bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5188: Phosphoinositide 3-kinase γ: Implications in breast cancer metastasis
Authors: Xie Yan , Kirui Joseph K. , Jiang Haihong , Deng Caishu , Tu Yaping 
Published: February 2011

Abstract
Metastasis is the major cause of breast cancer mortality. Type I phosphatidylinositol 3-kinases (PI3Ks), including α, β, γ and δ, play a pivotal role in diverse cell processes such as proliferation and motility. Of these PI3Ks, PI3Kγ is especially intriguing because it is: 1) normally expressed primarily in white blood cells which have a physiological need to migrate and 2) is specifically activated by G-protein coupled receptors (GPCRs). We recently reported that aberrant Gi-coupled receptor signaling promotes breast cancer metastasis (Xie et al., Cancer Res. 69: 5743-5751). The goal of the present study was to determine roles of PI3Kγ in breast cancer metastasis. We first examined the levels of PI3Kγ in different breast cancer cell lines by RT-PCR and Western blot analysis. We then immunohistochemically analyzed PI3Kγ protein expression in histologically benign and neoplastic cells of archival human breast tissues. We also investigated effects of PI3Ks inhibitors on migration and invasion abilities of breast cancer cells in Transwell chamber assays. Finally, we determined effects of PI3Ks inhibitors on lamellipodia formation, a key step involved in cancer metastasis. Our data indicated that PI3Kγ mRNA and protein were not detected in a normal human breast epithelial cell line (MCF-10A) or non-metastatic breast cancer cells (MCF-7 and T47D), but was found in metastatic breast cancer MDA-MB-231 cells and MDA-MB-436 cells. In contrast, PI3Kα, β and δ are ubiquitously expressed in these cell lines. In addition, immunohistochemical staining using a PI3Kγ-specific antibody showed that the expression of PI3Kγ protein was significantly increased in invasive human breast carcinoma and in breast cancer metastases to a regional lymph node as compared to the adjacent benign breast tissues or the noninvasive ductal carcinoma in situ. Thus, PI3Kγ expression level correlates with the metastatic potential of breast cancer cells. Interestingly, migration and invasion of metastatic breast cancer cells were inhibited by a selective inhibitor of PI3Kγ but not α or β isoforms. Furthermore, blocking PI3Kγ but not α and β disrupted the Rac-dependent lamellipodia formation induced by the activation of Gi-coupled receptor CXC chemokine receptor 4, but not epidermal growth factor tyrosine kinase receptor. Taken together, these results indicate that up-regulated PI3Kγ conveys the metastatic signal initiated from GPCRs in breast cancer cells and suggest that PI3Kγ may be a novel therapeutic target for the treatment of breast cancers. Supported by Nebraska State LB692 (YX).
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 5188.
Abstract 520: Inhibition of uPAR and uPA reduces invasion and degradative potential in papillary thyroid carcinoma cells
Authors: Nowicki Theodore S. , Kummer Nicolas T. , Iacob Codrin , Suslina Nina , Moscatello Augustine , Schantz Stimson , Schaefer Steven , Shin Edward , Tiwari Raj K. , Geliebter Jan 
Published: February 2011

Abstract
Papillary thyroid cancer (PTC) is the most prevalent endocrine and thyroid malignancy. The ability of PTC to invade and migrate great distances contributes to distant metastases, which represent the most common cause of PTC-related death. The urokinase plasminogen activator (uPA) and the urokinase plasminogen receptor (uPAR) are key mediators of tumor invasion. Upon binding to uPAR, pro-uPA is converted to its active form, which is then capable of cleaving plasminogen to plasmin. Plasmin can then degrade components of the basement membrane and extracellular matrix, a prerequisite for tumor cell invasion and metastasis. The binding of uPA by uPAR also seems to mediate several signaling events that contribute to a migratory phenotype, as well as various growth signals. In this study, we analyzed uPA and uPAR expression in PTC and normal thyroid tissue, and examined in vitro how uPA and uPAR contribute to an invasive/metastatic phenotype, as well as the functional consequences of inhibiting this system. uPA and uPAR RNA were also significantly higher in patients with metastatic disease. Casein-plasminogen zymography and western blotting demonstrated increased active uPA secreted by BCPAP cells compared to NTHY-Ori-3-1. Fluorimetric assays revealed that BCPAP CM was able to activate plasminogen, resulting in measureable casein hydrolysis. This casein hydrolysis was prevented by the addition of several specific uPA inhibitors. The in vitro invasion phenotype of BCPAP cells was augmented by the addition of plasminogen, and this augmentation was reversed by inhibitory anti-uPA and anti-uPAR antibodies. Cells transfected with siRNA against uPAR demonstrated decreased migratory and invasive potentials as measured by Matrigel invasion assays. Finally, uPAR-knockdown cells exhibited decreased proliferation when compared to non-targeting siRNA transfectant cells. These data provide new functional evidence of the uPA/uPAR system's role in PTC invasion/metastasis and demonstrate the attractiveness of uPA and uPAR as molecular biomarkers and therapeutic targets.
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 520.
Abstract 5201: Erk activation of p21 activated kinase-1 is critical for medulloblastoma migration
Authors: Yuan Liangping , MacDonald Tobey J. 
Published: February 2011

