bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C34: WAVE3 is required for TGF-β-mediated EMT
Authors: Taylor Molly A. , Davuluri Gangarao , McCue Brian , Plow Edward F. , Schiemann William P. , Sossey-Alaoui Khalid 
Published: August 2014

Abstract
Breast cancer (BC) is the second leading cause of cancer death in women in the United States. Metastasis accounts for the death of ~90% of these patients, yet the mechanisms underlying this event remain poorly defined. WAVE3 belongs to the WASP/WAVE family of actin-binding proteins that mediate essential roles in regulating cell shape/morphology, actin polymerization and cytoskeleton remodeling, and cell motility and invasion. Accordingly, we have shown that WAVE3 promotes the acquisition of invasive and metastatic phenotypes by human BCs. Along these lines, we also established that members of the miR-200 family, together with miR-31 suppress WAVE3 expression, thereby limiting its prometastatic behavior. We show here that Transforming Growth Factor-beta (TGFβ;) robustly decreases miR-31 expression and induces WAVE3 expression through a Smad2 and β3-integrin dependent mechanism. Moreover, WAVE3 expression is required for BC cells to undergo epithelial-mesenchymal transition (EMT) in response to TGF-β;. Accordingly, stable depletion of WAVE3 expression in metastatic MDA-MB-231 or 4T1 BC cells prevented TGF-β; from inducing the EMT as determined by monitoring changes in the actin cytoskeleton and expression of EMT markers by real-time PCR. Along these lines, WAVE3 depletion significantly inhibited the ability of 4T1 cells to migrate and proliferate in response to TGF-β;. Moreover, WAVE3 deficiency abrogated the outgrowth of MDA-MB-231 and 4T1 cell organoids in 3D organotypic cultures. In vivo bioluminescent imaging indicated that WAVE3 knockdown also decreased tumor growth and metastasis in 4T1 tumors that possess enhanced autocrine TGF-β; signaling. Collectively, these findings indicate that WAVE3 activity is required for TGF-β;-mediated EMT and suggest that measures capable of inactivating WAVE3 may alleviate BC metastasis stimulated by TGF-β;.
Citation Format: Molly A. Taylor, Gangarao Davuluri, Brian McCue, Edward F. Plow, William P. Schiemann, Khalid Sossey-Alaoui. WAVE3 is required for TGF-β-mediated EMT. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C34.
Abstract C42: MLKs regulate the activities of the small GTPases, Rho and Rac, to drive both single cell and collective cell migration in breast cancer invasion
Authors: Rattanasinchai Chotirat , Misek Sean , Chen Jian , Gallo Kathleen A. 
Published: August 2014

Abstract
Most mortality of breast cancer patients is caused by metastasis to vital organs. One of the key steps of breast cancer metastasis is invasion through the basement membrane, which is controlled by several signaling cascades including small GTPases, Rho and Rac. Mixed lineage kinases (MLKs) are a family of MAP3Ks that activate multiple MAPK pathways, including the c-Jun N-terminal kinase (JNK) pathway. Our lab has determined that MLK3-JNK signaling is critical for migration, invasion and metastasis of triple negative breast cancer cells. Herein, the effect of a small molecule pan-MLK inhibitor on tumor cell migration in 2D wound healing and in 3D dissemination in collagen type I, the most abundant collagen in the body, was determined. Cancer cells can utilize distinct modes of migration. MDA-MB-231 and 4T1 cells were chosen as models for the study of single and collective cell migration, respectively. In addition, the effect of MLK3 on Rho-GTP and Rac-GTP levels was determined. Data from this study demonstrate that an MLK inhibitor is sufficient to block migration of multiple breast cancer cell lines in wound healing assays. Furthermore, this inhibitor dramatically reduces the dissemination of cancer cell lines that utilize single, as well as, collective cell migration. Silencing of MLK3 results in enhanced Rho activity and decreased Rac activity, as well as defective focal adhesion turnover. Inhibition of the activity of MLKs or the downstream MAPK, JNK, also increases Rho activity, which is accompanied by an increase in the number and/or size of focal adhesions and an increase in actin stress fibers. Consistent with the idea that MLK inhibition reduces migration through relieving Rho suppression, addition of a Rho/ROCK inhibitor, Y-27632, partially rescues the migratory defect of MLK inhibition by reducing peripheral focal adhesions and actin stress fibers. Taken together, these data suggest that MLK3 could play a role in controlling the balance between Rac and Rho activity required for cancer cell migration and invasion. Thus, MLK inhibitors could be therapeutically useful in the context of breast cancer metastasis.
Citation Format: Chotirat Rattanasinchai, Sean Misek, Jian Chen, Kathleen A. Gallo. MLKs regulate the activities of the small GTPases, Rho and Rac, to drive both single cell and collective cell migration in breast cancer invasion. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C42.
Abstract C47: Assessing the role of Wnt secretion in prostate cancer skeletal metastasis
Authors: Valkenburg Kenneth C. , Williams Bart O. 
Published: August 2014

