has been reported in solid tumors from a variety of tissues. The presence of pseudogenes and differentially expressed protein isoforms complicates the accurate detection of the physiologically relevant forms of these proteins in cancer stem cell research. Here, we report the development of MILLIPLEX® MAP multiplex assays for the simultaneous, specific and sensitive detection of the pluripotency markers Oct-3/4, Sox2, KLF4 and Nanog as well as several other stem cell relevant proteins in cellular lysates. Application of the assay to a panel of 25 human cancer cell lines from a variety of organs revealed Sox2 to be the most often expressed protein among these lines. Of the cell lines assayed, only one breast cancer cell line expressed detectable levels of all three transcription factors, suggesting a role for Oct3/4, Sox2 and Nanog in cancer stem cells of this particular cell line. These experiments demonstrate the utility of this pluripotency marker panel for the sensitive analysis of stem cells from a variety of lineages. The expression of the panel analytes was also examined in induced pluripotent stem cells (iPS) and a human embryonic stem cell (hES) line for reference. Taken together we show the successful development of a multiplex immunoassay that can be used to investigate the role of pluripotency marker proteins in stem cells or cancer cell immortalized or primary lines.
Citation Format: Frederick W. Wiese, Nikolai Stankiewicz, Ralf Reiners, Tim Warmke, Reeti Maheshwari. Multiplex detection of stem cell pluripotency markers in reference cancer cell lines. [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 2652. doi:10.1158/1538-7445.AM2013-2652
Abstract 2656: Using Nanog expression to identify breast cancer stem cell populations.
Authors: Brooks Alan D. , de Kluyver Rachel L. , Stauffer Jimmy K. , Kaddoura Marcella , Sayers Thomas J. 
Published: August 2014

Abstract
Many tumors have been demonstrated to contain a subpopulation of cancer stem cells (CSC) whose epigenetic modifications convey resistance to conventional therapies. Furthermore, tumor expression of genes associated with pluripotent embryonic cells, such as Oct-4, Sox-2 and Nanog, often correlates with poor prognosis. We hypothesized that expression of transcription factors that are required for induction and maintenance of pluripotency (Oct-4, Sox-2 and Nanog) would be a possible alternative to cell surface phenotype for identification of CSC populations. Therefore we evaluated Nanog expression in 4T1.2 murine breast carcinoma cells, as a biomarker for CSC sub-populations. Introduction of a Nanog promoter reporter that drives destabilized GFP into 4T1.2 cells resulted in a stable expression of GFP in about 1% of the cells. These GFP+ cell could be easily isolated by FACS cell sorting. On subsequent in vitro cell culture of GFP+ populations, up to 80% of the cells became GFP- over a period of 4 weeks. This would be consistent with a subsequent differentiation of these cells. By contrast GFP- populations remained 100% GFP-. In vitro CSC surrogate assays show that Nanog-GFP+ cells produced more spheroids in soft agar and under non-adherent growth conditions. More importantly, in vivo cell transfer studies demonstrated that Nanog-GFP+ cells were more efficient at generating experimental lung metastases when compared to Nanog-GFP-cells. Interestingly Nanog-GFP+ cells were more resistant to the chemotherapeutic drugs paclitaxel and bortezomib. However targeting the extrinsic apoptosis pathway with a combination of bortezomib and agonist antibodies to the TRAIL death receptor DR5 was equally effective against both Nanog-GFP+ and Nanog-GFP- cells. These findings suggest that Nanog promoter activity is a robust marker of highly metastatic 4T1.2 CSC subpopulations, and suggests that eradication of such cells may be required for improved anti-cancer therapies.
Funded by NCI Contract HHSN261200800001E
Citation Format: Alan D. Brooks, Rachel L. de Kluyver, Jimmy K. Stauffer, Marcella Kaddoura, Thomas J. Sayers. Using Nanog expression to identify breast cancer stem cell populations. [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 2656. doi:10.1158/1538-7445.AM2013-2656
Abstract 266: Notch3 is a marker of tumor-propagating cells in non-small cell lung cancer and is required for their self-renewal.
Authors: Zheng Yanyan , de la Cruz Cecile , Sayles Leanne , Alleyne-Chin Chris , Xu Yue , Hoang Chuong D. , Shrager Joseph B. , Jackson Erica , Sweet-Cordero Alejandro 
Published: August 2014