Abstract
We previously identified that overexpression of the platelet-derived growth factor receptor (PDGFR) is associated with metastatic medulloblastoma (MB) and showed that PDGF treatment increases ERK activity and promotes MB cell migration. In this study, we investigated whether ERK regulates Rac1/Pak1 signaling and is critically linked to MB cell migration. Herein we demonstrate that PDGF-BB treatment of MB cells induces concomitant activation of PDGFRβ, MEK1/ ERK, Rac1 and Pak1, but suppresses Rho activity, which together significantly promotes cell migration. Conversely, cells transfected with either PDGFRβ or Pak1 siRNA or treated with an inhibitor of Rac1 (NSC23766) or N-myristoyltransferase-1 (Tris-dipalladium) are unable to activate Rac1 or Pak1 in response to PDGF, and consequently, are unable to undergo PDGF-mediated cell migration. Furthermore, we also demonstrate that either chemical inhibition of MEK/ERK (U0126) or stable downregulation of PDGFRβ by shRNA similarly results in the loss of PDGF-induced ERK phosphorylation and abolishes Rac1/Pak1 activation and cell migration in response to PDGF. However, specific depletion of Pak1 by siRNA has no effect on PDGF-induced ERK phosphorylation, indicating that in MB cells ERK signaling is Pak1-independent, but PDGF-induced migration is dependent on ERK-mediated activation of Pak1. Finally, using tissue microarrays, we detect phosphorylated Pak1 in 53% of medulloblastomas and show that immunopositivity is associated with unfavorable outcome. We conclude that Rac1/Pak1 signaling is critical to MB cell migration and is functionally dependent on PDGFRβ/ERK activity.
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 5201.
Abstract 5203: Domains that distinguish Akt1 from Akt2 in cell migration
Authors: Natarajan Sharmila B. , Zhou Guo-Lei , Field Jeffrey M. 
Published: February 2011

Abstract
Domains that distinguish Akt1 from Akt2 in cell migration
Sharmila B. Natarajan, Guo-Lei Zhou and Jeffrey Field
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
The Akt family of kinases, Akt1, Akt2 and Akt3 are activated in many cancers where they play critical role in cell survival, metabolism and migration. There are distinctive roles for Akt1 and Akt2 in cell migration where, depending on the cell type, loss of Akt1 can either stimulate or inhibit cell migration. Previous work from our lab demonstrated that loss of Akt2 stimulated cell motility and that, based on chimeras, the kinase domains of Akt1 and Akt2 are interchangeable. Specificity is conferred by the PH domain and a linker domain that separates the PH domain from the kinase domain. To address regions that are required to rescue Akt1 knockouts, which have reduced cell motility, we performed rescue experiments with mouse embryo fibroblasts from Akt1 knockout mice. Our results are in concordance with a study by E. K. Kim et al., (Cell Signaling, 2008) where they found that the linker region is again likely to confer specificity. Importantly, we found that a new construct, in which only the linker domain of Akt1 was swapped into Akt2, stimulated cell migration of Akt1 knockouts. Additionally, we find that both Akt1 and Akt2 associate with the Pak protein kinase but through different mechanisms. These studies suggest that differences in interaction with Pak may underlie the opposing effects of Akt1 and Akt2 on cell migration.
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 5203.
Abstract 5213: KiSS1R signaling in breast cancer
Authors: Zajac Matthew M. , Babwah Andy , Bhattacharya Moshmi 
Published: February 2011