Abstract
Aberrant Wnt signaling is associated with prostate cancer tumorigenesis, progression, and bone metastasis. Bone metastasis is responsible for substantial morbidity and mortality in patients with advanced prostate cancer. No curative treatment currently exists for patients with bone metastasis. Wnt signaling plays an integral role in the bone-tumor environment during prostate cancer bone metastasis, particularly osteoblastic lesion formation, but the cell type that secretes Wnt ligands in this process is unknown. This knowledge would result in improved targeting strategies for chemotherapeutics. We hypothesize that Wnt ligand secretion by prostate tumor cells is necessary to establish and/or mediate progression of prostate tumor growth and associated bone formation within the skeleton. We targeted two proteins that are essential for Wnt secretion. Porcupine (Porcn) is an acyltransferase responsible for adding fatty acids to Wnt ligands, which precedes their interaction with the chaperone protein Wntless (Wls). Both Porcn and Wls are essential for Wnt ligand secretion. Without secretion, Wnt ligands are retained inside Wnt-producing cells, and therefore cannot activate Wnt receptors in an autocrine or paracrine manner. Using shRNA, we created stable Wls knockdown C42B4 prostate cancer cell lines and confirmed knockdown via quantitative PCR. We saw that when Wls is knocked down by approximately 95%, the Wnt target gene Axin2 decreased in expression by approximately 50%. This indicates that autocrine signaling is occurring in these cells, supporting our hypothesis. We have also generated three xenograft models in immune-deficient Nod-Scid-ILR2gamma-deficient (NSG) mice and are currently assessing the ability of Wls-deficient cells to metastasize and establish tumors in bone. In addition, we will treat mice injected with prostate cancer cells with a chemical Porcn inhibitor to determine the therapeutic value of such inhibitors in treating advanced prostate cancer. Given that Porcn inhibitors are in early stage human clinical trials for other cancers, our work could provide support for using said inhibitors for treatment of patients with advanced prostate cancer.
Citation Format: Kenneth C. Valkenburg, Bart O. Williams. Assessing the role of Wnt secretion in prostate cancer skeletal metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C47.
Abstract C52: Gene silencing of c-met leads to brain metastasis inhibitory effects
Authors: Lee Se Jeong , Lee Hye Won , Song Mi Young , Lee Kee Hang , Lee Young-Eun , Joo Kyeung Min 
Published: August 2014

