bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5077: Metastasis suppressors regulate the tumor microenvironment by blocking recruitment of pro-metastatic TAMs
Authors: Rabe Daniel C. , Frankenberger Casey , Bainer Russell , Sankarasharma Devipriya , Chada Kiran , Krausz Thomas , Gilad Yoav , Becker Lev , Rosner Marsha R. 
Published: August 2015

Abstract
Triple-negative breast cancer (TNBC) patients have the highest risk of recurrence and metastasis. Because they cannot be treated with targeted therapies, and many do not respond to chemotherapy, they represent a clinically underserved group. While physiological inhibitors of metastasis (metastasis suppressors) play key roles in regulating tumor growth, invasion and metastasis, their role in regulating the tumor microenvironment and immune system is unknown. We hypothesized that the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP) regulates stromal cells, which then affect tumor invasiveness.
Using species-specific RNAseq we determined that expression of RKIP in tumors markedly reduces the number and metastatic potential of infiltrating TAMs. While TAMs isolated from TNBC xenografts drive in vitro invasion, RKIP+ derived TAMs did not drive invasion and had decreased secretion of pro-metastatic factors including SLPI, OPN, MMP-12, Galectin-3, VEGF-A, VEGF-D, TNFR2, and PGRN. We determined that RKIP regulates TAM recruitment by blocking HMGA2, which activates CCL5 expression. CCL5 rescued TAM infiltration as well as tumor intravasation. We additionally showed that factors decreased in RKIP-derived TAMs were restored in CCL5-derived TAMs. Finally, we demonstrated the TAM secreted factor PGRN is both necessary and sufficient for TAM driven invasiveness.
To determine the clinical utility of these TAM genes we combined their expression with RKIP signaling in the tumor to create a signature that strikingly separates TNBC patients based on outcome. Our results demonstrate for the first time that metastasis suppressors can regulate the microenvironment, regulating invasion through TAMs. Our results also suggest TNBC patients with decreased RKIP activity and increased TAM infiltration may respond to therapies targeting CCL5 or PGRN.
Citation Format: Daniel C. Rabe, Casey Frankenberger, Russell Bainer, Devipriya Sankarasharma, Kiran Chada, Thomas Krausz, Yoav Gilad, Lev Becker, Marsha R. Rosner. Metastasis suppressors regulate the tumor microenvironment by blocking recruitment of pro-metastatic TAMs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5077. doi:10.1158/1538-7445.AM2015-5077
Abstract 5090: Targeting metastatic prostate cancer with polyisoprenylated cysteinyl amides
Authors: Poku Rosemary Aniwaa , Nkembo Augustine , Salako Olufisayo , Amissah Felix , Flores-Rozas Hernan , Mazu Tryphon , Lamango Nazarius S. 
Published: August 2015

Abstract
Background: Metastatic castration-resistant prostate cancer (mCRPC) poses a major clinical management challenge due to lack of effective therapies. Monomeric G- proteins of the Ras superfamily such as Rho, Rac and Cdc42 are critical mediators in prostate cancer progression and metastasis, due to their effect on F-actin organization in cell migration. These proteins are polyisoprenylated and subject to regulation by polyisoprenylated methylated protein methyl esterase (PMPMEase). We hypothesized that metabolism of monomeric G-proteins by PMPMEase regulates growth, survival and differentiation as well as cell migration and invasion through its effects on F-actin assembly.
Methods: The effects of polyisoprenylated cysteinyl amides (PCAIs), NSL-RD-036, NSL-BA-040, NSL-BA-055 and NSL-BA-056 on the viability and proliferation of prostate cancer cell lines were investigated using the MTS assay. Docetaxel and paclitaxel were used as positive controls. Metastatic PC -3 cell migration and invasion in the presence of NSL-RD-036 were determined using the scratch and matrigel invasion assays. The effect of NSL-RD-040 on F-actin organization in TagRFP F-actin marker-transfected PC 3 cells was also investigated.