Abstract
We investigated tumor cell heterogeneity in mouse models of non-small cell lung cancer (NSCLC) that recapitulate key genetic events in this disease. In tumors driven by simultaneous expression of an oncogenic Kras allele and loss of the tumor suppressor Trp53, only a relatively rare subset of tumor cells is capable of propagating tumor growth in both a clonogenic in vitro assay and an in vivo orthotopic transplantation assay. The tumor-propagating cell (TPC) population was enriched by sorting for the combination of the cell surface markers CD24, ITGB4 and Notch(1-4). We demonstrate a critical and specific role for Notch3 signaling in the maintenance of TPCs in the KrasG12D; Trp53fl/fl mouse model. Knock-down of Notch3, but not Notch 1, 2 or 4, decreased self-renewal of TPCs in vitro. In addition, knock-down of Notch3 was critical for tumor propagation in vivo. The relevance of these studies to human NSCLC was confirmed by demonstrating a significant effect of Notch inhibition on the self-renewal of primary human lung adenocarcinoma cells in ex vivo cultures established directly from patients. These findings identify a novel subpopulation of tumor cells with distinct functional capabilities, underscoring the importance of interrogating heterogeneity in NSCLC. The unique role of Notch3 in tumor propagation may provide a novel therapeutic target for the treatment of non-small cell lung cancer.

Citation Format: Yanyan Zheng, Cecile de la Cruz, Leanne Sayles, Chris Alleyne-Chin, Yue Xu, Chuong D. Hoang, Joseph B. Shrager, Erica Jackson, Alejandro Sweet-Cordero. Notch3 is a marker of tumor-propagating cells in non-small cell lung cancer and is required for their self-renewal. [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 266. doi:10.1158/1538-7445.AM2013-266
Abstract 2663: SPECT/CT analysis of distribution of intracranially infused interleukin-13 Pseudomonas exotoxin, a targeted agent for interleukin-13 receptor expressing brain tumors.
Authors: Suzuki Akiko , Leland Pamela , Choyke Peter L. , Inoue Tomio , Joshi Bharat H. , Puri Raj K. 
Published: August 2014

Abstract
Interleukin-13 Pseudomonas exotoxin (IL-13PE), a powerful targeted agent for IL-13 receptor α2 (IL-13Rα2) - positive tumors is being tested for safety and effectiveness in glioblastoma multiforme (GBM) clinical trials. However, distribution of IL-13PE after intra-cranial convection-enhanced delivery (CED) has not been determined. To study this, we radiolabeled IL-13PE with 125I and determined its binding and biological activity in vitro and distribution in a murine model of GBM. 125IL-13PE maintained its specific binding activity to IL-13Rα2 positive U251 glioblastoma tumor cells but not to T98G cells, as these cells did not express IL-13Rα2. 125IL-13PE was as cytotoxic to glioblastoma cells as non-radiolabeled IL-13PE, which killed U251 tumor cells in a concentration dependent manner but not T98G cells. Both binding and cytotoxic activities were blocked by a 100-fold excess of IL-13, which indicated that IL-13PE binding was specific. Athymic nude mice with intracranially implanted U251 tumors were given stereotactic intratumoral injections of 125I-IL-13PE by either a bolus injection or a 3-day-CED. Animals were imaged by micro-SPECT/CT at various time points. SPECT/CT imaging revealed retention of 125I-IL-13PE in U251 tumors. CED showed significantly higher volumes of distribution and maintained detectable drug levels for longer periods of time compared to bolus injection. SPECT/CT images of whole brains corroborated with the autoradiography results performed on sectioned brain. These results indicate that IL-13PE can be successfully radiolabled with 125I without the loss of binding and cytotoxic activity and that 125I-IL-13PE administered by CED showed higher volumes of distribution than the bolus route. Thus, future clinical studies with 125I-IL-13PE or other agents should consider the CED mode of delivery for better distribution in intracranial environments.
Volume of distribution of 125I-IL-13PE after bolus or CED administration into mouse brain Injection parameters SPECT Time Vi (μl)* Vd (mm3)** Vd:Vi ratio Bolus - day 1 10 minutes 5 10.2 ± 0.4 204.7 ± 7.0 Bolus - day 7 10 minutes 5 0.1 ± 0.02 2.0 ± 0.4 CED - day 1 3 days 100 120.4 ± 21.8 120.4 ± 21.6 CED - day 7 3 days 100 81.7 ± 6.9 81.7 ± 6.7 *Vi: Volume of injection **Vd: Volume of distribution
Citation Format: Akiko Suzuki, Pamela Leland, Peter L. Choyke, Tomio Inoue, Bharat H. Joshi, Raj K. Puri. SPECT/CT analysis of distribution of intracranially infused interleukin-13 Pseudomonas exotoxin, a targeted agent for interleukin-13 receptor expressing brain tumors. [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 2663. doi:10.1158/1538-7445.AM2013-2663
Abstract 2692: Dendrimer delivery of RNA based Twist1 inhibitors to reduce breast cancer cell metastasis.
Authors: Finlay James B. , Roberts Cai M. , Glackin Carlotta A. 
Published: August 2014