Abstract
An unfortunate consequence of improvements in the treatments of advanced primary cancers is the concurrent increase of metastatic brain tumors. Despite of unfavorable clinical prognosis, radiation therapy is still the only viable treatment option for brain metastases. Expression of c-Met induces cell migration and invasion in many cancers, which are indispensable steps for metastasis. Accordingly, we examined the effects of gene silencing of c-Met on brain metastasis to evaluate the possibility of c-Met as a potential target. MDA-MB-435 cells were transfected with c-Met targeting short hairpin RNAs (shRNAs). Effects of c-Met shRNAs on the expression of epithelial mesenchymal transition (EMT) related proteins, in vitro migration, and in vivo brain metastasis were examined. Expression of mesenchymal markers and in vitro migration of MDA-MB-435 cells were significantly inhibited by introduction of c-Met shRNAs. When c-Met-silenced MDA-MB-435 cells were stereotactically implanted into the brains of immune-compromised mice or injected into the right internal carotid arteries, c-Met-silenced MDA-MB-435 cells produced significantly smaller tumor masses or survival time was significantly prolonged, respectively, compared with MDA-MB-435 cells transfected with control shRNA. The data reveal the novel function of c-Met in the process of brain metastasis and its potential as a preventive and/or therapeutic target in this disease.
Citation Format: Se Jeong Lee, Hye Won Lee, Mi Young Song, Kee Hang Lee, Young-Eun Lee, Kyeung Min Joo. Gene silencing of c-met leads to brain metastasis inhibitory effects. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C52.
Abstract C87: Regulation of stemness by Hippo-YAP pathway under hypoxia in hepatocellular carcinoma
Authors: Kim Ji Su , Ahn Ei Yong , Park Young Nyun 
Published: August 2014

Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer-related death. The Hippo-YAP signaling pathway is gaining recognition as it plays an important role in both organ size control and tumorigenesis. Liver-specific ablation of WW45 in rodent models (one of the tumor suppressive Hippo pathway components in mammals) has been reported to increase liver size and expand hepatic stem/progenitor cells (oval cells) and to develop HCC eventually. The expression of YAP also has been reported as an independent poor prognostic marker for human HCCs. Amphiregulin is a downstream target of YAP and is a member of the EGF family, which is implicated in cancer stem cells in HCC. Cancer stem cells have the ability to self-renew, differentiate, and proliferate, and have greater tumorigenicity, chemoresistance, and resistance to hypoxia. HCCs expressing stem cell makers have actually been reported to be associated with poor prognosis and aggressive biological behavior. The aim of this study is to investigate the Hippo-YAP pathway and its related oncogenic signaling in HCCs expressing stem cell markers. The effect of amphiregulin on the regulation of the Hippo-YAP pathway was also studied to identify potential molecular therapeutic targets for HCCs expressing stem cell markers. Under hypoxic condition, the expression of cancer stem cell markers (EpCAM, CD133, and CK19) was upregulated in a time dependent manner and the Hippo-YAP pathway was oncogenically activated in four HCC cell lines (HepG2, Hep3B, Huh7, and SK-Hep1). In addition, the treatment of recombinant human amphiregulin dephosphorylated and activated YAP pathway. Therefore, up-regulation of cancer stem cell markers with activation of oncogenic YAP pathway in HCC cell lines might suggest the acquisition of survival advantage of tumor cells under hypoxia. The relationship between the regulatory mechanism of cancer stem cells and the Hippo-YAP pathway can be used for molecular target of chemotherapy for HCC.
Citation Format: Ji Su Kim, Ei Yong Ahn, Young Nyun Park. Regulation of stemness by Hippo-YAP pathway under hypoxia in hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C87.
Abstract IA14: Inhibition of Ron kinase blocks conversion of micrometastases to overt metastases by boosting antitumor immunity
Authors: Welm Alana 
Published: August 2014

Abstract
Many “non-metastatic” cancers have spawned clinically undetectable metastatic colonies even prior to diagnosis. Eventual outgrowth of these microscopic lesions is the cause of metastatic relapse and death from cancer, yet the events that dictate when and how disseminated cancer cells convert to overt metastasis are largely unknown. We utilized mouse genetics and tissue complementation strategies in a murine model of spontaneous metastasis to interrogate the role of macrophage stimulating protein (MSP) and its receptor, Ron, in metastasis. Our data reveal the MSP/Ron pathway as a key mediator in conversion of micrometastases to bona fide metastatic lesions through immune suppression. Genetic deletion of Ron tyrosine kinase activity specifically in the host profoundly blocked metastasis. Our data show that loss of Ron function promotes an effective anti-tumor CD8+ T cell response, which specifically inhibits outgrowth of seeded metastatic colonies. Treatment of mice with a Ron-selective kinase inhibitor prevented outgrowth of lung metastasis, even when administered after micrometastatic colonies had already been established. Our findings indicate that Ron inhibitors may hold potential to specifically prevent outgrowth of micrometastases in cancer patients in the adjuvant setting.
Citation Format: Alana Welm. Inhibition of Ron kinase blocks conversion of micrometastases to overt metastases by boosting antitumor immunity. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr IA14.
Abstract IA15: HIFs, hypoxia, and tumor progression
Authors: Simon M. Celeste 
Published: August 2014