Results: The PCAIs were cytotoxic to all prostate cancer cell lines (PC-3, DU 145, LNCaP and 22Rv1). In all the cell lines, NSL-BA-040 showed the highest activity (EC50 4.3 - 5.0 μM) followed by NSL-RD-036 (EC50 2.0 - 9.2 μM), NSL-BA-056 (EC50 4.8 - 7.5 μM) and NSL-BA-055 (EC50 2.9 - 11.2 μM) while docetaxel and paclitaxel were not as effective (EC50 &gt;100 μM). Metastatic PC-3 cell proliferation was inhibited in a concentration-dependent manner by NSL-RD-036 and at 2 μM PC-3 cell proliferation was halted. Exposure of PC-3 cells to NSL-BA-040 induced apoptosis and disrupted F-actin cytoskeleton organization in TagRFP F-actin marker transfected metastatic PC-3 cells. NSL-RD-036 also significantly inhibited PC-3 cell migration and invasion through matrigel.
Conclusions: Polyisoprenylated small molecules suppress migration and invasion as well as disrupt F-actin organization of metastatic PC-3 cells. Polyisoprenylated small molecules could serve as a new class of therapeutic agents in metastatic castration resistant prostate cancer.
Citation Format: Rosemary Aniwaa Poku, Augustine Nkembo, Olufisayo Salako, Felix Amissah, Hernan Flores-Rozas, Tryphon Mazu, Nazarius S. Lamango. Targeting metastatic prostate cancer with polyisoprenylated cysteinyl amides. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5090. doi:10.1158/1538-7445.AM2015-5090
Abstract 5093: Pre-clinical assessment of a novel anti-invasion nanoparticle therapeutic in combination with bevacizumab for the treatment of glioblastoma
Authors: Murray David W. , O'Halloran Philip , Jarzabek Monika , MacCarthy Brian , Sarkaria Jann N. , Schiffelers Raymond M. , Symons Marc , Byrne Annette T. 
Published: August 2015

Abstract
Glioblastoma (GBM), a highly invasive primary brain tumour, remains an incurable disease (1). Angiogenesis, the formation of new blood vessels, is a defining feature of GBM (2). Targeting GBM angiogenesis with Bevacizumab (Bev) is associated with improved progression free survival, but may also significantly enhance local tumour invasion (3). RhoGTPases and their activators, guanine nucleotide exchange factors (GEFs), play central roles in the invasive process (4). Herein, we sought to identify and target GEFs of importance in meditating GBM invasion with a view to improving Bev response. We report a novel strategy by which GBM tumours invade and proliferate via overexpression of the GEF beta-PIX which was shown to be increased at the invasive edge in 74% of GBM tumours assessed (n = 19) compared with tumour core (5). We have further shown that siRNA-mediated knockdown of beta-PIX in GBM patient-derived xenograft cell cultures and cell lines resulted in decreased cell invasion in 3D, cell proliferation and survival assays in vitro. Furthermore, we have uncovered a role for beta-PIX expression in endothelial cell function, as knockdown of beta-PIX inhibits HUVEC cell migration in vitro. To interrogate in vivo effects, we established an imagable orthotopic model of invasive GBM in mice, by stereotactically implanting GBM cells stably overexpressing firefly luciferase (U87R-GFP-luc2). beta-PIX-(human and mouse) specific siRNA or scrambled control siRNA (2 × 10 μg i.c.) were delivered to tumours using an alphaVbeta3 integrin targeting-(RGD peptide conjugated)-nanoparticle (InVivoPlex Aparna Bio Corp, Rockville, MD). Animals were treated with- or without- Bev (6 × 10mg/kg i.p. over 12 days). Initial data has shown that animals treated with beta-PIX siRNA nanoparticles in combination with Bev had an improved median survival of 100 days compared with Bev- alone treated mice (median: 88 days). Our data may support the future clinical use of a beta-PIX-targeting nanoparticle therapeutic, to improve Bev outcomes in GBM.