Abstract
Breast cancer in women is a leading cause of cancer related deaths in the United States with metastatic disease being the chief cause of mortality. Metastatic breast cancer tumors are often found in their later stages making them difficult to remove or treat. Inhibition of tumor cell dispersion is therefore a key component to a reduction in mortality rates among women with breast cancer. Epithelial-Mesenchymal Transition (EMT) is the process by which cancer cells downregulate proteins associated with cell to cell adhesion (e.g. E-cadherin) resulting in cells that are able to mobilize. Breast cancer cells are known to commandeer the EMT process through overexpression of Twist1, thus allowing the cells to metastasize beyond the primary tumor. Twist1 therefore serves as an excellent therapeutic target whose disruption would result in fewer metastatic cancer cells and correspondingly reduce cancer mortality. Twist1 is also a desirable target because it is almost nonexistent in adult tissues and thus its silencing would have minimal side effects.
Our lab has elected to use an siRNA mediated gene silencing approach to decrease the expression levels of Twist1 in two highly invasive breast cancer cell lines (SUM 1315 and MCF7-Tw). Due to their fragile nature, siRNA molecules are often difficult to deliver at therapeutic levels. We have overcome these delivery limitations through the optimization and use of Poly (amidoamine) (PAMAM) dendrimers. We hypothesize that suppression of the activity of Twist1 via dendrimer-delivered Twist1 siRNA will inhibit metastatic behavior of aggressive breast cancer cells. Here we demonstrate successful delivery of Cy3-labled siRNA using two different dendrimers (Generation 5 and a modified Generation 3) with transfection efficiency results exceeding those of Lipofectamine 2000 and with far less toxicity to cells. We also show up to a 90% reduction (lasting at least 4 days) in Twist1 expression using Western Blot and qPCR analysis. Phenotypically we were able to appreciate a significant decrease in the invasive nature of the breast cancer cells using migration/invasion assays. Taken together these results demonstrate successful knockdown of Twist1 using siRNA dendrimer complexes resulting in an altered cellular phenotype. These data will serve as a foundation for optimization of future in vivo experiments with both orthotopic and metastatic breast cancer models.
Citation Format: James B. Finlay, Cai M. Roberts, Carlotta A. Glackin. Dendrimer delivery of RNA based Twist1 inhibitors to reduce breast cancer cell metastasis. [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 2692. doi:10.1158/1538-7445.AM2013-2692
Abstract 2695: Osteopontin regulated epithelial-mesenchymal transition via PI3K/AKT signaling pathway in hepatocellular carcinoma.
Authors: Dong Qiongzhu , Zhu Xu-Chao , Dai Chun , Zhang Xiao-Fei , Jia Hu-Liang , Ye Qing-Hai , Qin Lun-Xiu 
Published: August 2014

Abstract
Our previous studies demonstrated that osteopontin (OPN) plays a crucial role in hepatocellular carcinoma (HCC) metastasis. However, its function in epithelial-mesenchymal transition (EMT) remains obscure. In this study, we reported the critical role of OPN in EMT mediated HCC metastasis. Increased expression of OPN in human HCC predicts poor survival and disease recurrence after surgery. HCC tumors overexpressing OPN were featured by active EMT and motility/invasion of tumor cells both in vitro and in vivo, whereas silencing OPN expression attenuated
EMT. OPN overexpression enhanced twist through activation of Akt, a critical EMT regulation of transcription factor. Suppression of the PI3K-AKT-Twist pathway interfered with OPN-mediated EMT and invasion. Consistently, we have observed a significant correlation between OPN expression and twist levels in a cohort of HCC patients, and found that combination of these two parameters is a more powerful predictor of poor prognosis.
Conclusions: OPN plays a pivotal role in EMT mediated HCC metastasis and may serve as a novel prognostic biomarker and therapeutic target.
Citation Format: Qiongzhu Dong, Xu-Chao Zhu, Chun Dai, Xiao-Fei Zhang, Hu-Liang Jia, Qing-Hai Ye, Lun-Xiu Qin. Osteopontin regulated epithelial-mesenchymal transition via PI3K/AKT signaling pathway in hepatocellular carcinoma. [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 2695. doi:10.1158/1538-7445.AM2013-2695