Abstract
Intratumoral hypoxia and expression of Hypoxia Inducible Factor 1α (HIF1α) correlate with metastasis and poor survival in sarcoma patients. We demonstrate here that hypoxia controls sarcoma cell metastasis through a novel mechanism in which HIF1α induces the expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). PLOD2 hydroxylates procollagen, consequently altering the structure of extracellular collagen fibers along which transformed cells migrate in primary tumors. We show that loss of HIF1α or PLOD2 expression disrupts collagen deposition, cell migration and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSL-KrasG12D/+; Trp53fl/fl murine sarcoma models. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF1α-deficient cells and tumors, and microarray analyses of human sarcomas reveal elevated HIF1α and PLOD2 expression in metastatic primary lesions. Collectively, these data indicate that whereas HIF1α activity modifies pre-metastatic niches in carcinomas, it controls sarcoma metastasis through PLOD2-dependent collagen deposition in primary tumors. Therefore, we conclude that PLOD2 is a novel therapeutic target in sarcomas and successful inhibition of this enzyme may reduce tumor cell dissemination.
Citation Format: M. Celeste Simon. HIFs, hypoxia, and tumor progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr IA15.
Abstract IA19: Understanding the dynamics of cancer: From developmental pathways to in vivo imaging
Authors: Reya Tannishtha 
Published: August 2014

Abstract
Our research focuses on the signals that control hematopoietic stem cell self-renewal and differentiation, how these signals are utilized during regeneration and how their dysregulation may lead to cancer. Using a multitude of genetic models, we have shown that classic developmental signaling pathways such as Wnt, Hedgehog and Notch play key roles in stem cell growth and regeneration and are dysregulated during leukemia development. In addition, we have used real-time imaging strategies to show that hematopoietic stem cells have the capacity to undergo both symmetric and asymmetric division, and that shifts in the balance between these modes of division are controlled by the microenvironment and subverted by oncogenes. Importantly, we have shown that regulators of this process, including the cell fate determinant Musashi, can promote aggressive cancers and could serve as critical targets for diagnostics and therapy. Most recently, we have developed a high resolution in vivo imaging system that has allowed us to begin to map the behavior and interactions of hematopoietic stem cells with the microenvironment within living animals, and to define how these change during regeneration and cancer formation.
Citation Format: Tannishtha Reya. Understanding the dynamics of cancer: From developmental pathways to in vivo imaging. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr IA19.
Deficiency of MAPK-activated protein kinase 2 (MK2) prevents adverse remodelling and promotes endothelial healing after arterial injury
Authors: Kapopara Piyushkumar , Felden Johann von , Soehnlein Oliver , Wang Yong , Napp L. Christian , Sonnenschein Kristina , Wollert Kai , Schieffer Bernhard , Gaestel Matthias , Bauersachs Johann , Bavendiek Udo 
Published: August 2014