1. Kohler BA et al J Natl Cancer Inst. 2011; 103, 714-736
2. Jain RK et al Nat Rev Neurosci. 2007; 8(8):610-22
3. Norden AD et al Neurology 2008; 70: 779-787
4. Murray D et al Brit J Can 2014; 110(5):1307-15
5. Hoelzinger DB et al Neoplasia 2005; 7(1): 7-16
Citation Format: David W. Murray, Philip O'Halloran, Monika Jarzabek, Brian MacCarthy, Jann N. Sarkaria, Raymond M. Schiffelers, Marc Symons, Annette T. Byrne. Pre-clinical assessment of a novel anti-invasion nanoparticle therapeutic in combination with bevacizumab for the treatment of glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5093. doi:10.1158/1538-7445.AM2015-5093
Abstract 5101: The control of migration and invasion processes in colorectal adenocarcinoma is modulated by prion protein and its ligand STI1/HOP
Authors: Lacerda Tonielli S. , Dias Marcos Vinicius S. , Giudice Fernanda S. , Teixeira Bianca Luise , Martins Vilma Regina 
Published: August 2015

Abstract
The colorectal cancer is one of the most common types of cancer in the world. Previous results from our group and others revealed the Cellular Prion Protein (PrPC) as a possible therapeutic target in glioblastomas and ovarian tumors. Its activity depends on the interaction with the secreted form of the Stress Inducible Protein 1 (STI1), also known as HSP70/90 Heat Shock Organizing Protein (HOP). In the present work, we aimed to understand the mechanism by which PrPC-STI1/HOP complex can influence the aggressiveness of colorectal tumor cell lines. Cell migration and invasion assays were performed using recombinant STI1/HOP as a chemical attractant in boyden chambers coated with matrigel. The results showed that when stimulated with recombinant STI1/HOP, cells exhibited higher migration and invasion potentials than non-stimulated cells or those that were stimulated with STI1/HOP deletion mutant for the PrPC binding domain (STI1Δ230-245). Moreover, migration and invasion mediated by STI1/HOP were blocked by a STI1/HOP peptide (230-245), which mimics STI1/HOP binding site to PrPC, as well as by a neutralizing anti-PrPC antibody. To confirm the importance of PrPC-STI1/HOP complex in tumor progression and metastasis we generated a stable PrPC-knockdown colorectal adenocarcinoma cell line (WIDr). These cells showed a decreased invasion upon recombinant STI1/HOP stimulus, suggesting an important role of PrPC-STI1/HOP complex in the invasion process. In addition, as ERK signaling pathway has been related to invasion, we evaluated the ERK1/2 phosphorylation pattern in WIDr wild-type cells and their PrPC knockdown (KD) counterpart. Cells where PrPC was impaired showed a reduction in ERK1/2 phosphorylation when compared to those expressing the former protein. Experiments are under way to evaluate if these lower ERK1/2 levels are associated with decreased migration in PrPC-KD cells. In conclusion, our findings pointed that the disruption of PrPC-STI1/HOP complex could be a therapeutic target in colorectal adenocarcinoma.
Supported by São Paulo Research Foundation (FAPESP)
Citation Format: Tonielli S. Lacerda, Marcos Vinicius S. Dias, Fernanda S. Giudice, Bianca Luise Teixeira, Vilma Regina Martins. The control of migration and invasion processes in colorectal adenocarcinoma is modulated by prion protein and its ligand STI1/HOP. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5101. doi:10.1158/1538-7445.AM2015-5101
Abstract 5103: Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration
Authors: An Jing , Zhang Dongyun , Huang Chuanshu 
Published: August 2015

Abstract
Cell migration is a dynamic process that is central to a variety of physiological functions as well as disease pathogenesis. The modulation of cell migration by p27 (officially known as CDKN1B) has been reported, but the exact mechanism(s) whereby p27 interacts with downstream effectors that control cell migration have not been elucidated. By systematically comparing p27+/+ mouse embryonic fibroblasts (MEFs) with genetically ablated p272/2 MEFs using wound-healing, transwell and time-lapse microscopic analyses, we provide direct evidence that p27 inhibits both directional and random cell migration. Identical results were obtained with normal and cancer epithelial cells using complementary knockdown and overexpression approaches. Additional studies revealed that overexpression of manganese superoxide dismutase (MnSOD, officially known as SOD2) and reduced intracellular oxidation played a key role in increased cell migration in p27-deficient cells. Furthermore, we identified signal transducer and activator of transcription 3 (STAT3) as the transcription factor responsible for p27-regulated MnSOD expression, which was further mediated by ERK- and ATF1-dependent transactivation of the cAMP response element (CRE) within the Stat3 promoter. Collectively, our data strongly indicate that p27 plays a crucial negative role in cell migration by inhibiting MnSOD expression in a STAT3-dependent manner.