Abstract
KiSS1R, a G-protein coupled receptor (GPCR), and its ligands, collectively known as the kisspeptins, were originally discovered to have anti-metastatic effects. In melanoma, the expression of KiSS1R and the kisspeptins correlates with positive prognosis. However, in breast tumors, higher mRNA expression of KiSS1R and kisspeptins has been shown to correlate with progressing tumour grade. In large, the mechanism(s) by which kisspeptin-signaling via KiSS1R regulates breast cancer cell migration and invasion, required for metastasis, is unknown, and is the focus of this study. Commonly targeted in breast cancer therapy, aberrant signaling of the epidermal growth factor receptor (EGFR) is able to lead to increased migration and invasion, culminating in a more aggressive metastatic phenotype. EGFR's ability to interact with other GPCRs, whether directly by transactivation or indirectly by down-stream crosstalk, is well known. We have found that Kp-10, the most potent kisspeptin, stimulates the migration and invasion of highly invasive human MDA-MB-231 cells stably expressing FLAG-KiSS1R. In addition, we have observed co-localization of FLAG-KiSS1R and EGFR-GFP in human embryonic kidney (HEK 293) cells in response to Kp-10 or EGF stimulation. Stimulation of MDA-MB-231 cells with Kp-10 resulted in the activation of EGFR. Taken together, our findings suggest a potential mechanism by which kisspeptins and KiSS1R may stimulate breast cancer cell migration 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 5213.
Abstract 5215: CXCR6-mediated cellular and molecular events involved in breast cancer cell migration and invasion
Authors: Triplet Ashley , Sharma Praveen K. , Singh Rajesh , Lillard James W. , Grizle William E. , Singh Shailesh 
Published: February 2011

Abstract
Optimizing standard treatment modalities for breast cancer has improved the outlook for women afflicted with it. However, 40% breast cancer patients still die from the disease, primarily due to metastasis, which highlights the need for new therapies and better understanding of the mechanisms involved in disease progression. The reason(s) why breast cancer cells preferentially metastasize to lymph nodes, bone, brain, and lung is not fully understood. In this regard, chemokines and their corresponding receptor interactions in metastasis is an area of intense pre-clinical and clinical research. Analysis of breast cancer tissue micro-array in our lab demonstrated expression of CXCR6 by the breast cancer tissue. In confirmation with the TMA, breast cancer cell lines (MCF-7 and MDA-MB-231) also showed higher expression of CXCR6 in comparison to the normal transformed memory epithelial cell line (MCF-10A). We further investigated the role of CXCR6 in breast cancer cell migration and invasion, which are the key steps used by the cancer cells to achieve metastatic goals. Interestingly, breast cancer cells showed higher migratory and invasive potential towards the chemotactic gradients of CXCL16, which is the only natural ligand of CXCR6. This invasive and migratory potential was significantly inhibited after CXCR6 blockade. Our antibody array data show phosphorylation Src, FAK and ERK1/2 in breast cancer cells following CXCL16 treatment as compared to normal breast cancer cell. To determine the molecular mechanisms by which the CXCR6-CXCL16 axis mediates migration and invasion, inhibitors against Src kinase, FAK and ERK1/2 were used during the migration and invasion assay, which resulted in decreased migration and invasion. This suggests that Src, FAK, and ERK1/2 are required for CXCR6-mediated migration and invasion. Furthermore, an increase in F-actin polymerization was observed after CXCL16 treatment, which was significantly inhibited by the pharmacological inhibitors against Src, FAK, and ERK1/2, suggesting their potential role in CXCR6-mediated cytoskeletal rearrangement during breast cancer cell migration and invasion. Taken together, these results indicate clinical and biological significance of CXCR6-CXCL16 axis in breast cancer and targeting this axis may provide new therapeutic option.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 5215.
Abstract 5216: An Akt-EphA2 reciprocal regulatory loop controls tumor cell migration and invasion
Authors: Miao Hui , Guo Hong , Petty Aaron , Sloan Andrew , Danielpour David , Basilion James , Cutter Jennifer , Sedor John , Cohen Mark , Mukherjee Amitava , Wang Bingcheng 
Published: February 2011

Abstract
EphA2 is a member of Eph family receptor tyrosine kinases that has been implicated in many types of human cancers. Perplexingly, both pro- and anti-oncogenic properties have been attributed to EphA2 kinase. We report here that a possible cause for this apparent paradox is diametrically opposite roles of EphA2 in regulating cell migration and invasion. While activation of EphA2 with its ligand ephrin-A1 inhibited chemotactic migration of glioma and prostate cancer cells, EphA2 overexpression promoted migration in a ligand-independent manner. Surprisingly, the latter effects required phosphorylation of EphA2 on serine 897 by Akt, and S897A mutation abolished ligand-independent promotion of cell motility. Ephrin-A1 stimulation of EphA2 negated Akt activation by growth factors and caused EphA2 dephosphorylation on S897. In human astrocytoma, S897 phosphorylation was correlated with tumor grades and Akt activation, suggesting that the Akt-EphA2 crosstalk may contribute to brain tumor progression.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 5216.
Abstract 5224: Tracking the longitudinal physiological and vascular morphology changes in response to anti-angiogenesis treatment in breast tumors
Authors: Cao Ning , Cao Minsong , Liu Bo , Miller Kathy D. , Stantz Keith 
Published: February 2011