SummaryMaladaptive remodelling of the arterial wall after mechanical injury (e. g. angioplasty) is characterised by inflammation, neointima formation and media hypertrophy, resulting in narrowing of the affected artery. Moreover, mechanical injury of the arterial wall causes loss of the vessel protecting endothelial cell monolayer. Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), a major downstream target of p38 MAPK, regulates inflammation, cell migration and proliferation, essential processes for vascular remodelling and reendothelialisation. Therefore, we investigated the role of MK2 in remodelling and reendothelialisation after arterial injury in genetically modified mice in vivo. Hypercholesterolaemic low-densitylipoprotein- receptor-deficient mice (ldlr-/- ) were subjected to wire injury of the common carotid artery. MK2-deficiency (ldlr-/-/mk2-/- ) nearly completely prevented neointima formation, media hypertrophy, and lumen loss after injury. This was accompanied by reduced proliferation and migration of MK2-deficient smooth muscle cells. In addition, MK2-deficiency severely reduced monocyte adhesion to the arterial wall (day 3 after injury, intravital microscopy), which may be attributed to reduced expression of the chemokine ligands CCL2 and CCL5. In line, MK2-deficiency significantly reduced the content of monocytes, neutrophiles and lymphocytes of the arterial wall (day 7 after injury, flow cytometry). In conclusion, in a model of endothelial injury (electric injury), MK2-deficiency strongly increased proliferation of endothelial cells and improved reendothelialisation of the arterial wall after injury. Deficiency of MK2 prevents adverse remodelling and promotes endothelial healing of the arterial wall after injury, suggesting that MK2-inhibition is a very attractive intervention to prevent restenosis after percutaneous therapeutic angioplasty.
Prostaglandin E2 levels and platelet function are different in cord blood compared to adults
Authors: Haidl Harald , Leschnik Bettina , Leis Hans-Joerg , Heinemann Akos , Muntean Wolfgang , Schlagenhauf Axel 
Published: August 2014

SummaryNeonatal platelets support primary haemostasis and thrombin generation as well as adult platelets, despite observable hypoaggregability in vitro. High prostaglandin E2 levels at accouchement could account for inhibited platelet function via the EP4 receptor. We set out to determine prostaglandin E2 plasma levels in cord blood of healthy neonates and evaluate the impact of prostaglandin E2 on platelet function in adult and cord blood samples. Prostaglandin E2 plasma levels were measured in cord blood and venous adult blood using GC-MS. Impact of prostaglandin E2 on platelet aggregation was measured by spiking cord blood and adult samples. Contributions of EP3 and EP4 receptors were evaluated using respective antagonists. Intracellular cAMP concentrations were measured using a commercial ELISA-kit. Prosta-glandin E2 plasma levels were substantially higher in cord blood than in adult samples. Spiking with prostaglandin E2 resulted in a slight but consistent reduction of platelet aggregation in adult blood, but response to PGE2 was blunted in cord blood samples. Aggregation response of spiked adult samples was still higher than with non-spiked cord blood samples. Blockage of EP4 receptors resulted in improved platelet aggregation in adult platelets upon prostaglandin E2 spiking, while aggregation in cord blood samples remained unaltered. Intracellular cAMP concentrations after preincubation with prostaglandin E2 were only increased in adult samples. In conclusion, very high prosta -glandin E2 concentrations in cord blood affect platelet function. This effect may partially explain neonatal platelet hypoaggregability. Peak levels of prostaglandin E2 can potentially protect against birth stressinduced platelet activation.
Failure of dabigatran and rivaroxaban to prevent thromboembolism in antiphospholipid syndrome: a case series of three patients
Authors: Schaefer Jordan , McBane Robert , Black David , Williams Lindsy , Moder Kevin , Wysokinski Waldemar 
Published: August 2014

SummaryDirect oral factor inhibitors (DOFIs) are an attractive alternative to vitamin K antagonists (VKA) for the treatment of patients with antiphospholipid syndrome (APS). In the absence of prospective, randomised trial data, reports of therapeutic failures in clinical practice alert clinicians to potential limitations of DOFI therapy for this indication. Data for all cases were collected from a centralised system that contains complete medical records of all patients treated and followed at Mayo Medical Center. We present here three consecutive APS patients who had had no thromboembolism recurrence on warfarin but were switched to DOFIs. The diagnosis of APS was established according to currently recommended criteria. The three cases were as follows: A woman with primary APS developed thrombotic endocarditis with symptomatic cerebral emboli after transition to dabigatran. A second woman with primary APS experienced ischemic arterial strokes and right transverse-sigmoid sinus thrombosis after conversion to rivaroxaban. A man with secondary APS suffered porto-mesenteric venous thrombosis after switching to rivaroxaban. None of these patients had failed warfarin prior to the transition to DOFIs. Based on these three cases, we advocate caution in using DOFIs for APS patients outside of a clinical trial setting, until further data becomes available.