Citation Format: Jing An, Dongyun Zhang, Chuanshu Huang. Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5103. doi:10.1158/1538-7445.AM2015-5103
Abstract 5105: The imprinted tumor suppressor gene NDN inhibits cell motility in ovarian cancer by reactivating FAK and RhoA
Authors: Yang Hailing , Das Partha , Mao Weiqun , Marquez Rebecca T. , Lu Zhen , Bast Robert C. 
Published: August 2015

Abstract
Ovarian cancers exhibit a distinctive pattern of metastasis over the surface of the peritoneum. The ability of tumor cells to migrate and invade is a prerequisite for metastasis and cancer progression. Imprinted tumor suppressor genes are of particular interest in that only a single allele is expressed and function can be lost in a single event. Here we report that an imprinted tumor suppressor gene, NDN, can suppress ovarian cancer cell migration and inhibit cell motility. NDN is a maternally imprinted gene consistently expressed in normal ovarian epithelium, but dramatically downregulated in the majority of ovarian cancers. Little or no NDN expression could be detected by immunohistochemistry in 73% of 351 epithelial ovarian cancers. NDN was also downregulated in 10 ovarian cancer cell lines with total loss in 6 of 10. Re-expression of NDN in SKOv3ip cells significantly inhibited cell migration and invasion by wound healing and Boyden Chamber assays. NDN re-expression disrupted actin stress fiber formation and prevented focal adhesion kinase (FAK) and paxillin assembly at the focal adhesion site by fluorescence microscopy. NDN re-expression reduced FAKY397 autophosphorylation by 50% and reduced SrcY416 phosphorylation by 25%. NDN re-expression also blocked RhoA signaling pathway by decreasing levels of active GTP-RhoA. Our results indicate that NDN deactivates FAK-RhoA signaling pathway in ovarian cancer cells, leading to disruption in stress fiber and focal adhesion formation, and thus suppresses cancer cell motility.
Citation Format: Hailing Yang, Partha Das, Weiqun Mao, Rebecca T. Marquez, Zhen Lu, Robert C. Bast. The imprinted tumor suppressor gene NDN inhibits cell motility in ovarian cancer by reactivating FAK and RhoA. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5105. doi:10.1158/1538-7445.AM2015-5105
Abstract 511: Rictor/mTORC2 drives formation, progression and therapeutic resistance of HER2-amplified breast cancers
Authors: Morrison Meghan M. , Jones Bayley , Sanchez Violeta , Estrada Monica V. , Hicks Donna , Williams Michelle , Brantley-Sieders Dana , Cook Rebecca 
Published: August 2015

Abstract
The phosphatidyl inositol-3-kinase (PI3K)/Akt signaling pathway is aberrantly activated in nearly 60% of breast cancers, through HER2 amplification, PIK3CA mutation, PTEN inactivation, and other alterations. The mTOR complexes mTORC1 and mTORC2 operate as activators (mTORC2) or effectors (mTORC1) of Akt. We found that mRNA upregulation in the mTORC2 cofactors RICTOR and MAPKAP1 correlated with poor survival in breast cancer patients, while upregulation in the mTORC1 cofactor RPTOR did not. Genomic gains of RICTOR and MAPKAP1 occurred more frequently in breast cancers with PI3K pathway alterations than genomic RPTOR gains. Importantly, Rictor protein levels were increased in invasive over non-invasive breast tumors, while Raptor levels were not. RICTOR gene ablation in a transgenic mouse model of HER2-amplified breast cancer delayed tumorigenesis and decreased lung metastasis, Akt-S473 phosphorylation, cell growth and survival. In human HER2-amplified breast cancer cells, Rictor loss, but not Raptor loss, decreased Akt-S473 phosphorylation, reducing cell survival and motility/invasion. Interestingly, Rictor/mTORC2 loss or treatment with a dual mTORC1/2 inhibitor improved lapatinib-induced cell killing in parental and lapatinib-resistant tumor cells to a greater extent than mTORC1 inhibition. Akt re-activation rescued cell survival, but not motility/invasion, in Rictor-depleted cells. However, Rictor loss caused accumulation of the Rac inhibitor RhoGDI2, thus impairing Rac1-dependent invasion. We conclude that HER2-amplified breast cancers use Rictor/mTORC2 to drive Akt-mediated cell survival and Rac1-mediated cellular invasion. These studies support additional studies into mTORC2-specific inhibitors.