Abstract
VEGF and its receptor (VEGFR2 or flk1/KDR) play critical roles in tumor angiogenesis, which is essential for tumor growth and metastasis. The objective of this study is to track and quantify the longitudinal intra-tumor heterogeneous response to anti-VEGFR2 treatment using a combination of imaging modalities: dynamic contrast-enhanced CT (DCE-CT) and photoacoustic computed tomography (PCT). DCE-CT is used to measure vascular physiology and PCT is used to monitor its morphological changes based on its hemoglobin status within the tumor.
A cohort of athymic mice bearing MCF-7VEGF (MCF-7 cells transfected with VEGF gene) tumors were divided into three groups: a control group (received non-specific, rat immunoglobulin IgG1, i.v.), a low dose therapeutic group (30 mg/kg DC101, i.v.), and a high dose therapeutic group (150 mg/kg DC101, i.v.). Twenty-four hours prior to treatment, baseline DCE-CT and PCT scans were acquired. Successive scans were taken 2 days, 1 week, and 2 weeks post treatment to track both physiological and morphological changes. For the former, a two-compartmental kinetic model is fit to contrast enhanced curves on a voxel-by-voxel basis to determine tumor physiological parameters of perfusion (F), permeability-surface area (PS), fractional plasma volume (fp) and fractional interstitial space (fis). Maximum intensity profiles (MIPs) and hemoglobin profiles were extracted from PCT images.
The preliminary results show a dose dependent response to DC101 treatments. Two days post treatment, low dose reduced F by 36% and fp by 22%; high dose reduced F by 72% and fp by 39%. Tumor perfusion remained reduced two weeks post treatment, while fp in treated mice rebounded to similar levels as the control group after one week and exceeded the control group by week two. This decoupling of fp and F over time indicates a step-wise progressive nature to the formation of a vascular network and its functionality associated with the VEGF/VEGFR2 pathway. Photoacoustic results confirm the link between the changes in vascular morphology and physiology, and provide an in vivo link between vascular structure and function in response to anti-angiogenic therapy. Future work will focus on measuring the oxygen saturation levels and hemoglobin concentration in tumors by analyzing the spectroscopic information afforded by PCT.
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 5224.
Abstract 5227: Dynamic bioluminescent imaging and fluorescent imaging evaluation of vascular targeting agents combretastatin-A4P on brain tumor xenografts
Authors: Liu Li , Mason Ralph P. , Gimi Barjor 
Published: February 2011

Abstract
Bioluminescent imaging (BLI) is an inexpensive, high-throughput approach to assess tumor growth in small animals. Recent experiments show that vascular targeting agents, which disrupt the blood supply rapidly, cause reduction and delay in emitted light as assessed by the kinetics of BLI signal intensity in breast tumor.
We transfected 9L rat glioma cells to express luciferin under the HRE promoter, and transduced these cells with a retrovirus to constitutively express GFP and mCherry. Different numbers of 9L-3HRE-luc/GFP/mCherry cells were implanted in the lower back regions of nude mice. When tumors reached about 3 to 7 mm diameter, they were imaged first with Fluorescence imaging (FLI) to detect GFP and mcherry signal. Then, 80 µl luciferin (40 mg/kg) was administered S.C and a BLI time course was acquired over 50 mins using a Caliper Xenogen Spectrum. Combretastatin-A4P (CA4P) was then administered IP (150 mg/kg in 100 μl saline) and FLI and BLI repeated following the administration of fresh luciferin 2 h and 4h later. The processes were repeated at the 24 h and 96 h time points.
We examined the effect of CA4P on 9L-3HRE-luc/GFP/mCherry that are implanted as S.C xenografts in nude mice, and found highly reproducible curves under control conditions. 2h following CA4P, the BLI signal was reduced by 90%, 4h later, some recovery was observed. After 24 h, the light emission continued to recover. After 96 h, signal was observed mainly from the periphery of larger tumors, probably owing to central necrosis. Notably, the GFP and mCherry fluorescent signals were slightly reduced after 2 h, further declined after 4 h, and GFP signal was completely eliminated after 24 h, attributable to the vascular hemorrhage absorbing GFP. Similarly, after 96 h, both GFP and mCherry signal could be detected in the periphery of larger tumors. Three tumors were developed under similar conditions and examined simultaneously, which provides a valid assessment of vascular shutdown. This technique can be utilized to optimize future therapeutic drug dosage and combinations.
Support: NIH R01 EB007456 and NCI SAIRP U24CA126608
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 5227.