Citation Format: Meghan M. Morrison, Bayley Jones, Violeta Sanchez, Monica V. Estrada, Donna Hicks, Michelle Williams, Dana Brantley-Sieders, Rebecca Cook. Rictor/mTORC2 drives formation, progression and therapeutic resistance of HER2-amplified breast cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 511. doi:10.1158/1538-7445.AM2015-511
Abstract 5115: An orthotopic lung tumor model for image-guided microirradiation in rats
Authors: Zhang Zhang , Wodzak Michelle , Belzile Olivier , Zhou Heling , Mason Ralph , Brekken Rolf , Chopra Rajiv , Story Michael D. , Timmerman Robert , Saha Debabrata 
Published: August 2015

Abstract
Introduction:
Studies have confirmed that a new lung cancer treatment called stereotactic body radiation therapy (SBRT) can cure certain patients with early stage tumors situated peripherally in their lungs, using a non-invasive, outpatient procedure. While nearly curative for peripheral lung tumors, SBRT also may present life-threatening toxicity for patients with centrally located lung tumors. Moreover, large, hypoxic tumors are at a further risk of radiotherapy failure with SBRT. The efficacy of SBRT application can be improved through the addition of agents designed to sensitize the tumor and/or protect normal tissue. To investigate and validate the response to SBRT, alone or in combination with radiomodulating compounds, it is necessary to develop a tumor model for image-guided high-dose irradiation of rodent tumors and normal tissues in a manner that closely mimics delivery of SBRT in humans. Therefore, the purpose of this study was to develop a rat orthotopic lung tumor model with a solitary intrapulmonary nodule to study the effects of high-dose radiation.
Methods:
Adult female athymic nude rats were anesthetized, intubated and then placed on a ventilator (Inspira, Harvard Apparatus, Holliston, MA) prior to surgery. A small incision (1.0 cm) was made between ribs 5 and 6 on the right side. The right lung was captured using a forceps, clamped with a carotid clamp and H460-luc/A549-luc NSCLC cells (one million cells and matrigel in 20 μl) were then injected into the right lung. The tumor growth was monitored by in vivo bioluminescent imaging (BLI) weekly. Other imaging modalities, including microCT, CBCT, and MRI, were also performed. At the end of study, the rats were sacrificed and lungs were harvested to confirm tumor location and size.
Results:
We achieved 100% survival from this surgical orthotopic implantation procedure. We also achieved &gt;90% success in generating solitary lung tumors in the rats, whereas percutaneous orthotopic injection of tumor cells/chunks in our previous model met only 50 to 60% success in producing solitary tumors.
Conclusion:
This study presents a successful solitary lung tumor model in rodents which provides investigators a useful model to apply conformal radiation treatment, using a sophisticated treatment planning system and significantly preventing normal tissue damage.
Citation Format: Zhang Zhang, Michelle Wodzak, Olivier Belzile, Heling Zhou, Ralph Mason, Rolf Brekken, Rajiv Chopra, Michael D. Story, Robert Timmerman, Debabrata Saha. An orthotopic lung tumor model for image-guided microirradiation in rats. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5115. doi:10.1158/1538-7445.AM2015-5115